Fight Aging!

Various forms of glial cell exist in the brain, supporting and protecting neurons. Over the years, researchers have discovered that glial cells are deeply involved in many of the important functions of neurons, such as the establishment and maintenance of synaptic connections. Some forms of glial cell, such as microglia, are a part of the innate immune system. They differ in many aspects from similar types of immune cell elsewhere in the body, macrophages, but have much the same set of responsibilities: clean up debris; consume pathogens; destroy errant cells; assist in regeneration from injury. In the aging brain, immune dysfunction sets in similarly to the rest of the body. Immune cells become overly activated, inflammatory signaling grows, but at the same time the immune system becomes less capable of carrying out its core tasks.

Of late, the research community has devoted increasing attention to the balance of states in microglia and macrophage populations. These cells have a number of overlapping states, or polarizations, a way of characterizing their behavior. The M1 state is less helpful in regeneration, and more inflammatory and aggressive in pursuit of pathogens. The M2 state, on the other hand, suppresses inflammation and helps to generate a supportive environment for regeneration. A wide range of age-related conditions are characterized by the presence of too many M2 and too few M1 microglia or macrophages, likely one of the many complex detrimental reactions to accumulations of underlying cell and tissue damage. Adjusting this balance many prove to be helpful, even in the absence of efforts to address low-level damage, but reliable methods of achieving that goal have yet to emerge.

In this open access paper, the authors review the present state of research into glial cells and aging in flies, and the relevance of these studies to the understanding of mammalian aging. They focus on parts of the bigger picture in which enough is known to pick out relationships, but not yet enough to understand how the same mechanism can apparently contribute to both neurodegeneration and defense against neurodegeneration. Cell metabolism is complex, the immune system is complex, and the brain is particularly complex. These are good reasons not to try too hard to intervene downstream from the comparatively simple root causes of aging; if less complicated opportunities arise, then by all means, but in most cases trying to manipulate the damaged state of metabolism is an expensive path to poor results.

Role of Glial Immunity in Lifespan Determination: A Drosophila Perspective

The chronic inflammatory status that accompanies human aging, also known as inflammaging, is considered a significant risk factor for many chronic pathologies including cancer, cardiovascular and neurodegenerative disorders. In the context of aging, increased levels of pro-inflammatory cytokines such as TNF-alpha and Interleukine (IL)-6 are found upregulated in brain tissue. With age, mammalian microglia, which are the brain immune cells exhibit primed profile characterized by increased activation and enhanced secretion of pro-inflammatory cytokines. Decline in microglial function, migration, and chemotaxis are also observed with age. For instance, microglia's engulfment capacity of amyloid-beta (Aβ) or alpha-synuclein (α-Syn) oligomers, whose accumulation is characteristic for Alzheimer's and Parkinson's disease, respectively, are compromised in aged animals. Moreover, activated microglia and neuroinflammatory profiles are observed in most neurodegenerative disorders.

Drosophila, the common fruit fly, is an excellent versatile model organism to investigate the interplay between innate immune function and brain physiology among the effects of this interaction to host lifespan. There is a high degree of evolutionary conservation of the molecular mechanisms of innate immunity between flies and mammals. Similar to mammalian models, both chronic innate immune activation as well as decline in phagocytic activity of glia are observed in the aging Drosophila brain. It is thus apparent that glial immunity is linked to both, healthy aging and age-dependent neurodegeneration.

In the mammalian brain, under normal physiological conditions, microglia provide the first line of defense against brain injury and infection. These cells are able to sense pathogens via pathogen recognition receptors, activate innate immune signaling pathways, phagocytose microorganisms, and clear cellular debris. Microglia also have the capacity to secrete neurotrophic factors and anti-inflammatory molecules, therefore, playing a protective role in these contexts. On the other hand, the neurodegenerative process itself can trigger inflammation, leading to detrimental effects on the brain. It is, therefore, important to understand the mechanisms by which, changes in the same signaling pathway (e.g., NF-kB) lead to two distinct phenotypes, namely healthy aging associated with neuroprotection and neurodegeneration.

It is becoming increasingly evident that glial cells play an important role in neuroprotection and in organismal physiology throughout lifespan. In the recent years, studies in the model organism Drosophila have revealed numerous aspects of glial contribution toward both, healthy aging, and the development and progression of age-related pathologies of the nervous system. Dysregulation of glial innate immune reactions such as improper NF-κB signaling or impaired Draper-based phagocytosis results in early onset neurodegeneration and lifespan shortening. Thus, both branches of the innate immune response seem to contribute in host neuroprotection and longevity. Additional work is needed to investigate whether these two pieces of the innate immune response possess synergistic properties and identify possible cellular factors that regulate both the inflammatory and phagocytic pathways in glial cells.

I'm of the opinion that there simply isn't enough data on extremely old humans to do more than roll the dice on the outcome produced by any one statistical analysis, though the results noted here are based on a large enough study population to perhaps demand more attention than past efforts. The researchers have avoided the very sparse data for supercentenarians (110 and older) by focusing on people aged 105 to 110. They conclude that mortality rates stay much the same across that span, at more or less a 50% yearly attrition. This disagrees with one of the more recent attempts to run the numbers for supercentenarian mortality rates.

Aging is defined as the increase of intrinsic mortality rate over time, and a lack of increase is therefore classed as functional immortality by some researchers. Not the useful, desirable sort of immortality, of course. This phenomenon has good supporting data in flies, a species that readily exhibits a late life mortality rate plateau. Whether this happens in mammals, and particularly in humans, is much debated. There are arguments on both sides. It is interesting to ponder whether this functional immortality represents only a temporary buffer in the state of a few critical systems, or would instead continue for much longer, were there enough data to follow mortality that far into physiological loss of function.

The answers may never be known. It is unlikely that many times more physiologically extremely old people than exist today will ever exist. Rejuvenation therapies will emerge over the decades ahead as a counterpoint to demographic aging. The natural state of aged humanity, the fate of everyone absent the ability to repair the root causes of aging, will come to an end. Whether the few survivors at the end of a natural lifetime are strangely immortal will be a question for future computational scientists and their advanced models, not future demographers. Given the lack of interest in modeling exact outcomes of extinct disease states today, I'm not convinced that future scientific and funding communities will care enough to investigate.

Researchers tracked the death trajectories of nearly 4,000 residents of Italy who were aged 105 and older between 2009 and 2015. They found that the chances of survival for these longevity warriors plateaued once they made it past 105. The findings challenge previous research that claims the human lifespan has a final cut-off point. To date, the oldest human on record, Jeanne Calment, died in 1997 at age 122. "Our data tell us that there is no fixed limit to the human lifespan yet in sight. Not only do we see mortality rates that stop getting worse with age, we see them getting slightly better over time."

Specifically, the results show that people between the ages of 105 and 109, known as semi-supercentenarians, had a 50/50 chance of dying within the year and an expected further life span of 1.5 years. That life expectancy rate was projected to be the same for 110-year-olds, or supercentenarians, hence the plateau. The trajectory for nonagenarians is less forgiving. For example, the study found that Italian women born in 1904 who reached age 90 had a 15 percent chance of dying within the next year, and six years, on average, to live. If they made it to 95, their odds of dying within a year increased to 24 percent and their life expectancy from that point on dropped to 3.7 years.

The researchers used data from the Italian National Institute of Statistics. They credit the institute for reliably tracking extreme ages due to a national validation system that measures age at time of death to the nearest day: "These are the best data for extreme-age longevity yet assembled." As humans live into their 80s and 90s, mortality rates surge due to frailty and a higher risk of such ailments as heart disease, dementia, stroke, cancer, and pneumonia. Evolutionary demographers theorize that those who survive do so because of demographic selection and/or natural selection. Frail people tend to die earlier while robust people, or those who are genetically blessed, can live to extreme ages.

Link: http://news.berkeley.edu/2018/06/28/supercentenarians/

Researchers here report on the identification of a mechanism in mice that amplifies the harms done by an excess of oxidative molecules. Aging is accompanied by a general increase in oxidative stress in cells, and suppressing this amplication mechanism is shown to improve measures of health and slow the progression of aspects of aging. This is similar in spirit to a number of other lines of research that seek to attenuate oxidative stress in old tissue, such as the use of mitochondrially targeted antioxidants, but tackling the challenge at a completely different point of action. Arguably none of this addresses root causes: rising levels of oxidative stress are a consequence of lower level forms of damage and change in aging. So we should expect the scope of benefits to be limited; the results of mitochondrially targeted antioxidants in flies and mice over the past decade might set the expected ballpark.

Aging is characterized by a number of physiological changes including loss of cell division, oxidative stress, DNA damage, nuclear changes, and increased expression of senescence-associated genes. It has been known for some time that oxidant stress plays a central role in the aging process, and is causally involved in the injury to cellular proteins and DNA. When reactive oxygen species (ROS) accumulation exceeds the detoxifying ability of the cell, the resulting oxidative stress induces damage, senescence, and apoptosis.

We recently reported that the Na/K-ATPase - Src - EGFR signaling pathway serves as a feed-forward amplification loop for oxidants (Na/K-ATPase oxidant amplification loop, NKAL), a signaling cascade resulting in additional ROS generation. We further showed that this NKAL is involved in various disease models ranging from uremic cardiomyopathy to obesity. Our group developed a peptide, pNaKtide, from the N domain of the Na/K-ATPase α1 subunit. This peptide binds Src kinase; ultimately inhibiting the Na/K-ATPase feed forward amplification of ROS. Based on these earlier observations, we hypothesized that the NKAL might play a role in the aging process and antagonism of this pathway by pNaKtide might attenuate the aging process.

We previously showed that a western diet (WD) induced Na/K-ATPase signaling and increased oxidative stress in mice. We used this dietary approach to investigate the effects of age and oxidative stress in adipose tissue, and heart, which are both affected by the aging processes. In both of these organ systems, old mice and old mice fed a WD had evidence for oxidant injury, which was related to the stimulation or inhibition of the NKAL with the WD or pNaKtide, respectively. In our experiments, old mice had increased fat deposition along with large adipocytes and increased TNFα levels; these changes were accentuated in the old mice fed a WD. Aging of heart tissues is associated with impaired function detectable with echocardiography and fibrosis measurable with histology. These changes were exacerbated by the WD and attenuated by pNaKtide treatment as well. Again, these changes in adipose tissues were negated with pNaKtide treatment.

Link: https://doi.org/10.1038/s41598-018-26768-9

Every cell contains a herd of bacteria-like mitochondria. These are the power plants of the cells, responsible for packaging chemical energy store molecules. They replicate by division, but also fuse together and exchange component parts. For reasons that are far from fully understood, the mitochondria in old tissues are much changed and degraded in comparison to their counterparts in youthful tissue. Their shapes are different, the balance of fusion and fission altered, they generate too little in the way of energy store molecules and too much in the way of oxidative molecules. Some of this is a matter of damage to mitochondrial DNA, which produces its own additional serious set of downstream issues, but much of it seems more akin to a reaction to damage and altered signaling in cells and the surrounding tissue, rather than any inherent malfunction in the mitochondria themselves.

To the degree that this global mitochondrial malaise is a consequence of the accumulated damage and resultant changing character of signaling in aging, then it should end if the root causes of aging are addressed. When the chronic inflammation, altered cell signaling, and issues elsewhere in cell structures are reversed, then we should expect mitochondrial function to improve in turn. This strategy of identifying and fixing root causes is still a minority approach in research and development, however. Most work on mitochondrial aging is focused instead on finding ways to override some of the signals that produce mitochondrial loss of function, to eke out greater capacity for a longer period of time. The history of such approaches doesn't provide much confidence in the ability of the research community to produce large gains via such an approach, however. The best plausible near future therapies are forms of exercise mimetic, perhaps, and those people who exercise a great deal don't live more than a small number of years longer than the rest of us.

Mitochondria and aging: A role for the mitochondrial transition pore?

Mitochondria are central organelles in the cell. They are present in all cells of humans and animals (except red blood cells). They generate cellular energy, produce reactive oxygen species (ROS) that regulate physiological processes, and are involved in the control of cell death. Therefore, it is not surprising that mitochondria could be involved in the normal mammalian aging process. One of the unique characteristics of mitochondria is that they possess their own genetic material in the form of a close circular DNA molecule. According to this latter theory, aging of cells would be due to the constant delivery of ROS inside mitochondria throughout life, damaging mitochondrial DNA which is vulnerable as it is not protected by protein histones or repairing enzymes such as nuclear DNA. The damaged mitochondrial DNA leads to deficiency of key electron transport enzymes and subsequent ROS generation, thus causing a vicious cycle of ROS resulting in a decrease in energy production.

Although a large amount of data support the role of mitochondrial ROS production in aging, other features of mitochondrial physiology and dysfunction, including the mitochondrial permeability transition, have been more recently implicated in the mechanisms of aging. The mitochondrial permeability transition corresponds to the sudden increase in the permeability of the inner mitochondrial membrane to molecules of molecular mass up to 1,500 Da. The opening is due to a nonspecific pore called the mitochondrial permeability transition pore (mPTP) occurring when mitochondria become overloaded with calcium. The sensitivity of the mPTP to calcium is enhanced under oxidative stress conditions, adenine nucleotide depletion, high phosphate concentrations, or membrane depolarization. mPTP opening induces swelling of the organelle matrix, collapse of membrane potential, and uncoupling of oxidative phosphorylation. This phenomenon plays a critical role in different types of cell death. Although the conditions leading to permeability transition are well known, the exact composition of the pore remains unknown.

Currently, a common agreement considers that cyclophilin D (CypD), a soluble protein located within the mitochondrial matrix, is the main partner of the mPTP and that mPTP formation is greatly sensitized by CypD which lowers the calcium threshold required to trigger mPTP opening. The crucial role of CypD has been shown by deletion of the gene in mice, allowing mitochondria to sustain high calcium concentrations and thus conferring major desensitization of mPTP. Two opening states of the pore have been distinguished, a permanent or long-lasting state which is associated with cell death, and a transient opening state having a physiological role by providing a pathway to release ROS and calcium from mitochondria which is also regulated by CypD. The mPTP is now considered to be central in numerous conditions such as heart, brain, or liver ischemia-reperfusion, drug-induced liver injury, age-related neurodegenerative diseases, and accumulating data imply the mPTP in organ dysfunction occurring during aging. Conversely, caloric restriction, which is a proven strategy to delay aging and age-related disease, is associated with the inhibition of mPTP opening.

Recently, a large number of studies demonstrated that the mPTP, which is not definitely characterized at the molecular level, is more sensitive to opening in aged animals and in aging-associated diseases and that its inhibition can enhance lifespan. This appears logical as the cellular modifications occurring during aging, that is, impaired calcium homeostasis, increased oxidative stress, oxidative modifications of proteins, enhancement of CypD level, and apoptosis, are factors contributing to and modulated by mPTP opening. However, doubts persist about the involvement of mPTP in the progression of aging and definitive experimental proofs of mPTP involvement have to be provided to demonstrate whether it is a cause or a consequence of aging. A better knowledge of the structural composition and of the regulation of the pore will probably help to elucidate the role of mPTP in longevity and healthspan.

The honor of running the first trial of a senolytic drug, albeit inadvertently, goes to one of the groups testing dasatinib or navitoclax back when those pharmaceuticals were first evaluated for cancer therapies. At that time nobody knew that these drugs could selectively destroy senescent cells, and were thereby far more valuable as a starting point for rejuvenation therapies than as cancer treatments. The first intentional human trial was started last year by Betterhumans, a non-profit organization. Now Unity Biotechnology has recently announced that their first human trial is underway, testing the ability of their initial candidate senolytic to treat osteoarthritis. You may recall that the evidence in animal models for the accumulation of senescent cells to be a primary cause of osteoarthritis is fairly compelling. We can hope that this holds up in humans; results will likely start to appear in a preliminary form next year.

UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to extend healthspan by slowing, halting, or reversing diseases of aging, today announced the treatment of the first patient in the Phase 1 clinical trial evaluating UBX0101 in moderate to severe osteoarthritis of the knee. "For many people, we believe that osteoarthritis is the main reason why it hurts to get old. By designing a treatment to selectively eliminate senescent cells in the joints of patients diagnosed with painful osteoarthritis, our goal is to alter the otherwise disabling course of this disease. This is an important milestone for UNITY. This is the first time we have treated a patient with a drug to eliminate senescent cells. While this study is designed to establish safety, we are also looking for the earliest signals of reducing senescent cell burden in this disease of aging."

The Phase 1 clinical trial of UBX0101 is a randomized, double-blind, placebo-controlled, single ascending dose study that will evaluate safety, tolerability, and pharmacokinetics of a single intra-articular injection of UBX0101 in patients diagnosed with moderate to severe osteoarthritis of the knee. Patients will be randomly assigned to receive UBX0101 or placebo in 3:1 randomization by dose level cohort.

Cellular senescence is a natural biological state in which a cell permanently halts division. Senescent cells accumulate with age and secrete as many as 100 different biologically active proteins, including pro-inflammatory factors, proteases, pro-fibrotic factors, and growth factors that disturb the tissue microenvironment. This collection of secreted proteins is referred to as the Senescence Associated Secretory Phenotype, or SASP. In addition to its effects on tissue function, the SASP contains factors that induce senescence in neighboring cells, setting off a cascade of events that culminates in the formation of the functionally aged and/or diseased tissue that appears to underlie a variety of age-associated diseases. UNITY believes that the elimination of senescent cells will remove SASP factors - addressing a root cause of diseases of aging. Senolytic medicines, or treatments designed to selectively remove senescent cells, target the SASP at its source, and may have a more durable impact on disease than current therapies.

Link: http://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-inc-announces-first-patient-treated-ubx0101

I think it a little much to be calling the artificial cell structures reported here T cells; the similarities are few. They are pseudo-cell-like membranes that can be decorated with surface features capable of interacting with other cell populations. The goal touted here is to influence the immune system, but in principle any sort of cell to cell communication that relies on surface decoration could be targeted in this way. Being able to build membranes that can pass for cells in the body, and thus avoid the attention of the immune system, seems more useful for the ability to hide molecular machinery inside them, however. Plasmids that can generate specific proteins, for example - a great deal might be accomplished with the ability to introduce durable protein factories into a specific tissue.

Researchers have developed synthetic T lymphocytes, or T cells, that are facsimiles of human T cells. Such cells could eventually be used to boost the immune system of people with cancer or immune deficiencies. Natural T cells are difficult to use in research because they're very delicate, and because after they're extracted from humans and other animals, they tend to survive for only a few days. "We were able to create a novel class of artificial T cells that are capable of boosting a host's immune system by actively interacting with immune cells through direct contact, activation, or releasing inflammatory or regulatory signals. We see this study's findings as another tool to attack cancer cells and other carcinogens."

The team fabricated T cells using a microfluidic system. They combined two different solutions - mineral oil and an alginate biopolymer, a gum-like substance made from polysaccharides and water. When the two fluids combine, they create microparticles of alginate, which replicate the form and structure of natural T cells. The scientists then collected the microparticles from a calcium ion bath, and adjusted their elasticity by changing the concentration of calcium ions in the bath.

Once they had created T cells with the proper physical properties, the researchers needed to adjust the cells' biological attributes - to give them the same traits that enable natural T cells to be activated to fight infection, penetrate human tissue, and release cellular messengers to regulate inflammation. To do that, they coated the T cells with phospholipids, so that their exterior would closely mimic human cellular membranes. Then, using a chemical process called bioconjugation, the scientists linked the T cells with CD4 signalers, the particles that activate natural T cells to attack infection or cancer cells.

Link: https://www.eurekalert.org/pub_releases/2018-06/uoc--rds062618.php

Those of us who do not work at the California Life Company, Calico, have very little idea as to what it is the staff there are up to, at least when it comes to the details. The organization is very heavily funded by the overspill of resources from Alphabet, employs a great many scientists, and - so far as the world peering in from the outside can determine - is engaged in fundamental aging research with the goal of producing pharmaceutical treatments to intervene in the aging process at the end of the day. The little research they have made public is very distant from SENS and the idea of repairing damage, and looks more likely to lead to the same old story of manipulating the operation of metabolism in order to modestly slow the progression of aging.

But it is very hard to say. Calico could be undertaking an energetic senolytics program, or otherwise be working on something quite interesting to the SENS rejuvenation research community. We have no idea. The dominant character of the organization is secrecy: those working there and those in charge say nothing about what they are doing. It makes it hard to criticize the principals on anything other than that count, which might be the intent. That said, I think most of us have by now written off Calico as the second coming of the Ellison Medical Foundation, which is to say a sizable investment in extending the day to day work of the National Institute on Aging, carrying out projects focused on the details of the progression of aging that, while advancing the state of knowledge, are unlikely to produce meaningful therapies at the end of the day.

Even that knowledge, covering the molecular biology of the progression of aging in humans without access to rejuvenation therapies, will be obsolete a few decades from now. It will not actually have helped all that much to bring about the era of rejuvenation therapies. Those therapies will emerge from the SENS-focused and other similarly oriented research communities, those building ways to repair the well-described molecular damage that distinguishes old tissues from young tissues. Creating proficient means of damage repair does not require any great knowledge of how exactly that damage progresses to disease and death: just fix it and observe the outcomes. Further, damage repair will always outperform efforts to tinker with the damaged state without repairing it - and it doesn't much matter whether we are talking about an electronic device, an automobile, or a mammal. The principle is the same. Calico seems like a missed opportunity at this point, some years down the line from its creation.

A monster discovery deal between AbbVie and Google's Calico gets a new lease on the lab, with $1B more to back aging research

Nearly 4 years after AbbVie and Google's fledgling Calico stepped up to the altar of drug science and committed themselves to a $1.5 billion partnership on developing a pipeline of anti-aging drugs, they've decided to renew their vows. And this time they're backing it up with a joint $1 billion pledge - $500 million each - to keep the alliance going for some years to come, with an eye to slowly stepping up the relationship in a move toward the clinic. In a rare public display of affection, the two companies are touting the advance of more than two dozen late discovery projects, with a special focus on cellular stress that they believe has some profound long term implications for human health. Another piece of info: The famously quiet Calico has built a big team of 150-plus around an HQ base in South San Francisco, with plans to add more.

But that's about it. If they are working on a revolution in drug development aimed at putting more life into lengthy spans of living, don't expect any claims along the way about curing cancer, or diabetes, or arthritis in mice. Press execs on what they've been working on, though, and you get pointed to a long lineup of papers Calico has published on their work, but no specifics on the most promising targets in their chosen field. How about the budget? Did they spend the $1.5 billion? Nothing. "We're not going to be specific about molecular targets. It hasn't been in our nature to hype about what we have. What I can tell you is that we are very pleased with the progress of the collaboration. We have a number of potential viable clinical programs. Our interest in aging goes to the basic roots of aging."

One of the most studied areas of metabolism and its interaction with aging involves the activities of, and relationships between, IGF-1, insulin, growth hormone, and their cell surface receptors, all of which are among the mechanisms strongly influenced by calorie restriction. Genetic engineering to disable growth hormone or its receptor produces dwarf mice that live 60% longer, and IGF-1 can be similarly manipulated to produce a less exceptional life extension. It is worth noting that the equivalent growth hormone loss of function mutants in our species do not live 60% longer, though they may be modestly more resistant to age-related disease. Short-lived species have evolved a far greater plasticity of life span in response to calorie restriction or interventions that directly manipulate the related cellular mechanisms. Development of therapies based upon these findings seem unlikely to produce sufficiently sizable effects on human health to justify the investment, given the range of better alternatives on the table.

Diminished growth hormone (GH) and insulin/insulin-like growth factor-1 (IGF-1) signaling extends lifespan in many laboratory models. Likewise, several dwarf models, including Ames, Snell and growth hormone receptor knockout (GHRKO) mice, are exceptionally long lived. A specific role for IGF-1 receptor (IGF-1R) signaling in the mediation of mammalian longevity was first established in IGF-1R haploinsufficient mice, which lived 33% longer than controls, but unlike other models of reduced somatotropic signaling, this effect was female specific. This unique sex difference was subsequently confirmed in two follow-up studies, though with more modest reported improvements in female lifespan, while a life shortening effect was observed in males. The underlying mechanisms linking reduced IGF-1 signaling to improved mammalian lifespan is thought to involve improved stress defenses and lower risk for proliferative diseases, though the reason for sex differences in this response remains unresolved.

Several examples have also now emerged suggesting the GH/IGF-1 signaling pathway is relevant to human aging, including the discovery of functional mutations in the IGF-1R gene in individuals with exceptional longevity, resulting in relative IGF-1 resistance, and in subjects lacking functional GH receptors (Laron dwarfs). Remarkably, low IGF-1 levels also predict better survival in nonagenarians, and similar to lessons learned in IGF-1R heterozygous mice, this effect is female specific. Thus, given the accumulating evidence across species implicating this pathway as integral to aging and its associated diseases, the development of therapeutics aimed at modulating IGF-1 signaling in humans could prove highly effective as a translational tool to delay aging. However, given that previous demonstrations of longevity resulting from disruption of this pathway occurred either at conception or in young adulthood, whether benefits can be achieved by targeting this pathway later in life is unclear.

Anti-IGF-1 receptor (IGF-1R) monoclonal antibodies (mAbs) were developed for clinical use in treating advanced stage cancers. We postulated that IGF-1R mAbs could represent a viable therapeutic tool to target IGF-1 action, and potentially mimic the beneficial effects associated with diminished IGF-1 signaling observed in animal models. In order to test this possibility, we engineered a murinized version of the anti-IGF-1R mAb, L2-C (L2-Cmu), in order to reduce effector function and enable chronic administration in mice. L2-Cmu proved feasible and well tolerated in older animals, and consistent with genetic models of IGF-1R heterozygosity, improves female healthspan and increases median lifespan by 9%. Importantly, these effects were achieved even though treatment was not initiated until 18 months of age. Thus, these data suggest that late-life targeting of IGF-1R signaling can recapitulate effects observed in genetic models of constitutive IGF-1R haploinsufficiency on lifespan. As IGF-1R mAbs are readily available for human use, these observations warrant further study into potentially harnessing these drugs to target at least some manifestations of aging.

Link: https://doi.org/10.1038/s41467-018-04805-5

Naked mole rats live nine times longer than other, similarly sized rodents. They are also near immune to cancer. Researchers are mining the biochemistry of this species in search of mechanisms that might inform the development of ways to treat cancer or influence the processes of degenerative aging. Cancer is a consequence of mutation in nuclear DNA, and the consensus of the majority of the research community is that this random mutational damage, stem and progenitor cells, is a meaningful cause of aging. Thus should we expect naked mole rats to have highly effective DNA repair in comparison to short-lived rodents? It seems to be the case that they do.

Aging and cancer are accompanied by the accumulation of mutations in the genome, genomic instability and dysregulation of transcription patterns. DNA repair systems have evolved to counteract genomic instability. However, whether long-lived and cancer-resistant animal species have more efficient DNA repair is unclear. The naked mole rat (NMR), Heterocephalus glaber, is the longest-lived rodent with the maximum lifespan of 32 years, which is almost ten times longer than a house mouse. Furthermore, NMRs are resistant to cancer with spontaneous tumors being extremely rare.

NMRs evolved a variety of adaptations that may contribute to longevity and cancer resistance. Some of these adaptations may promote genome and proteome stability and increase resistance to stress. NMR proteins involved in redox processes are more resistant to denaturing agents and are able to maintain function under oxidative stress. High accuracy of translation process, increased level of expression of key chaperones and more active proteasomes help to maintain a pool of functional proteins.

Transcriptome analyses by RNA sequencing showed that several genes involved in DNA repair are up-regulated in H. glaber cells. However, transcript levels do not always unambiguously reflect the level of protein expression and activity. NMR cells were found to be more resistant than mouse cells to a variety of stressors. Cell survival under stress is a function of the repair capacity, cell cycle checkpoints, and apoptotic responses. Therefore, NMRs may have more efficient base excision repair (BER) and nucleotide excision repair (NER) systems that protect the cells from mutations coupled with heightened stress responses.

Here we performed the analysis of BER and NER systems in NMR and mouse fibroblasts in response to UVC-light exposure. We evaluated post-irradiation changes in mRNA transcription of several key reparative proteins and measured the activities of the key BER and NER enzymes. Our results suggest that NMR has more efficient BER and NER systems than the short-lived and tumor-prone mouse, which may contribute to longevity and cancer resistance of this species.

Link: https://doi.org/10.18632/aging.101482

Present investigations and attempts to influence nicotinamide adenine dinucleotide (NAD+) metabolism in aging might be viewed as the direct descendant of the heavily hyped sirtuin research of a nearly decade ago. We can check the boxes for (a) mechanisms linked to mitochondrial activity, (b) supplements claimed to adjust age-related changes in those mechanisms, and (c) many of the same people in the scientific community being involved. At the end of the day this may well arrive at the same destination as that sirtuin development, which is to say nothing of any practical use to improve human longevity, but at least the outcome of an incrementally greater understanding of this narrow section of mammalian cellular metabolism.

The data for benefits to result from some of the presently available supplements that might increase NAD+ levels is admittedly considerably better than was the case for tinkering with sirtuins, but that is nonetheless a low bar to pass. Even so, some of these approaches clearly produce the same old story of unreliably, tiny effects that tend to vanish given more care and more rigorous studies. The best outcome we could hope for in the near future is a modestly useful exercise mimetic that can help the unfit to evade some fraction of the consequences of their lack of fitness. Rigorous data has yet to arrive, however, and it could all still come to nothing much yet. That best outcome is still not rejuvenation in any meaningful sense. It is tinkering with the damaged machinery, hoping to get a few extra percentage points of operational capacity out of it, without actually trying to fix the breakages.

Does loss of NAD+ and related decline in mitochondrial function affect the processes that cause cells to become senescent, and thereafter linger and cause harm to surrounding tissues? Since mitochondria are central to most aspects of cellular health, by virtue of providing the chemical energy stores needed for the cell to run at all, and are also central to the processes of programmed cell death that determine whether senescent cells self-destruct or linger, this seems plausible. The details matter, however: what is the size of the effect, in comparison to, say, the decline of the immune system, or other factors in age-related mitochondrial dysfunction, in determining how many senescent cells are present in a tissue? How does it vary between tissues? Further, the methodology used here to reduce NAD+ levels may or may not be a good substitute for what takes place in aging; as a general rule, few such models are, and it is always a question of whether or not the differences happen to be large enough or relevant enough to be a problem for the present area of interest.

Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence

The retinal pigment epithelium (RPE) performs numerous functions essential to normal retinal health and function. RPE is implicated directly and prominently in the pathogenesis of most degenerative diseases of the retina, including age-related macular degeneration (AMD), the leading cause of blindness among persons aged 60 and above worldwide. AMD is a complex multifactorial disease and, as its name implies, age is a primary risk factor for its development.

Interestingly however, most available experimental models and related studies have focused more heavily on identifying, understanding, and limiting secondary consequences of aging and related RPE dysfunction (e.g., increased oxidative stress, inflammation, altered cholesterol metabolism) as opposed to targeting directly factors, such as energy deprivation, that precipitate accelerated aging at a cellular level. The consequence of the latter is an imbalance in homeostatic processes and subsequent damage, as shown in many specific cell types. This is the premise of a number of recent studies including the present investigation in which we focused on nicotinamide adenine dinucleotide (NAD+) and factors governing its bioavailability in relation to the overall impact on RPE viability.

NAD+, a central metabolic cofactor, plays a critical role in regulating cellular metabolism and energy homeostasis. The ratio of NAD+ to NADH (oxidized to reduced NAD+) regulates the activity of various enzymes essential to metabolic pathways including glycolysis, the Kreb's cycle, and fatty acid oxidation. There is a wealth of clinical and experimental data stemming from studies of other primary diseases of aging demonstrating clearly a generalized decline in the availability of NAD+ in association with increased age and the related reduction in the activity of a number of downstream metabolic pathways that contribute to the development and progression of degenerative processes.

Neuronal cells and tissues appear to be especially sensitive in this regard. Importantly, the aforementioned studies additionally suggest that age-related degenerative processes might be prevented or at the least, the consequences thereof lessened in severity by therapies that boost NAD+. In the present investigation we focused on evaluating the impact of NAD+ and factors that regulate its availability on RPE viability both in vivo and in vitro. Cellular senescence is a common consequence of aging hence, the decline in NAD+ in RPE and the associated upregulated expression of markers of senescence that we observed was not totally surprising. Though there has been some debate over whether dysfunction occurs first in the RPE or in the overlying photoreceptors, the contribution of senescence-associated RPE damage to age-related RPE dysfunction is undeniable.

Here, using adult C57BL/6J mice across a broad range of ages (2-18 months), we first confirmed that NAD+ levels decline significantly in association with increased age as has been reported to occur in other retinal and non-retinal cell types. Our related evaluation of enzymes that drive key steps in NAD+ biosynthesis revealed NAMPT as the enzyme principally responsible for maintaining adequate NAD+ levels in RPE. This is congruent with recent work by others demonstrating that NAMPT-mediated NAD+ biosynthesis is essential for proper visual function. We used the compound to optimize a cell culture model system that allowed us to simulate and study the impact of decreased NAMPT expression and related NAD+ availability on RPE cell viability relevant to aging. Our studies in the human RPE cell line ARPE-19 demonstrated an increase in RPE cell senescence in conjunction with reduced NAMPT and NAD+ availability as indicated by analyses of the expression of senescence markers.

Our present data demonstrating an age-dependent decline in NAMPT expression and in turn, NAD+ generation in RPE which ultimately promotes RPE senescence supports strongly the rationale for enhancing NAMPT expression and associated NAD+ generation therapeutically. Indeed, such therapies may represent a viable strategy for preventing and treating RPE and consequent photoreceptor damage in aging/AMD and broadly, in other degenerative retinal diseases in which RPE is prominently affected.

Lack of exercise is harmful to health at all ages, and we live in a sedentary era, coddled by our machineries of transport and convenience. A perhaps surprisingly large degree of the decline into frailty is caused by the lack of exercise that sets in for many adults, and particularly lack are the forms of resistance training that builds strength. Thus there are plenty of studies like the one noted here that demonstrate benefits in elderly individuals who take up a structured program of exercise: most older people do not exercise as much as they can and should, and the consequence of that is a lower quality of life and higher mortality rate.

During ageing, regular exercise may reverse age-related physical deterioration and, at the same time, frailty, a very common syndrome among the elderly and which entails a higher risk of falls, hospital admissions, dependence and even death. This syndrome is more widespread among people living in residential care homes. In order to improve the life quality of this group, researchers designed a programme of physical exercise adapted to the capabilities of each individual. Strength, balance and stamina are worked on. The programme is run progressively and the intensities are increased as the capabilities of the people, for whom the adaptations of the body are greater, increase.

The effectiveness of the programme was analysed in a sample of 112 participants from 10 centres for the elderly. They were randomly divided into two groups: the control group that continued with its usual activities and care, and the experimental group that did two 45-minute sessions of physical exercise per week designed to improve strength and balance. The time they spent walking was gradually increased until they reached at least 20 minutes a day.

After three months, the study showed a significant improvement in most of the physical variables, such as strength, walking speed, and balance in the people who were doing physical exercise. By contrast, the people in the "control" group saw a reduction in their physical capabilities. The results obtained in the SPPB (Short Physical Performance Battery) were particularly significant. These tests are used to measure the degree of frailty and may predict the risk of falls, hospital admittances, dependence or death. Doing physical exercise generated a two-point increase in the SPPB while the result for the control group fell by one point. "A difference of a single point on this scale is already regarded as significant; 3 points are a clinically highly significant difference."

Link: https://www.ehu.eus/en/-/ariketa-fisikoak-hobetu-egiten-du-geriatrikoan-daudenen-bizi-kalitatea

Valuing abstract measures of the welfare of a group distinctly and separately from the welfare of the individuals making up that group is a particularly pernicious conceptual invention. Its most recognizable modern incarnations are nationalism and patriotism, but it has been serving as cover for inhumanity and disregard for considerably longer than that. It also serves as a way for people to argue against treating aging as a medical condition: the group is just fine, thank you, and thus it doesn't matter that all of the individuals in that group are doomed to suffer, diminish, and die. So why do anything about it? A healthier view of the world is that only individuals and their interactions with one another matter, but making that the default mode of thought is something of a challenge in an era of strong centralized governance and wall to wall propaganda for the nation state concept as an entity more important than its citizens.

One of the innumerable romanticizations of death that we're often presented with is that, as one generation dies out, it's just passing on the responsibilities of life to the next. Someone else will take on the task of perpetuating the species, and in general, it doesn't really matter who it is. Never mind that we all die; as long as there's someone to pass the torch to, somebody who will continue to play for team humanity, that's all it matters.

Humanity is not a football club, and neither are other, smaller groups of humans. The family of my great-grandfather, intended as himself, his wife, and their children, is dead. Their genes are still around, and other families have descended from them, in some case even bearing the same family name (another abstraction), but the specific individuals making up my great-grandfather's family are gone, and so is that specific family. You might argue that they're still alive in their descendants' memories and genes or that their name is being passed down, keeping alive the family, but these are all mental gymnastics to present the fact that they're dead in a less unappealing fashion. They're dead, and whether someone still remembers anything about them, or carries a few of their genes or their name, doesn't make them any less dead.

On the subject of future generations, one often hears that their well-being depends on our actions today, and thus we should work to leave them with a better world than we had; this is a commendable intention, and, in fact, it is one of the reasons why we should develop rejuvenation - to spare future human beings the plague of age-related diseases. However, future generations are not here yet; we are, and it's rather mystifying how everyone frets about the currently nonexistent needs of people yet to come but not so much about the very real needs of people who already exist. Today, people suffer from, and die of, age-related diseases; it's a concrete problem, with tangible effects on the world at large in the present; yet many people seem to worry more about the potential problems they imagine that rejuvenation might cause to future.

So, who's more important? Individuals or humanity? It should be clear by now that we'd better think in terms of individuals. The good of humanity shouldn't be about maintaining our presence in the universe just for the sake of being here; it should be about the well-being and life quality of the individuals that make up humanity - and when they're dead, or about to die, individuals aren't generally doing very well. Being concerned about future generations is both understandable and commendable, but it should not lead us to neglect who's already here. As long as we exist, and our good is taken care of, the preservation and the good of humanity will be ensured as well; future humans are welcome to join.

Link: https://www.leafscience.org/humanity-first-or-individuals-first/

There is a growing interest in the role of microbial populations of the gut in aging and health, with evidence from recent years suggesting that their level of influence might approach that of exercise. Some fraction of the benefits to health and longevity that occur due to the practice of either calorie restriction or intermittent fasting are thought to be mediated by resulting changes in gut microbe populations. This seems a safe assumption, given the evidence to hand, but the still open question is just how large or small that fraction might be. The consensus view remains that benefits largely result from increased cellular housekeeping, and the fact that calorie restriction fails to work in animals with disabled autophagy is telling.

Complicating the matter, however, calorie restriction and intermittent fasting are not just two ways of achieving exactly the same result. They produce significantly different patterns of gene expression in animal studies. Intermittent fasting without reducing calorie intake still produces health and longevity benefits in rodents. Calorie restriction lasting for less than three days in humans fails to produce the significant benefits to immune cell populations that fasting for four or longer days achieves. One could argue that the point is time spent in a state of hunger, but that seems overly simplistic given what is known. A mammalian body and its microbial fellow travelers are collectively a complicated system, and that system has correspondingly complicated responses to environmental circumstances.

In the open access paper here, researchers focus on one specific set of interactions between gut microbes and the immune system. Age-related (and other) changes to the microbiome can contribute to chronic inflammation and autoimmunity - here, the autoimmune condition in question is multiple sclerosis, in which immune cells attack the myelin sheathing of nerves, with catastrophic consequences. Intermittent fasting can help in this situation by reducing the influence of problematic microbial populations.

As is the case in all such investigations, the highly varied and dynamic nature of the gut microbiome makes it hard to settle on definitive results that are true for everyone at all times. Even for a given individual, what turns out to be a beneficial influence one year might be more or less beneficial the next year, because the state of the gut mitobiome shifts over time. Of all the presently available ways to manipulate gut bacteria, forms of calorie restriction appear the most reliable, but the degree to which they work in this matter is greatly obscured by the other reliable benefits they achieve in the operation of cellular metabolism.

Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota

Multiple sclerosis (MS) is more common in western countries. Dietary habits have been considered as a potential factor contributing to MS epidemiology. Different diets and dietary supplements have been implicated in MS risk, but the field is lacking robust scientific data to support this risk. Indeed, many studies highlight the importance of the complex interplay between nutrition, metabolic state, and immune-inflammatory responses in MS. Obesity during childhood/young adulthood is a risk factor for MS development as shown in several recent studies. This might be related to a low-grade chronic inflammatory state in obesity that could promote autoimmunity through altered adipokine production. An additional link between nutrition and immune-inflammatory responses is the gut microbiome. Diet is a critical determinant of the gut microbial composition. Gut commensal bacteria and their metabolites have the potential to exert both pro- and anti-inflammatory responses by regulating T cell differentiation and immune responses in the gut. Ultimately, this can have systemic effects and either drive or protect from autoimmune diseases.

Recently it has been reported that the gut microbiome in relapsing-remitting multiple sclerosis (RRMS) patients is altered compared with healthy controls. Further, calorie restriction (CR) has potent anti-inflammatory effects. Studies, including our own, demonstrated that chronic CR significantly inhibited progression of the MS model, experimental autoimmune encephalomyelitis (EAE). However, chronic CR is not likely to be feasible for most people. Intermittent fasting (IF) induces many of the same changes observed by chronic CR and would possibly be more acceptable. We therefore undertook studies of IF in the EAE model and in MS patients experiencing a relapse and showed that IF ameliorated EAE through effects at least in part mediated by changes in the gut flora.

IF induced protective changes in gut microbiome metabolic pathways and lamina propria lymphocytes as demonstrated by the fact that gut microbiome transplantation from mice on IF ameliorated EAE in recipient mice after immunization. To translate our findings in patients, we performed a small pilot randomized controlled trial. IF in MS patients having a relapse was a safe and feasible intervention associated with short-term metabolic and gut microbiome changes that recapitulated what was observed in the animal model.

IF had a striking effect on gut microbiota composition with enrichment of the Bacteroidaceae, Lactobacillaceae, and Prevotellaceae families. In EAE, alteration of the gut microbiota or their metabolites can modulate inflammation and demyelination. Of particular interest was the IF-induced enrichment in Lactobacilli, which are commonly used in probiotics because of their positive effects, including reduction of inflammatory immune responses. In the present studies, Lactobacillus species that were over-represented in the setting of IF included L. johnsonii and L. reuteri, which are well known to have immunomodulatory properties. In addition, enrichment in Prevotella family members with IF may be beneficial because of its enhancement of production of protective short chain fatty acids (SCFAs), such as butyrate. This is important because SCFAs are bacterial metabolites derived from indigestible carbohydrates that have been reported to inhibit EAE by expanding gut regulatory T cells.

The Life Extension Advocacy Foundation volunteers recently interviewed researcher Vadim Gladyshev. He has an interesting viewpoint on aging; he is one of the faction in the scientific community who think that near future significant progress in treating aging is unlikely, as greater understanding is required. This is more or less the polar opposite of the SENS rejuvenation research viewpoint, which states that the present understanding of the root causes of aging is sufficient for progress, and implementation is lagging far behind the state of the science. Gladyshev's laboratory is focused on the genetics of aging and redox biology - the modern end of the evolving view of how oxidative damage is involved in aging.

The early views of aging as being driven by an accumulation of oxidative damage to important molecules have been put aside as too simplistic. Numerous examples of life extension in lower animals have involved modest increases in the production of oxidative molecules: oxidation isn't just a form of damage, it is also a signal in a very dynamic, self-repairing system, one that can have positive outcomes. Oxidative molecules are required for the benefits of exercise to manifest themselves, for example, and those benefits can be blunted by overuse of antioxidants. So while it is clearly the case that older individuals have far greater levels of oxidation in their cells and tissues, that is probably secondary to issues such as mitochondrial and immune system dysfunction.

Why do you think we age?

We age because the process of living is associated with deleterious consequences (in the form of molecular damage, mutations, epigenetic drift, imbalance, dysfunction, etc.), which accumulate over time. We call these deleterious changes the deleteriome, as they are much broader than molecular damage. So, we age because of the increasing deleteriome.

Some scientists suggest that aging is a disease or, more specifically, a co-morbid syndrome; would you agree with this?

I think aging is neither a disease nor not a disease. On one hand, aging is a process, whereas disease is a condition. So, the question may need to be reformulated to whether being older is equivalent to having a disease. On the other hand, conceptually, both aging and disease are associated with deleterious changes, with pathology. Therefore, I think aging includes a combination of chronic diseases together with their preclinical development and other age-related, deleterious changes.

According to our current understanding, aging is the result of the accumulation of different types of damage and errors in the body. Which of these issues do you think will be the hardest to address?

Aging is not only the result of the accumulation of damage and errors but also other deleterious changes. This is why I think the term 'deleteriome' better reflects what happens during aging. In live organisms, every biological process produces deleterious changes. These changes are so diverse and numerous that it would be impossible to fix them all or even sense most of them. Instead, it may be best to alter an organism so that it accumulates fewer deleterious changes (i.e. its deleteriome grows slower) or dilute damage by cell replacement and cell division. I think focusing on a particular damage form is akin to focusing on a particular age-related disease. This approach has some merit, but it would not stop, reverse, or even significantly affect aging, as there could be no main or major damage form. Damage and other deleterious changes act together and need to be dealt with together if we are to target the aging process itself.

What piece of the aging puzzle are you and your lab tackling right now?

We work both on mechanisms of aging and mechanisms of longevity. To begin to target aging, first we need to understand what aging is, which, in turn, should lead to better approaches for lifespan extension. An important element in this research is the ability to measure the biological age of organisms. The first-generation biomarkers of aging, most notably the DNA methylation clock but also other clocks, have now been developed, and they should be useful in testing longevity interventions, rejuvenation approaches, and other treatments and manipulations. For this purpose specifically, we have developed the mouse blood DNA methylation clock.

Different scientists have different views on how close we are to developing the first rejuvenation therapies against human aging. What do you think?

We are not close. We do not even agree on what aging is, when it begins, whether aging is a disease, or what exactly should be targeted. If we consider the analogy to the history of chemistry, we are just moving away from alchemistry and developing the first chemical principles. In aging, we do not yet have the analog of the periodic table. As a field, we often apply approaches akin to alchemists trying to make gold from other metals. I firmly believe that we cannot solve the problem before we understand it, and the longer we avoid trying to understand it, the longer we will remain aging alchemists.

Link: https://www.leafscience.org/dr-vadim-gladyshev-harvard-university/

Atherosclerosis is an inflammatory condition. Oxidized lipids lead to the formation of fatty plaques that narrow and weaken blood vessels, the growth of those plaques driven by the activities of macrophages that try and fail to repair the damage. They become overwhelmed and die: plaques are a mix of fat and the cellular debris from dead macrophages. Prior to their destruction, macrophages generate inflammatory signaling as atherosclerosis worsens, but how is it that other sources of age-related chronic inflammation can accelerate the progression of atherosclerosis? Researchers here explore some of the less well-understood parts of the feedback loop between inflammation and mechanisms of atherosclerosis, in search of answers.

Investigators have identified a new cellular pathway that may help explain how arterial inflammation develops into atherosclerosis - deposits of cholesterol, fats, and other substances that create plaque, clog arteries, and promote heart attacks and stroke. "We have known for decades that atherosclerosis is a disease of chronic inflammation that ultimately results in the scarring of arteries and tissue damage. But the ongoing stimulus for this inflammation has been unclear."

A new study sheds light on this mystery by using a bacterial infection to reveal a cascade of cellular events that can lead to inflammation and atherosclerosis. Investigators focused on interleukin-1 beta, a type of protein that is assembled and released by immune system cells in response to infection and injury, including tissue damage caused by atherosclerosis. While interleukin-1 beta helps rally the immune system against these threats, it also can cause chronic inflammation. The study team wanted to understand how the interleukin-1 beta pathway might promote atherosclerosis.

To make its way out of the immune system cell, interleukin-1 beta can also use the same chemical channels that are used by cholesterol to exit the cell. The result is a "traffic rush" on those channels that blocks the exit of artery-damaging cholesterol and causes it to accumulate in the cell. Once it is released by the cell into the body, interleukin-1 beta suppresses a chemical receptor that enables niacin to be used in the body. This action is harmful because niacin works by removing cholesterol from cells in the artery walls. When niacin is blocked, cholesterol can accumulate in the walls. The suppression of the niacin receptor has another negative effect: It reduces the number of chemical channels that cholesterol uses to exit the immune system cell, causing more cholesterol to be trapped inside. That is because the niacin receptor, besides enabling niacin, also increases these channels as part of its normal function.

These discoveries are especially significant because drugs that inhibit interleukin-1 beta have shown promise in combating atherosclerosis and heart disease. A major clinical trial, led by another research institution and published last year, reported that administering one such drug to patients who had a prior heart attack reduced inflammation and lowered the risk of another cardiovascular event. The study raises the possibility that by using drugs to block the initial production of interleukin-1 beta, rather than just neutralizing it, a stronger positive effect could be obtained for these patients.

Link: https://www.eurekalert.org/pub_releases/2018-06/cmc-ncp062118.php

The accumulation of senescent cells with age causes age-related disease and dysfunction. The most important factor driving this accumulation may be the decline of the immune system, as immune cells are responsible for cleaning up the tiny fraction of all senescent cells that fail to self-destruct, but that has yet to be determined with any great rigor. Regardless of the reasons for this accumulation, periodic removal of senescent cells has been shown to improve health and extend life span in mice, as well as reverse specific aspects of tissue aging in a variety of organs. Therefore a great deal of interest is currently focused on finding new and better ways to go about the targeted destruction of senescent cells. That starts with further mining of the biochemistry of these cells, such as in the research results noted here.

There are at present a limited number of proven approaches to senolytic therapies, those that can selectively destroy senescent cells without causing any great harm to normal cells. Immunotherapy targeting surface markers on senescent cells, as at SIWA Therapeutics, suicide gene therapy tied to expression of senescence-associated proteins inside senescent cells, as at Oisin Biotechnologies, and small molecule / pharmacological approaches, as at Unity Biotechnology. Of these, the latter has the broadest variety at the moment, each class of pharmaceutical targeting a different mechanism associated with senescence, usually those involved in holding back programmed cell death in lingering senescent cells.

In the pharmacological camp, the known mechanisms include: the Bcl-2 inhibition common to most of the repurposed chemotherapeutics, such as navitoclax; whatever it is that dastinib is doing under the hood instead of Bcl-2 inhibition, not well understood at this time; interfering in the FOXO4-p53 interaction; interfering in the MDM2-p53 interaction; and so forth. Anyone turning up a new approach beyond these few, and people will do just that, since all molecular mechanisms inside cells have many surrounding connections, has the potential to create in a lucrative line of research and development. The market for a working rejuvenation therapy based on removal of senescent cells is so large that many competing approaches could thrive, and all of the existing pharmacological approaches under development could be improved upon. That is the incentive for further exploration of the detailed biochemistry of cellular senescence, and why much more funding is available for that line of work these days.

Cells stop dividing when this gene kicks into high gear, study finds

Senescence is a natural occurrence in the life of a cell, and researchers have sought to learn about it for a couple of reasons. First, it's connected to old age: Senescent cells are thought to contribute to heart disease, arthritis, cataracts, and a bevy of other age-linked conditions. Second, a lack of senescence is a hallmark of cancer cells, which bypass this process to replicate in an uncontrolled manner.

A new study illuminates genes involved in cellular senescence, and highlights one in particular that seems tightly associated with this crucial biological process.In experiments, researchers discovered that a gene called CD36 is unusually active in older, senescent cells. What's more, the scientists were able to cause young, healthy cells to stop dividing by heightening CD36 activity within those cells. The effect spread to nearby cells, with almost all of the cells in a petri dish showing signs of senescence when only a small fraction of those cells - about 10 to 15 percent - were overexpressing CD36. New cells placed in the growth medium that previously housed the senescent cells also stopped replicating.

The results point to CD36 as an exciting topic of future research. The gene's exact role in senescence remains a mystery: Scientists know that the gene guides the body in building a protein of the same name that sits on the surface of cells, but this protein's functions are still being studied. Proposed activities include helping cells import lipids, and influencing how these lipids are used within cells.

An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence

Cellular senescence, the irreversible ceasing of cell division, has been associated with organismal aging, prevention of cancerogenesis, and developmental processes. As such, the evolutionary basis and biological features of cellular senescence remain a fascinating area of research. In this study, we conducted comparative RNAseq experiments to detect genes associated with replicative senescence in two different human fibroblast cell lines and at different time points. We identified 841 and 900 genes (core senescence-associated genes) that are significantly up- and downregulated in senescent cells, respectively, in both cell lines.

Our functional enrichment analysis showed that downregulated core genes are primarily involved in cell cycle processes while upregulated core gene enrichment indicated various lipid-related processes. We further demonstrated that downregulated genes are significantly more conserved than upregulated genes. Using both transcriptomics and genetic variation data, we identified one of the upregulated, lipid metabolism genes, CD36, as an outlier.

We found that overexpression of CD36 induces a senescence-like phenotype and, further, the media of CD36-overexpressing cells alone can induce a senescence-like phenotype in proliferating young cells. Moreover, we used a targeted lipidomics approach and showed that phosphatidylcholines accumulate during replicative senescence in these cells, suggesting that upregulation of CD36 could contribute to membrane remodeling during senescence. Overall, these results contribute to the understanding of evolution and biology of cellular senescence and identify several targets and questions for future studies.

While present thinking in the research community is leaning towards tau rather than amyloid-β as the primary cause of cell death and dysfunction in later stage Alzheimer's disease, it is still the case that too much amyloid-β is toxic to cells. Researchers here propose a treatment based on suppressing one of the mitochondrial mechanisms of programmed cell death that is triggered by the presence of amyloid-β. This is in many ways a classic example of what I consider to be a problematic focus in medical research: ignoring the root cause damage, the amyloid-β, in favor of tinkering with cellular mechanisms in the hope of improving the dysfunctional, damaged state of cells and tissues.

There are no doubt a hundred places in which one could reasonably try to intervene downstream of the presence of amyloid-β - and a good twenty of those are probably fairly independent of one another, requiring separate research and development project to address. But why build twenty projects when you could build one to achieve the same effect? Target the root causes. Don't mess with the downstream state. I wish that more of that philosophy of development was in evidence in the research community. Sadly it remains a minority viewpoint, barely worked on, judging by what I see in the output of the medical life sciences.

Alzheimer's disease (AD) is the most prevalent type of dementia in the developed world. Despite the enormous efforts made by the scientific community, an effective therapeutic strategy against AD has yet to be developed. The importance of mitochondrial dysfunction in the pathogenesis of AD and other neurodegenerative diseases has been increasingly recognized. A causal relationship has been found between mitochondrial dysfunction and amyloid β (Aβ)-induced neuronal and vascular degeneration. Indeed, mitochondrial pathology, oxidative stress, and energy metabolism impairment are implicated in the pathogenesis of AD, preceding formation of Aβ plaques, cell death, and memory loss.

Mitochondrial-specific therapies are emerging as promising therapeutic tools. It is interesting that mitochondrial therapies have shown beneficial effects in different models of neurodegenerative pathologies, where mitochondrial dysfunction and apoptotic cell death are known to be involved, such as AD, Parkinson's disease, and Huntington's disease.

Carbonic anhydrases (CA) are enzymes involved in the reversible conversion of carbon dioxide and water into bicarbonate and protons. They are present in all the vertebrates, showing different intracellular locations and regulating pH and ion transport. CA-VA and CA-VB have a mitochondrial localization. CA-II, known as cytoplasmic, was also recently shown to be increased in brain mitochondria in aging and neurodegeneration. CA inhibitors (CAIs) are used to treat a variety of disorders. In this study, we examine multiple mitochondrial pathways of amyloid toxicity in neuronal and cerebral endothelial cells (ECs), and evaluate CAIs methazolamide (MTZ) and, for the first time, its analog acetazolamide (ATZ), on specific Aβ-mediated pathways of mitochondrial dysfunction and apoptotic cell death. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function.

Due to the long-term use of MTZ and ATZ in chronic conditions, the efficacy and the safety of their systemic administration have been widely assessed, making clinical trials for CAIs in AD a concrete possibility. Our novel findings on the mitochondrial effects of MTZ and ATZ against neuronal and vascular amyloid toxicity justify the selection of these drugs as a therapeutic strategy for AD and cerebral amyloid angiopathy.

Link: https://doi.org/10.1111/acel.12787

Autophagy is a collection of several quality control processes in which broken cell components, damaged proteins, and metabolic waste are broken down and recycled. In the most familiar of these processes, the material to be recycled is wrapped in a membrane, an autophagosome, which then migrates to a lysosome, another membrane-bound organelle packed with enzymes capable of taking apart just about any molecule it is likely to encounter.

Unfortunately, this recycling process falters with age in a number of ways, the consequences particularly apparent in very long-lived cells such as the neurons of the central nervous system. Lysosomes become packed with the few classes of compound that they struggle to break down, growing inefficient and bloated. Autophagosomes lose the mechanisms required to transport their contents efficiently to their destination. Cells become overwhelmed with metabolic waste, and dysfunctional as a result.

This open access paper describes one of the outcomes of this decline, the accumulation of garbage dump organelles inside brain cells, probably lysosomes or autophagosomes or the fusion of both that have come to the point of outright failure of function. If autophagy can be restored in aged neurons, will these additional waste-packed organelles start to vanish? That would be one of the more direct ways to try to get a handle on cause and effect, and there are a few possible approaches to that end that might work well enough in the lab to obtain useful data. The ones I tend to favor are those of the LysoSENS program: find ways to break down the worst and most persistent metabolic waste, which should allow lysosomes to cope with the rest.

During aging, neuronal organelles filled with neuromelanin (a dark-brown pigment) and lipid bodies accumulate in the brain, particularly in the substantia nigra, a region targeted in Parkinson's disease. We have investigated protein and lipid systems involved in the formation of these organelles and in the synthesis of the neuromelanin of human substantia nigra. Membrane and matrix proteins characteristic of lysosomes were found in neuromelanin-containing organelles at a lower number than in typical lysosomes, indicating a reduced enzymatic activity and likely impaired capacity for lysosomal and autophagosomal fusion.

The presence of proteins involved in lipid transport may explain the accumulation of lipid bodies in the organelle and the lipid component in neuromelanin structure. The major lipids observed in lipid bodies of the organelle are dolichols with lower amounts of other lipids. Proteins of aggregation and degradation pathways were present, suggesting a role for accumulation by this organelle when the ubiquitin-proteasome system is inadequate. The presence of proteins associated with aging and storage diseases may reflect impaired autophagic degradation or impaired function of lysosomal enzymes.

The identification of typical autophagy proteins and double membranes demonstrates the organelle's autophagic nature and indicates that it has engulfed neuromelanin precursors from the cytosol. Based on these data, it appears that the neuromelanin-containing organelle has a very slow turnover during the life of a neuron and represents an intracellular compartment of final destination for numerous molecules not degraded by other systems.

Link: https://doi.org/10.1038/s41531-018-0050-8

Researchers recently published a study on attitudes to longevity that is reminiscent of the 2013 Pew survey. When asked, people want to live a little longer than their neighbors, at the high end of the normal life span for old individuals today. When asked how long they want to live given the guarantee of perfect health, people pick a number close to the maximum recorded human life span. This sounds like a collusion between the instinctive desires for first conformity and secondly hierarchy, deeply entwined with the human condition, present in all of our primate cousins, a self-sabotaging gift from our evolutionary heritage. We are hardwired to feel comfortable in a hierarchical social structure. We desire to be higher in the hierarchy than those around us, yet not so high that we are non-conforming.

One might argue that the interaction between the need for hierarchy and need for conformity is also at the root of the essential conservatism in human nature: the urge to preserve the present state of the world, to change it as little as possible. Given a teacup, ambition is restrained to the safe, conformist goal of two teacups - rather than, say, the disruptive change of a tea set factory, a house, an end to aging, the colonization of Mars, the cure for cancer. We live in an age of radical change, a revolution in the capabilities of biotechnology presently underway, but when you ask people what they want for their health, they'll claim nothing more than ten more years. That is the least of what might be achieved soon in the medical sciences, but without the desire for more than that, the rejuvenation research projects capable of providing far more will continue to struggle to find funding.

At the same time as the potential has arisen for a future in which the suffering and death of aging is banished, all disease controlled through advanced medicine, the vast majority of people still march stolidly towards what they assume to be the same fate as their grandparents. They are conforming. They expect to live a life that is the same in shape as it was for those born in the early to mid 1900s, somehow holding this idea in their minds at the same time as retaining the memory of living through the computing and internet revolutions, alongside any number of other sweeping changes in the nature of the human experience. How do we change this story that people are telling themselves? That is the fundamental question for all advocacy for radical change, such as the radical change of bringing an end to aging.

Around the World, People Have Surprisingly Modest Notions of the 'Ideal' Life

It seems reasonable that people would want to maximize various aspects of life if they were given the opportunity to do so, whether it's the pleasure they feel, how intelligent they are, or how much personal freedom they have. In actuality, people around the world seem to aspire for more moderate levels of these and other traits. People said, on average, that they ideally wanted to live until they were 90 years old, which is only slightly higher than the current average life expectancy. Even when participants imagined that they could take a magic pill guaranteeing eternal youth, their ideal life expectancy increased by only a few decades, to a median of 120 years old.

In one study, researchers analyzed data from a total of 2,392 participants in Australia, Chile, China, Hong Kong, India, Japan, Peru, Russia, and the United States. Participants in each region received a questionnaire translated into their native language. In response to a series of questions, participants reported their ideal level of intelligence; they also reported how long they would choose to live under normal circumstance and how long they would choose to live if they could take a magic pill ensuring eternal youth. A second study with 5,650 participants in 27 countries produced a similar pattern of results.

How Much Is Enough in a Perfect World? Cultural Variation in Ideal Levels of Happiness, Pleasure, Freedom, Health, Self-Esteem, Longevity, and Intelligence

The maximization principle - that people aspire to the highest possible level of something good if all practical constraints are removed - is a common yet untested assumption about human nature. We predict that in holistic cultures - where contradiction, change, and context are emphasized - ideal states of being for the self will be more moderate than in other cultures. In two studies (N = 2,392 and N = 6,239), we asked this question: If participants could choose their ideal level of happiness, pleasure, freedom, health, self-esteem, longevity, and intelligence, what level would they choose? Consistent with predictions, results showed that maximization was less pronounced in holistic cultures; members of holistic cultures aspired to less happiness, pleasure, freedom, health, self-esteem, longevity, and IQ than did members of other cultures. In contrast, no differences emerged on ideals for society. The studies show that the maximization principle is not a universal aspect of human nature and that there are predictable cultural differences in people's notions of perfection.

Cancer research will accelerate meaningfully towards the goal of control of all cancer only when a majority of researchers are working on mechanisms common to large number of different cancer types. There are too many subtypes of cancer and too few scientists to make real progress when tackling cancers one by one. Shutting down metastasis is one grail of cancer research, as the majority of cancer deaths are caused when cancer spreads throughout the body, not by the initial tumor. Thus a search for common mechanisms of metastasis is one of the few presently viable approaches to the production of broader cancer therapies. Researchers here find eleven genes that are critical to low-level processes in metastasis, broadly common across cancers. This provides a new set of targets that may lead to future ways to suppress the spread of cancer, making the condition much less dangerous.

"Metastasis kills 90 per cent of all patients who have cancer, and with this study we have discovered new ways to potentially end metastasis." In the study, the team used a unique platform it created - a shell-less avian embryo - to visualize the growth and spread of cancer cells in real time. The researchers used a molecular tool called a knockout library to insert short hairpin RNA (shRNA) vectors into cancer cells that bound to specific genes in the cells and stopped them from activating. They then inserted those cancer cells into the shell-less embryos and observed as they formed clusters of cancer, identifying which ones showed properties of being non-metastatic.

"When we found compact colonies of cancer, that meant that the key steps of metastasis were blocked. After that we could pull them out, query what the gene is and then validate that the gene is actually responsible for metastasis." The approach allowed the team to detect and identify 11 genes that play essential roles in cancer cell metastasis. According to the researchers, the genes discovered are widely involved in the process of metastasis and not unique to any one cancer. They now plan to test the metastasis-associated genes and gene-products as drug targets with an aim of stopping metastasis.

"We know that cancer, once it becomes metastatic, will keep spreading to other parts of the body and continue to get worse because of that. If we can stop metastasis at any step of progression in cancer patients, we're going to have a significant effect on survival." The team is now hoping to progress its research to human trials over the next few years. The team is also expanding efforts to explore for other types of genes called microRNAs that may present even stronger therapeutic targets for preventing metastasis.

Link: https://www.folio.ca/discovery-advances-efforts-to-prevent-spread-of-cancer/

Researchers here overstate the potential relevance of an approach demonstrated to improve defenses against molecular damage caused by oxidation in flies. Looking over the diagrams in the paper, reduced levels of TXNIP don't in fact increase life span all that much in flies - and consider that fly life span is far more plastic in response to this sort of manipulation than is the case in humans. A range of approaches that greatly increase fly life span, or nematodes, or mice, are known to do no such thing in our species, even though some may help to improve the quality of health along the way. This is the nature of aging and metabolism in short-lived versus long-lived species.

The researchers also lean heavily on oxidative theories of aging, which are showing their age these days. Oxidative stress certainly increases in later life, and that increase causes downstream issues, but it is entirely possible to argue based on the evidence that it isn't as important as other aspects of aging. It is also secondary to issues such as mitochondrial dysfunction and chronic inflammation. Removing excessive oxidative molecules or improving defenses against them can evidently produce some degree of benefits, but the details of the biochemistry are very important. Few of the approaches illustrated to date have sizable, unambiguous results that are worthy of further interest - perhaps mitochondrially targeted antioxidants, for example. Even those don't seem capable of significant rejuvenation, however, versus a slight slowing of aging.

Oxidative stress causes cells and entire organisms to age. If reactive oxygen species accumulate, this causes damage to the DNA as well as changes in the protein molecules and lipids in the cell. The cell ultimately loses its functionality and dies. Over time, the tissue suffers and the body ages. Researchers have now discovered the key regulator that is responsible for shifting the sensitive balance from vital to harmful amounts of reactive oxygen molecules and thus accelerating the aging process: A protein molecule called TXNIP (thioredoxin-interacting protein).

One way in which the body disposes of harmful reactive oxygen species is their conversion by the enzyme thioredoxin-1 (TRX-1). TRX-1 has been proven to play a role in protecting DNA from oxidative stress and slowing down aging processes. Its antagonist TXNIP inhibits thioredoxin-1 and thus ensures that the reactive oxygen molecules are retained. The researchers wanted to know whether more TXNIP is formed in the body with increasing age, thereby undermining the protective mechanism against oxidative stress. To this end, they first compared T cells from the blood of a group of over 55-year-old volunteers with the T cells of younger blood donors, who were between 20 and 25 years old. It turned out that the cells of older subjects produce significantly more TXNIP. The scientists have also observed similar findings in other human cell and tissue types.

The researchers also found that more TXNIP is produced in the fly Drosophila with increasing age. In order to test whether TXNIP is actually responsible for aging, they bred flies that produce significantly more TXNIP than their relatives as well as flies in which TXNIP synthesis is greatly reduced. "Flies that produced more TXNIP lived on average much shorter, while flies with less TXNIP had a longer average life. TRX-1 and its opponent TXNIP are highly conserved in the course of evolution; they hardly differ between flies and humans." It can therefore be assumed that the two proteins perform similar functions in flies and humans. If more TXNIP is produced with increasing age, this means that TRX is gradually switched off with its protection function. This leads to more oxidative stress, which damages cells and tissue and eventually causes them to die.

Link: https://www.dkfz.de/en/presse/pressemitteilungen/2018/dkfz-pm-18-38-Key-molecule-of-aging-discovered.php

We stand at the very beginning of the era of rejuvenation therapies. The first of those therapies, the repurposed chemotherapeutic pharmaceuticals called senolytics that can clear a fraction of senescent cells from aged tissue, exist but are not yet approved by regulators. They are not widely understood to provide a likelihood of benefit. While these therapies can be obtained, and some cost little as they are old enough to be generic, they are not exactly easily available for the average individual, someone without a background in the field as it stands today. Senolytics will likely not be approved by regulators until the mid 2020s, given the usual pace of the FDA and its peer organizations elsewhere in the world.

Thus there a lasting, hazy period of transition exists between the time at which a class of treatment is created and the time at which the first concrete implementation of that class is approved, well known, and widely available. It might be a decade or two in today's regulatory environment - just look at the progression of stem cell therapies since the turn of the century. Meanwhile, the clock is ticking and none of us are getting any younger yet.

What to do about this? The Forever Healthy Foundation, allied with the SENS Research Foundation and a strong material supporter of SENS rejuvenation research programs, is planning to build a longevity strategy guide. This will be a living how-to document for people who want to do what can be done about aging in advance of the very slow turning of wheels in the medical regulatory system. The Foundation is hiring research analysts, and it looks this project will build upon the start they have made on a database of approaches. There is certainly a need for a well defined and well researched strategy for the everyday individual: all of the organizations that might produce such a guide are either hopeless compromised by their commercial entanglement with the "anti-aging" industry of fraud, pills, and potions, or have neither the interest nor the resources to tackle this project.

What I would like to see emerge from this initiative is a line drawn under every past supplement and drug that has nothing but marginal evidence, all of the over-hyped approaches that cannot in principle produce meaningful impacts on aging. That baggage does nothing but slow and clutter any attempt to work seriously on human longevity. I'd advocate a fresh start, beginning with senolytics and moving forward from there as new technologies emerge. We shall see how close to that desired goal this project comes.

Forever Healthy Foundation is Hiring a Scientific Analyst for Rejuvenation Therapies

These are exciting times. The world has started the transition from an era where we were utterly helpless about our aging process to one where aging is under full medical control, and age-related diseases are a thing of the dark past. The theoretical groundwork has been laid out, scientists have started working on the fundamentals, and the first human rejuvenation therapies are already under development and might become available in the near future.

Even with future full-scale rejuvenation therapies still out of today's reach, there is already a growing array of early-stage therapies that can be used right now to slow our aging process or reverse some aspects of aging. As much as it is a blessing to live in an amazing time like is it also a great challenge. To take advantage of these exciting developments, most of us cannot wait for half a century until we have all the knowledge, perfect therapies and decades of experience on how to implement such treatments. To navigate this time of transition, we continuously need to make very personal decisions about which treatments to apply and when. Arming ourselves with the best knowledge about therapeutic options is key.

However, most of that knowledge is distributed over various experts, specialized communities, blogs, and websites, or buried in scientific research. Thus it is quite challenging to gather reliable information and make informed decisions on planning and implementing one's own early stage rejuvenation treatments. To change this, we have set out to continuously screen the knowledge on available and up-coming therapeutic options, turn it into actionable information and make it available to those interested. To accelerate this process, we are building a dedicated team of skilled professionals.

Personal Longevity Strategy

Even with future rejuvenation therapies still out of today's reach, there is already a lot of cutting edge medical knowledge and technology that can be used right now to significantly extend our healthy life spans. However, most of that knowledge remains unused because it is either distributed over various experts, specialized communities, blogs, websites, books and news feeds or buried deeply in scientific research results. Thus it can be quite hard to gather reliable information and make informed decisions regarding our personal health and longevity.

To change this, we have set out to unify the knowledge from the world's leadings sources, turn it into actionable information and create the most effective personal longevity strategy that can be implemented at present. In the spirit of the open source community we freely share our knowledge and invite everyone to participate.

There is a certain mode of writing positively about aging, with the intent of opposing ageism, in which the author pretends that aging isn't a harmful process of decline in health and capabilities. It seems to me that the best practical solution for ageism is to build the medical technologies that enable older people to be just as physically and mentally capable as younger people. I'm not sure that anything else is likely to work, given the length of time over which all of the other forms of attempt have been made. While it is worthy goal to convince people that is inhumane to reject and persecute others simply because they are less capable, that undesirable aspect of human nature has persisted since prehistory, despite the best efforts of better individuals than you or I. Using technology to change the nature of the human condition seems more likely to succeed than any amount of persuasion and philosophy.

A report by the Royal Society For Public Health, "That Age Old Question," endeavors to expose ageism and help end discrimination against older people. While it does make a handful of valid points, however, it seems to suggest that sweeping the true nature of aging under the rug will help to end ageism. Everything in the report revolves around attitudes towards aging and how the authors think that these should change in order to eliminate age-related discrimination. There is no mention of aging as the chronic, progressive process of deterioration found in the scientific literature; there is not a word about medical research with the potential to prevent age-related diseases, nor is the importance of intervening on the root causes of aging to prevent diseases, and indirectly, ageism, even hinted at.

Quite frankly, if you were an alien who had never heard of aging before and you read this report, you'd likely get the impression that the ill health of humans in old age is just a myth fueled by stereotypes and negative perception of the phenomenon. The poor mental and physical health of old age are described as being merely "negative stereotypes" very early on in the report's foreword, yet later sections of the report suggest bringing together nursing homes and youth clubs to better integrate generations; however, if nursing homes for the elderly exist, age-related ill health is obviously not merely a stereotype.

Similarly, while individual elderly people may be able to make meaningful contributions to the economy before age-related disease takes their lives, the economic burden of an aging population is a real problem, not just a stereotype. It is hard to believe that any society would come up with retirement if elderly people's ability to work was mostly comparable to that of younger people; it is similarly hard to believe that governments and economists who worry about the expected surge in the elderly population of the next few decades, and about the consequences that they might have on our pension systems, are worrying about something that originates in prejudice rather than biology - or that they're not worrying at all but didn't go through the trouble of letting the rest of us know.

To be clear, the authors of the report don't openly oppose medical research against aging. Given that no mention of it was made, it's unclear whether they're even aware of the possibility and if they would endorse it or not. Their intent to undo age-based discrimination is genuine, if misguided. Ending ageism is nearly as important as ending aging; for one, if ageism wasn't a thing, rejuvenation advocates wouldn't have to spend time debating people who think that older people living too long would lead to cultural stagnation because of their alleged "old people mentality". However, ageism won't be defeated by sugarcoating aging, which only adds insult to injury.

Link: https://www.leafscience.org/sugarcoating-aging-wont-fight-ageism/

Researchers recently found that the size of pancreatic cells is inversely correlated with species longevity, given data obtained from a few dozen different types of mammal. Since this is an unexpected new discovery, the paper here contains little more than an initial educated guess at why this might be the case. At first glance this metric doesn't obviously relate to any of the usual mechanisms linking the operation of cellular metabolism with pace of aging, and thus I expect that we'll have to wait for some years of further investigation and theorizing to learn more.

How organs reach and maintain their proper size is a major question in biology. Organ size is the product of total cell number, average cell size, and volume of the extracellular space. Cell number is considered the main determinant of organ size, and differences in cell number explain much of the size difference between organisms, such as mice and humans. However, within a given species, different organs vary considerably in the relative contribution of cell number and cell size to total organ size. For example, the increase in the total mass of blood from birth to adult life results from larger cell numbers, while postnatal growth of cardiac and skeletal muscle largely relies on increased cell size.

Despite the major differences in final size among mammalian species, the molecular and cellular mechanisms underlying organ growth are usually thought to be highly similar. In the case of the pancreas, embryonic progenitor cells initially proliferate and differentiate to form a miniature organ. After birth, progenitor cells largely disappear. The current consensus is that postnatal growth of the pancreas, in mice and by extension also in humans, relies on simple duplication of differentiated cells, consistent with the classic description of the pancreas as an "expanding tissue."

The size of cells in the adult pancreas is recognized to be plastic. For example, acinar cells shrink when luminal nutrients are not available, and beta cell size increases transiently in pregnant rodents. However, increased cell size is not typically considered a significant contributor to normal postnatal pancreas growth. Here we report surprising differences in the mode of postnatal pancreas growth among different mammals. While the human pancreas grows by pure hyperplasia, the rodent pancreas grows mostly by cellular hypertrophy. Acinar cells of the salivary glands present a similar trend, namely larger cells in mice compared with humans. Finally, we identify a surprising negative correlation between acinar cell size and organismal lifespan, based on analysis of 24 mammalian species.

Our findings suggest that the associations of metabolic rate and body weight with lifespan are mediated by differences in cell size. This suggests that animals employing acinar hypertrophy live shorter lifespans. What might be the evolutionary advantage of hypertrophy as a mode of organ growth? We propose that the key is the speed of postnatal growth. Both humans and mice (and their organs, including the pancreas) grow approximately 15-fold from birth to reproductive age; however, this age is reached ∼100 times faster in mice. We hypothesize that cellular hypertrophy contributes to the rapid growth of short-lived mammals. Indeed, the rate of postnatal growth is negatively correlated with lifespan, and this correlation is eliminated when controlling for cell size. This result supports a model whereby cellular hypertrophy promotes rapid postnatal growth rate and earlier sexual maturity at the expense of lifespan.

Link: https://doi.org/10.1016/j.devcel.2018.05.024

The paper I'll point out today walks through the ways in which exercise is known to beneficially affect the Hallmarks of Aging. The Hallmarks are a list of the significant causes of aging that I disagree with about half of. The SENS catalog of root causes of aging, first published earnestly in the literature back in 2002, isn't cited anywhere near as much as the much later Hallmarks of Aging - which owes a great deal to its predecessor while failing to mention it in any way. There is some overlap between the two, but many of the Hallmarks are not causes of aging, but rather manifestations of aging, meaning secondary and later consequences of underlying molecular damage.

This question of whether not any specific manifestation of aging is or is not a root cause is important. The strategy adopted in the development of therapies to treat aging matters. Addressing root causes is far more effective than addressing downstream consequences. Near all medical technology employed to date to treat age-related diseases fails to touch on the root causes of aging, however, and this is why these therapies are only marginally effective at best. They modestly slow progression, or modestly ease suffering, but they cannot meaningfully turn back any aspect of the progression of aging. We can continue along that road, or we can choose to attempt a better strategy.

Exercise is beneficial, and the degree to which it is beneficial is fairly well defined. Knowing something about the molecular biology taking place under the hood won't make exercising any more or less beneficial, but it is an interesting topic. Exercise, like calorie restriction, modestly slows the impact of aging. Unlike calorie restriction it doesn't have a large impact on maximum life span in mice, but does raise the average life span. Both are just as reliable and just as cheap - even small effects are worth the effort when they cost little and are guaranteed. It is when we start to talk about the cost of research and development for new medical technologies to treat aging that we must think about the expected size of the outcome on human longevity. Why chase small, expensive gains? If the cost is significant, it only makes sense to pursue a strategy that can produce sizable gains in health and life span.

Aging Hallmarks: The Benefits of Physical Exercise

Traditionally, aging was not seen as an adaptation or genetically programmed phenomenon. More recently, biologic currents point to two main theories: the programmed aging and the damage or error-based theories. The first suggests an intrinsic biologic programmed deterioration of the structural and functional capacity of the human cells. The latter highlights the cumulative damage to living organisms leading to intrinsic aging. Nonetheless, a combination of these theories is usually preferred. In this sense, a state-of-the-art review, proposed nine cellular and molecular hallmarks that contribute to the process of aging, including (1) genomic instability, (2) telomere attrition, (3) epigenetic alterations, (4) loss of proteostasis, (5) deregulated nutrient sensing, (6) mitochondrial dysfunction, (7) cellular senescence, (8) stem cell exhaustion, and (9) altered intercellular communication. These hallmarks should be expressed during normal aging, with their experimental aggravation speeding up the aging process, and in contrast, their experimental amelioration retards the normal aging process, thus increasing a healthy life span.

Along with the nine cellular and molecular hallmarks stated above, aging is known to be correlated with several cardiovascular, cardiorespiratory, musculoskeletal, metabolic, and cognitive impairments. In this sense, regular physical activity in the older population - especially aerobic and resistance training - plays an important role at a multisystem level, preventing severe muscle atrophy, maintaining cardiorespiratory fitness and cognitive function, boosting metabolic activity, and improving or maintaining functional independence. In addition, physical exercise has a positive antiaging impact at the cellular level, and its specific role in each aging hallmark is described below.

Genomic Instability

In the face of genomic instability, the organism has developed a panoply of DNA repair mechanisms that skirmish altogether to overcome nuclear DNA damage. Exercise plays a role in maintaining genomic stability. In rodent models, aerobic exercise improves DNA repair mechanisms. It augments DNA repair and decreases the number of DNA adducts (up to 77%), related to aging and several risk factors for cardiovascular diseases. In addition, a six-month resistance training program in an institutionalized elderly population showed a tendency to reduce cell frequency with micronuclei (~15%) and the total number of micronuclei (~20%), leading to a higher resistance against genomic instability.

Telomere Attrition

Telomere shortening is described during normal aging in human and mice cells. The fact that telomere length decreases with aging, contributing to the normal cell senescence process, suggested that this could be a potential marker for biological aging. Although the potential mechanism is unclear, exercise exhibits a favorable impact on telomere length, especially on a chronic pattern and particularly in older individuals antagonizing the typical age-induced decrements in telomere attrition. Several potential mechanisms have been discussed linking exercise and telomere length decrements to changes in telomerase activity, inflammation, oxidative stress, and decreased skeletal muscle satellite cell content.

Epigenetic Alterations

The relationship between epigenetic regulation and aging is controversial and complex. A multiplicity of epigenetic modifications affects all tissues and cells throughout life. The literature clearly reveals that the epigenetic response is highly dynamic and influenced by different environmental and biological factors, such as aging, nutrient availability, and physical exercise. Regular aerobic exercise can change the human genome through DNA methylation. Thus, by using epigenetic mechanisms, aerobic exercise can induce the transcription of genes encoding telomere-stabilizing proteins and telomerase activity not only in animals but also in humans.

Loss of Proteostasis

Aging and some aging-related diseases are linked to impaired protein homeostasis, also known as proteostasis. The array of quality control is guaranteed through distinct quality control mechanisms that prevent the aggregation of damage components and ensure the continuous renewal of intracellular proteins, degrading altered proteins. Aerobic exercise induces autophagy, thus preventing the loss of strength and muscle mass through the modulation of signaling pathways. Chaperone associated functions, such as folding and protein stability, are impaired in aging. In animal models, the upregulation of co-chaperones of the heat-shock proteins (HSPs) was associated with prolonged life-span phenotypes. Despite limited comparison studies, evidence supports that acute endurance- and resistance-type exercise protocols are associated with increased HSPs transcription not only during activity but also immediately postexercise or several hours following exercise, which points out the possible favorable impact of physical activity on proteostasis.

Deregulated Nutrient Sensing

Exercise plays an important role in not only the glucose-sensing GH / IGF-1 somatotrophic axis but also other nutrient-sensing systems, promoting a beneficial anabolic cellular state. The effect of exercise on glucose metabolism through increased glucose transporter type 4 production is another well-known mechanism of improved insulin sensitivity associated with physical activity. Additionally, exercise-induced GH and IGF-1 levels are influenced by exercise intensity, duration, and type (higher in intense interval protocols and resistance exercise).

Mitochondrial Dysfunction

The clear causal relationship between mitochondrial dysfunction and aging has long been a target of great discussion. With increasing age comes a decline in mitochondrial integrity and biogenesis because of alterations in mitochondrial dynamics and mitophagy inhibition, impairing dysfunctional mitochondria removal. The regular practice of physical exercise has a positive impact in mitochondrial function. In this sense, endurance-trained humans presented higher levels of mitochondrial proteins expression. Regular physical exercise may maintain a pool of bioenergetically functional mitochondria that, by improving the systemic mitochondrial function, contribute to morbidity and mortality risk reduction throughout one's life span.

Cellular Senescence

Senescent cell accumulation in different tissues seems to be dependent, in one hand, on an increased rate of senescent cell generation and, in other hand, on a decreased rate of clearance. Exercise, specifically aerobic, induces the secretion of antitumorigenic myokines and greater natural killer cell activity, contributing to a decreased incidence of oncologic disease and improved cancer prognosis. This may also impact clearance of senescent cells. Aerobic exercise has been inversely correlated with p16INK4a mRNA levels in peripheral blood T lymphocytes, which might promote protective outcomes against age-dependent alterations. Aerobic exercise suppresses liver senescence markers and downregulates inflammatory mediators.

Stem Cell Exhaustion

For the long-term maintenance of the organism, the deficient proliferation of stem and progenitor cells is harmful, but an excessive proliferation can also be deleterious by speeding up the exhaustion of stem cell niches. Within this line, physical exercise is one of the most potent stimuli for the migration/proliferation of the stem cell subsets from their home tissue to impaired tissues for later engraftment and regeneration. In this sense, regular physical exercise attenuates age-associated reduction in the endothelium reparative capacity of endothelial progenitor cells. In addition, exercise activates pluripotent cells' progenitors, including mesenchymal and neural stem cells, which improve brain regenerative capacity and cognitive ability.

Altered Intercellular Communication

The physiological aging process implicates several alterations on intracellular communication mechanisms, namely, in neuroendocrine, endocrine, and neuronal levels. Inflammation plays a central role in this age-related alteration. Muscle contraction is traditionally associated with myokine secretion (proteins, growth factors, cytokines, or metallopeptidases) elevated during and after exercise. Interestingly, the muscle-released IL-6 creates a healthy influence, inducing the production of anti-inflammatory cytokines. Within these lines, several authors associated lifelong aerobic exercise training with lower inflammatory levels, particularly in advanced decades of life.

Chronic obstructive pulmonary disease (COPD) is caused by long-term inhalation of smoke or other particulate or chemical irritants. In wealthier parts of the world, that usually means smoking. In less wealthy parts of the world, cooking fires and industrial processes also contribute. The condition shares some mechanisms with aging, particularly the accumulation of senescent cells and the chronic inflammation produced by those cells. In some ways, it is possible to consider aspects of COPD to be accelerated lung aging. In other ways it is entirely different. This is generally true of the environmental contributions that make up secondary aging, the various exposures that cause harm and dysfunction by speeding up specific, narrow forms of cell and tissue damage. The open access paper here is interesting for the comparisons it draws between aging and smoking as causes of increased cellular senescence in the lungs.

Most parts of the body including the lungs experience progressive damage with aging as well as impaired function. Lung aging is associated with loss of elasticity, a decrease in pulmonary function, loss of structural integrity, and an increase in inflammation which are among the key characteristics of chronic obstructive pulmonary disease (COPD). COPD is the third leading cause of chronic morbidity and mortality on a global scale. Growing evidence suggest that age-associated structural and functional alterations enhance pathogenetic susceptibility to COPD.

Along with other toxic gases, the most common etiological factor that develops COPD is cigarette smoke (CS) which results in several pathophysiological changes in the lung. Recent reports suggest that CS induces oxidative stress-mediated DNA damage and triggers cellular senescence in the lungs. Cellular senescence is a process of complete and permanent cell cycle arrest. The accumulation of metabolically active senescent cells in tissues during aging impairs tissue repair and function. Pro-inflammatory mediators are secreted which give rise to a phenomenon known as senescence-associated secretory phenotype (SASP). Senescent cells increase the damage of neighboring cells by virtue of their SASP phenotype. Previous reports proposed a network of cellular senescence, inflammatory response, and premature lung aging in the pathogenesis of COPD.

We hypothesized that aging-associated changes in lungs worsen the COPD by CS exposure. Younger and older groups of C57BL/6J mice were exposed to chronic CS for 6 months with respective age-matched air-exposed controls. CS caused a decline in lung function and affected the lung structure of both groups of mice. No alterations were observed in the induction of inflammatory mediators between the air-exposed younger and older controls, but aging increased the severity of CS-induced lung inflammation. Aging per se increased lung cellular senescence. Thus our data suggest that normal aging and chronic CS exposure independently induce cellular senescence in the lungs.

Link: https://doi.org/10.1038/s41598-018-27209-3

Calcification of soft tissues occurs in the cardiovascular system with age, one of the processes that causes arterial stiffening and other pathogenic conditions such as aortic stenosis. Considered at a very high level, this happens because a fraction of cells in the blood vessel walls malfunction and begin to act in ways more appropriate to a bone environment, laying down deposits of minerals. The causes of this malfunction are incompletely understood, but evidence suggests that the presence of senescent cells and their inflammatory signaling is an important cause.

In this open access paper, researchers investigate cellular signals carried via exosomes in the context of vascular calcification. Exosomes are a class of extracellular vesicle, small membrane-bound packages of molecules that carry a sizable fraction of the signaling traffic between cells. In recent years, scientists have been paying a lot more attention to these packages, as they appear to carry most of the signals that are important in, for example, the beneficial effects of stem cell transplants. They are also probably a sizable part of the harmful signals produced by senescent cells. While the authors don't mention cellular senescence here, it is interesting to speculate on the overlap between this research and what is being discovered of the role of vesicles in senescent signaling.

Vascular calcification (VC) is caused by hydroxyapatite deposition in the intimal and medial layers of the vascular wall, leading to severe cardiovascular events in patients. Importantly, exosomes have been demonstrated to be involved in VC recently. Exosomes have up-regulated secretion from vascular smooth muscle cells (VSMCs) in vivo after pro-calcifying stimulation and become "calcifying" exosomes to induce VC. Calcium binds with phosphate to form hydroxyapatite nodes on the inner and outside of "calcifying" exosomes membranes, which further initializes mineral deposition. Although these studies did reveal that exosomes participated in the calcification procession through promoting mineral deposition sites formation, they did not discuss exosomes functioning as mediators for RNAs transportation, which is vital for exosome function.

Exosomes are secreted by diverse cells to mediate cell-to-cell communications. However, how exosomes regulate VC has been only preliminarily explored. It is found that exosomes with diverse origins mainly mediate microRNAs (miRs) transporting to VSMCs in coronary artery calcification. A bioinformatics analysis revealed that cultured in osteogenic medium, mesenchymal stem cells secreted exosomes with alterations of miRs, comparing with normal culturing. Such alterations were suggested to accelerate calcification in other mesenchymal stem cells to modulate osteogenic phenotype transition. Thus, it implies that besides heterogeneous mineral deposition inside vessel wall, exosomes can also promote VC by transporting messages among cells.

Link: https://doi.org/10.1111/jcmm.13692

Cellular senescence is one of the root causes of aging. Nonetheless, the study of cellular senescence used to be a comparative backwater in aging research, and as a topic it was mostly of interest to cancer researchers seeking ways to better shut down the replication of cancerous cells. But there is nothing quite like having a company raise $300 million in venture funding for rejuvenation therapies based on manipulation and destruction of senescent cells to bring a little excitement to this part of fundamental aging research. Who knows how many useful, exploitable mechanisms are yet to be found in senescent cells and the signals they generate? Each one is a potential lottery ticket for the discovering institution and research group.

This was in fact always the case, and for decades a compelling set of evidence has strongly suggested that the accumulation of senescent cells is a significant contribution to aging. Yet next to no-one was funding or working on it seriously until the high-profile proof of concept study in mice reported in 2011, in which senescent cells were eliminated and health and life span improved as a consequence. After that point, the avalanche started, leading to today's crop of first generation senolytic therapies capable of selectively destroying a fraction of the senescent cells present in older individuals.

Today I thought I'd point out a couple of examples of the sort of paper that results from an influx of funding and interest to the study of the fundamental biochemistry of senescent cells. The research community is mining for gold. The first explores the harmful signals secreted by senescent cells, the major way in which they cause tissue dysfunction in aging and age-related disease. A faction within the research community is more comfortable interfering in these signals rather than destroying senescent cells, despite it likely being a far worse and more challenging approach to therapy. The second paper is one of many in which researchers explore the role of mitochondrial activity in senescence, in search of approaches that might modulate the activity in beneficial ways. Both papers are quite different in focus, but they emerge from the same newfound interest in senescence as a cause of aging.

Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype

Senescent cells lose their cell type specific functionality and replicative potential required for tissue regeneration and acquire a senescence-associated secretory phenotype (SASP). The SASP is characterized by the secretion of growth factors, pro-inflammatory cytokines and chemokines, as well as extracellular matrix (ECM) remodeling enzymes. These SASP factors are considered to over-proportionally exert negative effects on tissue homeostasis and regeneration in vivo if chronically present by acting in a paracrine manner on the neighboring cells and ECM. Attenuation of the negative effects of the SASP have been shown to restore the formation of functional human skin equivalents and has been suggested as a putative target in preventing age-associated diseases and frailty.

Recently, extracellular vesicles (EVs) and their cargo have been reported to act in a similar manner as hormones or cytokines during intercellular communication. They are secreted by many, if not all cells, and by encapsulation of their cargo, they transport proteins, mRNAs, lipids, and non-coding RNAs, specifically miRNAs, over short or long distances. Thus, although many protein based SASP factors have been identified, miRNAs and EVs are under suspicion to be part of the SASP. However, a systematic catalogue of SASP-miRNAs has not yet been established and their selective secretion during senescence has not been studied so far. Here, we confirm that EVs and their miRNA cargo are indeed part of the SASP (EV-SASP) and identified a set of selectively retained and secreted miRNAs after the onset of senescence. In addition, senescent cell derived EVs might contribute to an anti-apoptotic environment in tissues where senescent cells have accumulated.

Mitochondrial peptides modulate mitochondrial function during cellular senescence

Mitochondria play important roles in cellular energy production, metabolism, and cellular signaling. These organelles have their own genomes, the mitochondrial DNA (mtDNA). Epigenetic modification of mitochondrial DNA, including DNA methylation, is still controversial. The overall mitochondrial DNA methylation occurs at a lower frequency compared to nuclear DNA, but specific locations have been found to be differentially methylated in certain cellular conditions or in different biological samples.

Humanin is a 24-amino acid peptide encoded within the mtDNA. It is secreted in response to cellular stress and has broad cytoprotective and neuroprotective effects. MOTS-c is a 16-amino acid peptide encoded within the mtDNA that improves metabolic functions. Among the basic processes that are known to drive aging phenotypes and pathology are genomic instability, epigenetic alterations, mitochondrial dysfunction, and cellular senescence. Although humanin and MOTS-c have protective roles in multiple age-associated diseases, the roles of these peptides in cellular senescence have not been explored.

Senescent cells are metabolically active, producing energy-consuming effectors of senescence, despite the loss of proliferative activity. Depending on the inducer, senescent cells show higher levels of glycolysis, fatty acid oxidation, and mitochondrial respiration. Manipulating bioenergetic status can induce senescence and a SASP, suggesting that bioenergetics play a role in the senescence phenotype. Thus, altering the metabolic status of senescence cells may be an important strategy for eliminating the deleterious effects of senescence. In this study, we investigate mitochondrial energetics and mtDNA methylation in senescent cells, and evaluate the potential of humanin and MOTS-c as novel senolytics or SASP modulators that can alleviate symptoms of frailty and extend health span by targeting mitochondrial bioenergetics.

It remains the case that a great deal of aging research these days is purely observational, which is, I think, unfortunate. This is an age in which more than mere observation of aging might be achieved; the first interventions likely to reliably slow or reverse aspects of aging are making their way out of the laboratory and into clinical development. There should be a lesser emphasis in the research community on watching what happens to a population of older individuals who lack effective treatments for aging, and a correspondingly greater emphasis on getting those treatments built and into the clinic.

Given this, does it really matter how frailty and cardiovascular disease interact? Would the world be changed by knowing, in detail, the exact relationship between the two? Both of these conditions will be banished in the wealthier half of the world fifty years from now, defeated and controlled by forms of regenerative medicine that are periodically applied to remove the root causes of these conditions. That will be achieved by focusing on those causes, ignoring the detailed end-stage mechanisms and relationships of the conditions that result.

Aging as it exists today will be a curio of the past given a further fifty years of development after that point. How much scientific work today goes towards considering how exactly different patient populations experienced the now extinct condition smallpox in the absence of effective treatments? How valuable was that sort of research during the years in which the first meaningful treatments were deployed? I'd say that, at that time, observational lines of research added very little to progress in defeating smallpox - and the situation will be much the same for aging.

In older adults both cardiovascular disease (CVD) and frailty are highly prevalent. Novel and advanced cardiovascular therapeutic treatments have improved life expectancy and consequently led to an increasing number of older adults suffering from chronic CVD. This presents an enormous clinical and public health burden. Frailty describes a state of vulnerability due to an age-related decline in many physiological systems and is associated with a considerably increased risk of falling, disability, hospitalisation, and mortality. According to cross-sectional data, CVD appears to be positively associated with frailty in community-dwelling older adults. However, cross-sectional studies do not clarify if CVD leads to frailty or if frailty precedes the development of CVD.

From a pathophysiological point of view, both directions are plausible. For example, exercise related symptoms in patients with CVD could lead to physical inactivity making them more likely to become frail. Additionally, comorbidities, as well as physical and cognitive decline are common in older adults with CVD. This could lead to a loss of homeostatic capability to withstand stressors and increase the risk of frailty. Yet, one could also argue that physical inactivity and its sequelae (e.g. obesity) due to frailty is a risk factor for development of CVD. Also, frailty is associated with a chronic state of low-grade inflammation which could trigger CVD.

The present study studied the bidirectional effect of CVD on frailty among community-dwelling older adults. First, we observed cross-sectional associations between CVD and frailty. Patients with CVD, especially those with peripheral arterial disease and heart failure, were more likely to be frail. Longitudinally, mainly HF was associated with incident frailty. These patients were at least twice as likely to become frail, which puts these patients at an equal or even higher risk of incident frailty than subjects with chronic lung disease, arthritis, or diabetes. Analyses studying the reverse association revealed that in this older population, frailty does not precede development of CVD during three years of follow-up.

Link: https://doi.org/10.14336/AD.2017.1125

Ilia Stambler, historian of our longevity science community, is in illustrious company in the author list for this open access position paper. Regular readers will recall that the World Health Organization (WHO) is among the most conservative and hidebound of institutions when it comes to the development of means to treat aging. The WHO positions on aging studiously avoid any mention of the idea that aging can be changed at all through medical science. This is somewhere between ridiculous and outrageous, given what is going on in the labs and clinical development today. More activist members of the scientific community have, accordingly, berated and advocated by turn in journal articles these past few years.

Should a broken system be changed from within, or should it be rejected entirely and worked around? In my experience, the latter approach is the one more likely to produce change, but as a general rule far more effort goes towards the first. We can speculate as why this might be the case. Perhaps because those people most able to identify and articulate the problem in question tend to be experienced with, embedded in, and thus invested in, the broken system. It is comparatively rare for outsiders to appear with sufficient knowledge to build viable alternatives; matters must usually decline for a long time before that happens. That is certainly happening elsewhere in the scientific and medical communities, but not yet here.

It can be confidently stated that global population aging is both the greatest success of global public health efforts of the past, as well as the greatest challenge for the further global public health efforts of the future. Over the past decades, life expectancy at birth has increased globally. Considering that both rising longevity and population aging are likely demographic events in the coming decades, by 2050 the proportion of people over 60 years is expected to double from about 13% to nearly 25%, which, in absolute terms, means an increase from 962 million to 2.1 billion people. Rising longevity during the last 150 years is a testament to human ingenuity, and there is reason to believe further advances are possible.

According to World Health Organization's data, "Noncommunicable diseases (NCDs) kill 40 million people each year, equivalent to 70% of all deaths globally. Cardiovascular diseases account for most NCD deaths. Each year, 15 million people die from a NCD between the ages of 30 and 69 years; over 80% of these premature deaths occur in low- and middle-income countries." In other words, of the 57 million deaths in the world each year, nearly 50% occur due to chronic non-communicable diseases in the world's oldest population (70+), and over 60% in the older population (60+), making the health of older persons the worst and most urgent global health problem.

In view of the urgency of the problem, it seems highly surprising that in the forthcoming draft 13th General Programme of Work of the World Health Organization for 2019-2023 the issue of aging and aging-related ill health is excluded completely! Beside a cursory mention of the word "aging," this work program does not contain any specific objectives, deliverables, and actions to improve the health of the aged. This means that, through 2023, according to this document, the World Health Organization is not obliged to provide any services to care for the health of older persons or to improve their health, not to mention conduct any research and development to create new therapies and technologies for improving the health of the aged. The issues of aged health are not in the WHO work program!

How can this exclusion coexist with the mission of WHO's division on Ageing and Life Course? How can it coexist with the recently adopted WHO's Global Strategy and Action Plan on Ageing and Health (GSAP) for 2016-2020, endorsed by all the WHO member states? According to its goal statement, the GSAP must prepare for the "Decade of Healthy Ageing from 2020 to 2030" which was also announced by WHO. The coordination and consultation between various arms and branches of the WHO must improve. The developers of the WHO Work Program must avail of the world expertise on ageing health, within the WHO and externally, to develop an effective, strategically-minded and inclusive global health program. We also urge the readers to make your voice heard, advocate and increase publicity about the need to include and implement concrete measures to improve aging health, including research and development for healthy longevity, as a priority in the WHO work program.

Link: https://doi.org/10.14336/AD.2017.1120

One of the many important points made by the advocacy community for rejuvenation research is that participants in the mainstream of medical science and medical regulation are not imbued with a great enough sense of urgency. We are all dying, and yet with each passing year the regulatory process moves ever more slowly, rejects an ever greater number of prospective therapies, becomes ever more expensive. The number of new therapies reaching the clinic falls. Regulators continue to reject the idea that treating aging is an acceptable goal in medicine. We live in an age of revolutionary progress in the capabilities of biotechnology, and yet patients must accept that new medicines are rare, and that fifteen years might pass between lab and clinic. This is not an industry moved by any sense of urgency.

Naturally, those who do see the urgency and are frustrated by the present state of medical development reach for different options. Some of those options are bad: cherry-picking research; testing interventions without evidence; self-experimentation without data or consideration of risk; building an industry to deliver supplements and other products that don't perform as advertised. Some of those options are sound: responsible development and medical tourism that takes place outside regions with the most onerous regulation; self-experimentation within a framework that encourages an understanding of risk and supporting research; advocacy to change the regulatory system.

Self-experimentation is the only way to obtain early access to new classes of medical technology, those described in research, manufactured in the marketplace, but not yet run through the regulatory process. Many will never even enter the regulatory process. The only way to provoke the sort of development needed to produce good data is for a community of self-experimenters to report on their experiences, obtaining a critical mass sufficient to attract research interest and funding. This is essentially what happened over the past few decades for the practice of calorie restriction. It isn't a medical technology, but proceeded through the same path of early research, adoption by self-experimenters, growth of a community, and that community then influenced the research community to pay greater attention. As a result we now have far better human data on calorie restriction, showing that the early research was essentially correct and it is a useful practice that modestly slows many of the consequences of aging.

Most people who self-experiment wouldn't call it that - and probably justifiably so. They rely on hope and how they feel rather than solid data, and are too readily swayed by hype and cherry-picked or misrepresented research. Many of those who went further than their own health to organize business ventures, such as the many members of the anti-aging marketplace, have built an industry that does at least as much harm as good. We cannot let the bad drive out the good when it comes to the frustration with the lack of urgency in medical development that leads people to choose to strike out on their own. It is possible to achieve meaningful gains through ventures in medical tourism, through responsible development, through self-experimentation with data and publication. Where this does happen, however, it is frequently the case that the people involved have a foot in both camps.

Such is the case for the principal subject of the popular science article here. I can't condone most of the activities of the Life Extension Foundation; the heart is absolutely in the right place, but so very much of the implementation is at best a waste, and at worse actively harmful to progress. Supplements as marketed over these past four decades do nothing for longevity, do nothing for aging, and participants in this market have used their advertising megaphone to convince the world that anti-aging is a sham, a joke: pills and potions that do nothing. It is an industry built on self-evidently false claims. Yet the Life Extension Foundation uses the proceeds from that business to fund some degree of meaningful, useful research into aging and means to treat aging and age-related disease. They also clearly support better paths forward in medical science. It is my hope that working rejuvenation therapies and biomarkers of aging will drive out the fraud and the lies and the nonsense in the years ahead, but don't ask me to approve of the state of this market today.

Bill Faloon has pursued immortality for decades. Now he's got lots of company. What does science have to say?

At 63, Bill Faloon is old enough to remember when talk of life extension labeled you a kook or charlatan. In the late 1970s, he co-founded the Life Extension Foundation, a nonprofit promoting the notion that people don't need to die - and later started a business to sell them the supplements and lab tests to help make that dream real. Nowadays he also distributes a magazine to 300,000 people nationwide and invites speakers to monthly gatherings at the Church of Perpetual Life, billed as a science-based, nondenominational meeting place where supporters learn about the latest developments in the battle against aging. Their faith is in human technologies that might one day end involuntary death.

After an hour of mixing, we all head to the second-­floor nave and fill the pews for the evening's event. Several rows back sits a beer scientist. Next to me, two women in dresses and heels. At the front, an elderly gentleman with hearing aids. Tonight's speaker is Aubrey de Grey, a biomedical gerontologist and chief science officer of SENS Research Foundation, a Mountain View, California, outfit that studies regenerative medicines that might cure diseases associated with old age.

Today, it is easy to locate university-affiliated labs at places such as Harvard and Stanford investigating their own interventions in the process of growing old. Since the National Institutes of Health established its Institute on Aging division in 1974, scientists have dedicated more and more resources to the challenge. Over the past dozen years, the NIA's budget has doubled to more than $2 billion. Faloon predates them all. These days, the several ­hundred people who regularly attend events at the church are personal validation for Faloon, who thinks that anyone his age and younger, given the proper physiological tweaking, could live to a healthy age of 130. The hope is that, by then, new solutions will make death truly optional. Yet no amount of self-tinkering can assure him and his followers that day will ever come.

Across all these potential aging interventions, there is one common denominator, and that is their fallibility. The medical community doesn't know what slows or reverses the process in humans, let alone what might cause harm. For that reason, researchers caution against the kind of self-experimentation Faloon practices. "We're playing with a new treatment paradigm," the Mayo Clinic's James Kirkland says of their research. "I've been around long enough to know there are going to be unpredictable things that happen as we get into people."

Faloon believes he faces a bigger risk from waiting than from being his own guinea pig. "I'm afraid that with aging research, some of the people don't have a sufficient sense of urgency," he says. He continually incorporates different interventions into his life-extension regimen. He restricts his calories to some 1,200 a day, about half what the average man consumes. He also ingests more than 50 medications daily, including metformin and Life Extension's own concoctions of nutraceuticals. "Anything that might work, I am doing," he says. Because he's impatient for clinical trials to yield ­conclusive results, Faloon gives about $5 million a year in profits from the buyers club to underwrite medical research. So far, the data from two recent studies on NAD+ and rapamycin that he backed are unpublished. "If we don't accelerate all these different projects, I'm not going to make it," Faloon says.

The heart is one of the least regenerative organs in mammals. Damage to heart tissue, such as that resulting from a heart attack, produces a harmful inflammatory response and the formation of scar tissue rather than regeneration. Scarring disrupts normal tissue function, whether in the heart or elsewhere. The research community would like to suppress the unhelpful inflammation and scarring following injury in all types of tissue, but this phenomenon is particular problematic in the heart. Here, researchers demonstrate that the source of this inflammation may be largely the activity of B cells.

In a heart attack, blood is cut off from an area of the heart that then often dies. If the person survives, the body tries to heal the dead muscle by forming scar tissue - but such tissue can further weaken the heart. Yet another wave of damage can occur when well-intentioned immune cells try to heal the injured heart but instead drive inflammation. Pirfenidone is approved to treat a lung condition called idiopathic pulmonary fibrosis, a scarring of the lungs that has no known cause. The drug also has been known for its heart-protective effects in a number of different animal models of heart attack. Researchers had assumed that pirfenidone's protective action in the heart paralleled the reason it helps in lung disease. In the lungs, the drug slows the formation of scar tissue.

"That this drug also protects the heart is not new. But in our studies, pirfenidone didn't physically reduce scar tissue in the heart. The scar tissue is still there, but somehow the heart works better than expected when exposed to this drug. It wasn't clear why. So we set out to reverse engineer the drug to pick apart how it may be working. Since scar tissue was still present, we suspected inflammation was the main culprit in poor heart function after a heart attack." Most immune studies of the heart have focused on other types of immune cells, including macrophages, T cell lymphocytes, neutrophils, and monocytes. But the researchers found no differences in the numbers of such immune cells in the injured hearts of mice that received pirfenidone versus those that didn't. When they serendipitously measured B cells, however, they were surprised to see a huge difference.

"Our results showing B cells driving heart inflammation was quite unexpected. We didn't know that B cells have a role in the type of heart damage we were studying until our data pushed us in that direction. We also found that there isn't just one type of B cell in the heart, but a whole family of different types that are closely related. And pirfenidone modulates these cells to have a protective effect on heart muscle after a heart attack." When the researchers removed these cells completely, not only was the heart not protected, the beneficial effect of the drug went away. So the B cells are not exclusively bad, according to the scientists. "The protective effects of pirfenidone hinge on the presence of B cells. The drug may be working on other cells as well, perhaps directly or perhaps through the B cells. We're continuing to investigate the details."

Link: https://medicine.wustl.edu/news/scientists-id-source-of-damaging-inflammation-after-heart-attack/

For various historical reasons, none of them justified, researchers seeking to intervene in the aging process have avoided talking about extending human life span. Until comparatively recently, and after a great deal of work on the part of advocates such as those of the Methuselah Foundation and SENS Research Foundation, the leaders of the research and funding communities actively suppressed efforts to discuss or work on the treatment of aging as medical condition. This environment gave rise to euphemisms such as "healthy aging" or "successful aging," and the goal of compression of morbidity: extend the period of health within the present human life span, but never, ever talk about trying to extend that life span. This has distorted the scientific endeavor, holding back efforts to develop meaningful rejuvenation therapies.

"Healthy aging" is a nonsense phrase. Aging is, by definition, the rise in mortality risk, the growth in systemic damage and failure of function. Aging is the opposite of health. Yet the phrase is well established and unlikely to go away any time soon, sadly. Any researcher or institution settling on the goal of healthy aging sets up for defeat before the work even starts. To pursue healthy aging is to accept aging rather than seek to defeat it. It is to aim at small modulations of the aging process, tiny adjustments here and there, rather than the sweeping change of rejuvenation. It is the assurance of failure, of missing the opportunity to change the world for the better.

Expressions such as "healthy aging" and "aging gracefully" signify that while the aging processes are making no exception for you, you're relatively healthy and/or the cosmetic signs of aging aren't as pronounced as they could be. This, of course, betrays the obvious reality that, in general, this kind of aging isn't the norm but rather a special case. If things were the other way around, you wouldn't find any articles stating the obvious fact that it's possible to age gracefully; rather, you'd find articles saying that disgraceful or unhealthy aging, however exceptionally, may happen too.

This choice of words is rather problematic, especially now that the dawn of rejuvenation is visible on the horizon. The terms "healthy aging" and "successful aging" really are sharp contradictions in terms. If you read the scientific literature on aging, most if not all papers giving general introductions to the phenomenon define it as a chronic process of damage accumulation or a progressive decline in health and functionality. If we try to replace these definitions in the two expressions above, the results are frankly hilarious: "a healthy chronic process of damage accumulation" and "a successful progressive decline in health and functionality". What's that even supposed to mean? Given that this progressive decline in health and functionality happens of its own accord and it invariably kills you, one would think that you really don't need to put any special effort in achieving it, and it appears to be "successful" enough without any need for external intervention.

It's of course good that healthy aging, as defined as a mitigated and relatively disease-free decay process, is actively promoted. However, this unfortunate terminological choice perpetuates the false dichotomy between aging and age-related disease; it reinforces the completely unsubstantiated belief that you can age biologically and yet retain your health. To put it bluntly, it's one of the reasons why you have people saying that when their grandfather died, at age 95, he was "perfectly healthy". If everything with him was in perfect working order, what did he die of, exactly? Some may think he just died of "old age", as if old age were a separate cause of death entirely, but that's not the case. Death by old age is just an expression to mean that he died of one of the many health issues that, in humans, generally manifest only after the seventh or eighth decade of life.

Just like the term "life extension" - albeit somewhat improper - has become a proxy for the application of regenerative medicine for the prevention of age-related diseases, so "healthy aging" and similar phrases have become synonymous with "being less sick than you could be", even though they really sound more like "getting sick in a healthy way". The only way to eradicate these misleading expressions is to successfully explain the true nature of aging to the public.

Link: https://www.leafscience.org/getting-sick-in-a-healthy-way/

Today's open access review looks over the evidence for senescent cells to contribute to the age-related loss of muscle mass and strength, leading to sarcopenia and frailty. Regular readers will know that the research community has found many mechanisms that are arguably important contribution to the characteristic weakness of old age. This part of the field is rife with competing evidence for processes ranging from the comparatively mundane, such as an inadequate dietary intake of protein in older people, to the highly complex, such as the biochemical disarray that causes loss of neuromuscular junctions, and the interactions between those junctions and mechanisms of muscle tissue maintenance. The most compelling evidence points to stem cell dysfunction as the primary cause of loss of muscle and strength with age. But then we might well ask which of the fundamental causes of aging produces that stem cell dysfunction?

The review here argues for cellular senescence to be an important cause. Senescent cells accumulate over time, a tiny fraction of the countless cells that become senescent every day managing to linger rather than self-destruct. The immune system clears out near all of those, but the immune system falters with age. Cancer is an age-related disease in large part because of this loss of capability in the portions of the immune system responsible for destroying errant cells, and the accumulation of senescent cells is no doubt in the same boat. Yet even in very old tissues, only a small percentage of cells are senescent. The harm they cause is not direct, but rather results from the potent mix of signals that they generate. Those signals produce chronic inflammation, destructively remodel tissue structure, and change the behavior of surrounding cells for the worse.

Just looking at chronic inflammation, it is known that this state can disrupt the normal processes of tissue maintenance and regeneration. But there are many other mechanisms worth surveying when it comes to the ways in which cellular senescence might be acting to suppress the activity of stem cell populations, thus leading to atrophy and loss of function in tissues such as skeletal muscle. What if these senescent cells could be removed, however? Might we expect some degree of rejuvenation of stem cell activity? That doesn't seem an unreasonable goal, based on the evidence to date. Senolytic therapies capable of clearing a fraction of senescent cells already exist, albeit not packaged up for the mass market, and not yet run through rigorous human trials. More effective therapies are entering the regulatory pipeline, under development in a number of young companies, and will arrive in the clinic over the years ahead.

Musculoskeletal senescence: a moving target ready to be eliminated

Aged individuals can deteriorate exceptionally fast after the onset of complications affecting the musculoskeletal system. Tissue erosion due to life-long mechanical and biological stress can ultimately result in pathologies such as osteoporosis, sarcopenia, and osteoarthritis, and contribute to frailty. While not all elderly people develop the same age-related diseases, virtually everyone will experience musculoskeletal complications sooner or later. To extend, and possibly even restore, healthy life expectancy in old age, it is essential to understand the cellular changes underlying musculoskeletal decline.

Tissue regeneration by stem-cell differentiation is critical in overcoming the relentless day-by-day damage to the musculoskeletal system. In young tissues, differentiation proceeds without much hindrance unless one exercises excessively or suffers undue levels of stress. However, during aging, the number and function of adult stem cells declines. For example, Pax7-expressing satellite stem cells, can replace damaged muscle fibers. Removing Pax7-positive cells from mice impairs muscle regeneration after injury, whereas increased availability of these cells enhances muscle repair.

In addition to cell-intrinsic regulation, muscle stem cell regenerative capacity also depends intimately on the microenvironment. During aging, the levels of inflammation chronically increase, an affect known as inflammaging. Evidence for this is provided by studies showing that muscle stem cells (satellite cells) from aged mice become more fibrogenic, a conversion mediated by factors from the aged systemic environment. In contrast, frailty is reduced by the JAK/STAT inhibitor Ruxolitinib, which reduces inflammation in naturally aged mice. Stem-cell impairing cues do not necessarily have to come from local sources but can travel over a distance. Therefore, there is a great interest in developing methods to interfere with the age-associated pro-inflammatory signaling profile. The question is how? To address this question, cellular senescence has recently gained attention as a potential candidate for intervention.

As we age, each cell in our body accumulates damage. Earlier in life, this damage is usually faithfully repaired, but over time more and more damage gets left behind. This can trigger a molecular chain of events, resulting in the entry of cells into a permanent state of cell-cycle arrest, called cellular senescence. Senescence can be invoked in healthy cells that experience a chronic damage response, either involving direct DNA damage or events that mimic the molecular response, such as telomere shortening or oncogenic mutations. As a consequence, these cells undergo an irreversible cell cycle arrest, effectively limiting the damage. So far, so good, except that senescent cells secrete a broad range of growth factors, pro-inflammatory proteins, and matrix proteinases that alter the microenvironment: the Senescence-Associated Secretory Phenotype (SASP).

Senescent cells persist for prolonged periods of time and eventually accumulate during aging. This also means there is a gradual and, importantly, ever-present build-up of deleterious molecules. Thus, senescence can have continuous detrimental effects on tissue homeostasis during aging. That senescent cells are a direct cause of aging was proven beyond a doubt in studies in which senescent cells were genetically or pharmacologically removed. In these studies, both rapidly and naturally aged mice maintained healthspan for much longer, or even showed signs of aging reversal.

Factors secreted by senescent cells can induce pluripotency in vivo. As such, these can impair normal stem cell function by forcing a constant state of reprogramming, something we dubbed a `senescence - stem lock'. Age-associated inflammation may thus deregulate normal stem cell function at different levels, for instance by preventing stem cells from producing differentiated daughter cells. Due to the constant secretion of SASP factors, senescent cells could thus impair local and distant stem cell function and differentiation in times of need. Here, we will highlight the interplay between senescence, the SASP and stemness in the individual musculoskeletal compartments: muscle, bone, and cartilage.

The research community continues to make progress, slow but steady, in understanding the low-level biochemistry of neurodegenerative conditions. It is a very complex area of study. You might compare the research here, focused on amyloid, with results noted yesterday, focused on α-synuclein. The aging of the brain is accompanied by the aggregation of a number of altered proteins, producing solid deposits and a halo of surrounding changes in cell biochemistry that damage or kill brain cells. Beyond that summary, each is very different in mechanisms and outcome. Regardless, the end result is cognitive decline, a disruption of function in the brain. Control of protein aggregation is a major focus of the research community, but achieving any meaningful progress towards that goal has proven to been far more challenging than was hoped when these projects began in earnest.

The accumulation of amyloid peptides in the form of plaques in the brain is one of the primary indicators of Alzheimer's disease. While the harmful effects of amyloid peptide aggregates are well established, the mechanism through which they act on brain cells remains ill-defined. Researchers knew, for instance, that amyloid peptides disrupt synapses - the area of contact and chemical communication between neurons - but did not understand how they did so. Now, new findings have revealed the molecular mechanism that links amyloid aggregates and deficient synaptic function observed in animal models of Alzheimer's disease: peptide oligomers interact with a key enzyme in synaptic balance, thereby preventing its normal mobilization.

The molecule, called CamKII, usually orchestrates synaptic plasticity, an aspect of neuronal adaptability that enables neurons to reinforce their responses to the signals they exchange. Groups of neurons that code for an information to be memorized are connected by synapses, which are themselves under the control of mechanisms of synaptic plasticity. When the connection between two neurons must be reinforced in order to memorize information, for instance during intense stimulation, CamKII is activated and leads to a chain of reactions that strengthen the capacity to transmit messages between these neurons.

Synaptic plasticity is central to memory and learning. Amyloid peptides prevent CamKII from participating in this process of synaptic plasticity, and this blockage eventually leads to the disappearance of the synapse. This discovery could find an application in early phases of Alzheimer's disease when initial cognitive deficiencies are observed, which could be linked to this synaptic malfunction. The goal for researchers now is to continue studying amyloid aggregates, especially by trying to prevent their interaction with CamKII and the loss of synapses observed during the disease.

Link: http://www2.cnrs.fr/en/3128.htm

A fair amount of research on raised blood pressure, hypertension, and its risks has been published of late. Hypertension is a downstream consequence of loss of elasticity in blood vessels. That loss of elasticity arises from the molecular damage at the root of aging, and the resulting hypertension is one of the more noteworthy mediating mechanisms by which that low-level biochemical damage is translated into structural damage to organs. Hypertension causes pressure damage to sensitive tissues, increasing the rate at which small blood vessels rupture, killing the nearby cells. This is particularly important in the brain, where regenerative capacity is limited. Individually, each tiny area of damage has little effect, but taken as a whole it adds up over time to contribute to cognitive decline.

A new study indicates that patients with high blood pressure are at a higher risk of developing dementia. This research also shows (for the first time) that an MRI can be used to detect very early signatures of neurological damage in people with high blood pressure, before any symptoms of dementia occur. High blood pressure is a chronic condition that causes progressive organ damage. It is well known that the vast majority of cases of Alzheimer's disease and related dementia are not due to genetic predisposition but rather to chronic exposure to vascular risk factors. The clinical approach to treatment of dementia patients usually starts only after symptoms are clearly evident. However, it has becoming increasingly clear that when signs of brain damage are manifest, it may be too late to reverse the neurodegenerative process. Physicians still lack procedures for assessing progression markers that could reveal pre-symptomatic alterations and identify patients at risk of developing dementia.

This work was conducted on patients with no sign of structural damage and no diagnosis of dementia. All patients underwent clinical examination to determine their hypertensive status and the related target organ damage. Additionally, patients were subjected to an MRI scan to identify microstructural damage. To gain insights in the neurocognitive profile of patients a specific group of tests was administered. As primary outcome of the study the researchers aimed at finding any specific signature of brain changes in white matter microstructure of hypertensive patients, associated with an impairment of the related cognitive functions.

The result indicated that hypertensive patients showed significant alterations in three specific white matter fiber-tracts. Hypertensive patients also scored significantly worse in the cognitive domains ascribable to brain regions connected through those fiber-tracts, showing decreased performances in executive functions, processing speed, memory and related learning tasks. Overall, white matter fiber-tracking on MRIs showed an early signature of damage in hypertensive patients when otherwise undetectable by conventional neuroimaging. As these changes can be detected before patients show symptoms, these patients could be targeted with medication earlier to prevent further deterioration in brain function. These findings are also widely applicable to other forms of neurovascular disease, where early intervention could be of marked therapeutic benefit.

Link: https://www.eurekalert.org/pub_releases/2018-06/oupu-dcb061218.php

The quality of the vasculature is an important determinant of the pace of aging in the brain. There are probably several distinct processes involved, all of which tend to correlate with one another as aging progresses. Firstly the brain is an energy-hungry organ, but the network of tiny capillaries in tissues becomes less dense with age. A consequently lower supply of nutrients to cells causes loss of function. The same result may also occur due to the age-related weakening of the muscles of the heart. Secondly, blood vessels lose their elasticity in later life, and this in turn causes a rise in blood pressure as feedback mechanisms run awry. Higher blood pressure causes damage to sensitive tissues in many organs through a variety of means, such as a greater rate of rupture or blockage of tiny blood vessels. The brain of an older individual is riddled with the minuscule scars left by these events, and that damage adds up.

Why do blood vessels grow stiff with age? A mix of underlying causes, not all of which are fully understood. Persistent cross-links that our biochemistry cannot break down glue together structural proteins of the extracellular matrix, altering the structural properties of tissue. Rising inflammation and signals from senescent cells contribute to both calcification of blood vessel walls and dysfunction in the smooth muscle cells responsible for contraction and dilation. The behavior of smooth muscle is more responsive to lifestyle circumstances than other factors; better diet, avoiding excess fat tissue, and greater fitness are thought to have an impact, either through reduced inflammation and or other mechanisms, whereas there isn't much that can be done about existing calcification or cross-linking given the tools to hand today.

Greater fitness and better lifestyle choices only slow the progression of aging to some degree - and only meaningfully impact a fraction of its mechanisms. But in an era of rapid progress in medical biotechnology, in which the research community is finally waking to the potential of treating aging and its causes, it makes sense to adopt lifestyle choices that reliably help long-term health, even if the outcome at the end of the day is just a few years gained. Those few years may make a sizable difference, between on the one hand living long enough and in good enough health to benefit from future technologies of rejuvenation, and on the other hand missing that boat.

Better Physical Fitness and Lower Aortic Stiffness Key to Slower Brain Ageing

The rate of decline in certain aspects of memory may be explained by a combination of overall physical fitness and the stiffness of the central arteries, researchers have found. "Exactly why this occurs is unclear, but research indicates that exercise and physical fitness are protective. A healthier, more elastic aorta is also theorised to protect cognitive function, by reducing the negative effects of excessive blood pressure on the brain."

One hundred and two people (73 females and 29 males), aged between 60 and 90 years, living independently in aged care communities, were recruited. Their fitness was assessed with the Six-Minute Walk test which involved participants walking back and forth between two markers placed 10 metres apart for six minutes. Only participants who completed the full six minutes were included in the analysis, which assessed the stiffness of their arteries and cognitive performance. The researchers found that (along with Body Mass Index and sex) the combination of fitness and aortic stiffness explained a third of the variation in performance in working memory in older people.

Interestingly, physical fitness did not seem to affect central arterial stiffness, however only current fitness was assessed - long term fitness may be a better predictor of central arterial stiffness, however this has yet to be investigated. "Unfortunately, there is currently no effective pharmacological intervention that has proven effective in the long term in staving off dementia. The results of this study indicate that remaining as physically fit as possible, and monitoring central arterial health, may well be an important, cost effective way to maintain our memory and other brain functions in older age."

Physical Fitness and Aortic Stiffness Explain the Reduced Cognitive Performance Associated with Increasing Age in Older People

Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness. Our objective is to investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition.

Residents of independent living facilities, aged 60-90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis. Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation.

Thus greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline.

Parkinson's disease is strongly linked to quality control of mitochondria in neurons. The condition is characterized by the loss of a vital population neurons responsible for generating the neurotransmitter dopamine, and it is this loss that produces the tremors and other motor dysfunction observed in patients. Parkinson's disease is also a proteopathy, however, in which α-synuclein clumps together to form solid deposits that harm brain cells. In the research noted here, scientists show that this α-synuclein aggregation kills neurons by damaging mitochondria and triggering mitochondrial mechanisms that produce the form of cell death called apoptosis. This might suggest a link to what is already known of the important portions of the biochemistry of Parkinson's disease; more active mitochondrial quality control might slow the harm done by α-synuclein by removing damaged mitochondria before they can trigger apoptosis.

Parkinson's disease isn't the only synucleinopathy in which α-synuclein aggregation harms the function of the brain. Synucleinopathies are not the only class of proteopathy in the brain: amyloids and tau also form aggregates that are involved in the development of neurodegenerative conditions such as Alzheimer's disease. Finding ways to safely and reliably remove the excess molecular waste that accumulates within and between brain cells is a very important topic in medical research. Controlling one form of waste should provide benefits to patients suffering any of several varieties of neurodegeneration, but since aging brains tend to exhibit the signs of all of these forms of protein aggregate, clearing out all of them is most likely necessary in order to prevent or cure the most common age-related neurodegenerative conditions.

For years, scientists have known that Parkinson's disease is associated with a build-up of alpha-synuclein protein inside brain cells. But how these protein clumps cause neurons to die was a mystery. Using a combination of detailed cellular and molecular approaches to compare healthy and clumped forms of alpha-synuclein, researchers have discovered how the protein clumps are toxic to neurons. They found that clumps of alpha-synuclein moved to and damaged key proteins on the surface of mitochondria - the energy powerhouses of cells - making them less efficient at producing energy. It also triggered a channel on the surface of mitochondria to open, causing them to swell and burst, leaking out chemicals that tell the cell to die.

These findings were replicated in human brain cells, generated from skin cells of patients with a mutation in the alpha-synuclein gene, which causes early-onset Parkinson's disease. By turning patient skin cells into stem cells, they could chemically guide them into become brain cells that could be studied in the lab. This cutting-edge technique provides a valuable insight into the earliest stages of neurodegeneration - something that brain scans and post-mortem analysis cannot capture. "Our findings give us huge insight into why protein clumping is so damaging in Parkinson's, and highlight the need to develop therapies against the toxic form of alpha-synuclein, not the healthy non-clumped form."

Link: https://www.crick.ac.uk/news/science-news/2018/06/12/scientists-unravel-molecular-mechanisms-of-parkinson%E2%80%99s-disease/

This popular science article takes a high level look at the vast array of research data showing that excess visceral fat causes great harm to long term health. One of the more important mediating mechanisms is an increase in chronic inflammation, a state of dysfunction in the operation of the immune system that disrupts organ function and tissue maintenance, and accelerates the development of all of the common age-related diseases. There are numerous other connections between the pace of aging and the activities of visceral fat tissue, however. Becoming overweight is the path to a shorter life expectancy, greater incidence of age-related disease, and higher lifetime medical expenditures.

In general, if your waist measures 35 or more inches for women or 40 or more inches for men, chances are you're harboring a potentially dangerous amount of abdominal fat. Subcutaneous fat that lurks beneath the skin may be cosmetically challenging, but it is otherwise harmless. However, the deeper belly fat - the visceral fat that accumulates around abdominal organs - is metabolically active and has been strongly linked to a host of serious disease risks, including heart disease, cancer, and dementia. Weight loss through a wholesome diet and exercise - activities like walking and strength-training - is the only surefire way to get rid of it.

Unlike the cells in subcutaneous fat, visceral fat is essentially an endocrine organ that secretes hormones and a host of other chemicals linked to diseases that commonly afflict older adults. One such substance is called retinol-binding protein 4 (RBP4) that was found in a 16-year study of nurses to increase the risk of developing coronary heart disease. This hazard most likely results from the harmful effects of this protein on insulin resistance, the precursor to type 2 diabetes, and development of metabolic syndrome, a complex of cardiac risk factors.

The Million Women Study conducted in Britain demonstrated a direct link between the development of coronary heart disease and an increase in waist circumference over a 20-year period. Even when other coronary risk factors were taken into account, the chances of developing heart disease were doubled among the women with the largest waists. Every additional two inches in the women's waist size raised their risk by 10 percent.

Cancer risk is also raised by belly fat. The chances of getting colorectal cancer were nearly doubled among postmenopausal women who accumulate visceral fat, a Korean study found. A Dutch study published last year linked both total body fat and abdominal fat to a raised risk of breast cancer. When the women in the study lost weight - about 12 pounds on average - changes in biomarkers for breast cancer, like estrogen, leptinm and inflammatory proteins, indicated a reduction in breast cancer risk.

Perhaps most important with regard to the toll on individuals, families and the health care system is the link between abdominal obesity and risk of developing dementia decades later. A study of 6,583 individuals in Northern California who were followed for an average of 36 years found that those with the greatest amount of abdominal obesity in midlife were nearly three times more likely to develop dementia three decades later than those with the least abdominal fat.

Over all, according to findings among more than 350,000 European men and women published in The New England Journal of Medicine, having a large waist can nearly double one's risk of dying prematurely even if overall body weight is normal.

Link: https://www.nytimes.com/2018/06/11/well/live/belly-fat-health-visceral-fat-waist-cancer.html

Juvenescence appears to be hitting its stride in initial setup. It will, once further along in its plan, look much like many of the private equity funds that exist in the biotech space, with a portfolio of mutually supporting companies working on therapies for various aspects of aging. We know that at least some of the principals, such as Jim Mellon, are supportive of the SENS rejuvenation research agenda, but it remains to be seen whether or not that will turn out in practice to involve investment in the young companies that have arisen in the SENS community in the past few years. The Juvenescence principals want to be making $5-10 million series A round investments, but if one happens to be looking for focused SENS startups coming up to that point, the list at present is not a long one. So, inevitably, there will be investment in infrastructure biotechnologies or things like mTOR inhibitors and NAD+ upregulation - approaches that I think are probably not going to move the needle all that much. There is a certain urgency in venture matters: once you have raised funds you can't then sit around and wait for the perfect opportunity.

It is my hope that Juvenescence will follow through with their declared intent to do more than just graze the crop of aging-related companies as they emerge, and will actively engage with the research and entrepreneurial communities to cultivate new projects and new companies. If there is one thing that all parties involved do poorly at present, it is the various steps of the transition from lab to entrepreneur. Researchers don't reach out to capital or entrepreneurs, there are too few entrepreneurs in biotech as a whole, not many of whom understand aging and the potential for rejuvenation therapies, and most institutions capable of deploying capital sit around waiting for entrepreneurs to show up with the science already nicely packaged with a bow on top. It is a crisis of inaction, and one of the reasons why there is a yawning gulf between research in the laboratory and clinical development in companies.

It is at least the case that anyone who builds a fund to make A-round investments is reliant on much larger movements of capital into the market later, in order to fund the really expensive work of pushing therapies through the regulatory process, and ultimately to purchase the companies in order to provide a return to investors. This means that the Juvenescence principals can be counted on to continue to loudly promote their agenda, and in doing so attract more support and funding to the vital field of rejuvenation research. It is a useful alignment of interests, one that creates a positive feedback loop once it is underway. Capital attracts capital, and in this case that will benefit us all in the long run.

Juvenescence aims to tap longevity 'money fountain'

Juvenescence, a UK start-up developing anti-ageing therapies, has raised $50m in Series A financing, with another $100m funding round planned for later this year and an initial public offering in 2019. Juvenescence is building a team of 20 scientists and drug developers in London who will co-ordinate its investments. The biggest investment so far is $8.3m in Insilico Medicine, an artificial intelligence company in the US that applies "deep learning" technology to drug discovery and ageing research. On Monday Insilico itself announced a funding round of $5m to $10m led by WuXi AppTec of China.

Also on Monday, Juvenescence announced a $5m investment in AgeX of California, which is using stem cell technology to regenerate human tissues that are failing through age-related degenerative disease. The most exotic investment is LyGenesis, a spinout from the University of Pittsburgh, which aims to use the patient's own lymph nodes as a bioreactor to grow a replacement organ if the original is destroyed by disease or fails in old age. It is focusing first on liver regeneration for people with end-stage hepatic disease, and future targets include the thymus, pancreas, and kidney. Juvenescence has also signed commercialisation deals with the Buck Institute for Research on Aging in California and is in negotiation with other biomedical organisations.

AgeX Therapeutics Closes on $5 Million Strategic Investment From Juvenescence

AgeX Therapeutics, Inc., a subsidiary of BioTime, Inc., focused on prolonging healthspan through an understanding of the fundamental mechanisms of human aging, today announced that it has closed a $5 million equity financing, through the sale of two million AgeX common shares to Juvenescence Ltd. "This investment, combined with the $10.8 million we previously raised from investors, the recently-announced cash received of approximately $3.2 million from the sale of Ascendance Biotechnology, and our recently-announced $386,000 grant from the NIH, provide sufficient capital for the continued development of our programs into 2020."

AgeX Therapeutics, Inc. is a biotechnology company focused on the development of novel therapeutics for age-related degenerative disease. The company's mission is to apply the proprietary technology platform related to telomerase-mediated cell immortality and regenerative biology to address a broad range of diseases of aging. The products under development include two cell-based therapies derived from telomerase-positive pluripotent stem cells and two product candidates derived from the company's proprietary induced Tissue Regeneration (iTR) technology.

Secondary aging is, more or less, that part of age-related decline that is driven by lifestyle choices and environmental factors. It adds to the primary aging caused by internal processes that we can presently do comparatively little to address. The mechanisms involved are similar and overlapping. Chronic inflammation, for example, will grow in later life even given an exemplary approach to personal health, and contributes to the progress of all of the common age-related diseases. That is primary aging. But let yourself become overweight and take up a smoking habit, and greater levels of chronic inflammation will result. That is secondary aging.

The publicity materials here help to make the case that for much of the population, a sizable fraction of age-related hypertension - increases in blood pressure - is driven by unhealthy lifestyle choices. These are the usual suspects: a poor diet, excess fat tissue, lack of exercise. While one can't defeat aging and its varied manifestations by living well, actively making things worse seems like a poor choice in an age of accelerating progress in biotechnology, with rejuvenation therapies somewhere on the horizon. Whether or not one lives an extra few years, or experiences an extra decade of comparatively good health, is no longer moot in the long run. Some people will live for long enough to benefit from the coming era of progressively improving rejuvenation therapies, and some people won't. It makes sense to employ the sensible, everyday health practices that cost little and adjust the odds in your favor.

The program noted here is essentially a form of calorie restriction and/or calorie management, packaged up and prettified. That approach tends to work for people who are overweight, and will improve most health metrics as weight is lost, particularly those associated with metabolic disease deriving from excess fat and too little exercise. If this group and others manage to find ways to sell a lower calorie diet to people who wouldn't otherwise choose to benefit, then more power to them. It is a pity that we live in a world in which it doesn't work to comprehensively demonstrate, again and again, over decades, that fewer calories are better. Adoption requires the packaging and prettifying.

Researchers have demonstrated that a program aimed at helping people modify lifestyle factors such as diet and exercise is as effective as medication at reducing blood pressure. Participants in the study saw their blood pressure drop 19 points, on average, after taking part in the program for just 14 days. Other studies have shown that a blood pressure reduction of this magnitude can cut a person's risk of heart disease or stroke in half. "By adapting selected lifestyle health principles, half of the people in our study achieved normal blood pressure within two weeks while avoiding the side effects and costs associated with blood pressure medications. The Newstart Lifestyle program works quickly, is inexpensive and uses a palatable diet that allows for moderate amounts of salt and healthy fats from nuts, olives, avocado and certain vegetable oils."

The reduction in blood pressure accomplished by the program was equivalent to what can be achieved using three half-dose standard medications for blood pressure. In addition, 93 percent of the participants were able to either reduce the dose (24 percent) or eliminate their blood pressure medications (69 percent). People participating in the Newstart Lifestyle program follow a vegan diet, walk outside daily, drink substantial quantities of water, get adequate daily sleep and participate in optional spiritual activities. The program's vegan diet consists of foods, such as legumes, whole grains, vegetables, fruits, nuts, seeds, olives, avocados, soymilk, almond milk and whole-grain breads.

For the study, the researchers evaluated data from 117 people with high blood pressure who had participated in the Newstart Lifestyle program for 14 days. At the end of the program, half of the participants achieved a systolic blood pressure below the recommended 120 mmHg. The program was effective at lowering blood pressure in varying types of individuals, including otherwise healthy men and women and people with diabetes or who were obese and those with high cholesterol levels. Next, the researchers plan to test the program in more people over a longer time period to better understand its long-term effects and biological basis.

Link: https://www.eurekalert.org/pub_releases/2018-06/n2-alh053118.php

The Life Extension Advocacy Foundation (LEAF) volunteers have started to maintain a Rejuvenation Roadmap resource. This is intended to be a reference and visual summary of the state of progress in the various lines of research the LEAF staff consider relevant to the treatment of aging as a medical condition. We can always disagree on the details, such as the choice to use the Hallmarks of Aging rather than SENS as a categorization strategy, but I think that this sort of project is very helpful as our community grows. New arrivals benefit greatly from summaries and starting points. In the years ahead the present set of disagreements found in summaries of the field and strategic choices in research should be washed away by data from clinical trials - questions of what works and what doesn't will start to have firm answers.

One of the most commonly asked questions we receive is "How is progress going in aging research?" It is something we are asked so often that we decided to provide the community with a resource that will help them to keep track of progress directly. To that end, today we have launched our new curated database, the Rejuvenation Roadmap, which will be tracking the progress of the many therapies and projects in the rejuvenation biotechnology field. This database aims to give a quick visual summary of the status of each drug or therapy along with some additional information for people interested in learning more about them.

We believe that an informed community is an effective one, and this was one of our motivations for developing this new database. There are many resources for scientists, such as the superb databases of the Human Ageing Genomic Resources maintained by Dr. João Pedro de Magalhães, which are excellent for researchers. However, we noticed that there was no database that tracked the efforts of the many researchers and projects in the field, and while some people do maintain lists, they are often not public facing, easy to access, or user-friendly.

Obviously, this is very much a work in progress, and the current list of therapies is relatively small, but it does give an idea of how it will work, and it is not hard to see how this could grow into a comprehensive resource for the community. The database will continue to grow and be updated as time passes, giving a unique, up-to-date overview of where the science and progress currently is. We hope that you like what we are doing with The Rejuvenation Roadmap and that you will find it useful.

Link: https://www.leafscience.org/the-rejuvenation-roadmap/

The open access paper I'll point out today makes the case for raising the profile of mechanisms other than protein aggregation in neurodegenerative conditions. The authors focus on Alzheimer's disease, characterized by the aggregation of amyloid and tau in the brain, but the argument works just as well for most other forms of age-related dementia. That Alzheimer's disease is the result of multiple mechanisms, each of which contributes to pathology to a similar degree, is one of the better explanations for the ongoing failure of clinical trials that focus solely on amyloid clearance. One only has to look at the sizable fraction of Alzheimer's patients who are also diagnosed with vascular dementia to suspect that something of this nature might be an issue. If there are, for example, five important and somewhat independent mechanisms driving a specific medical condition, then the positive outcomes that result from partially addressing just one of those mechanisms may well get lost in the noise.

This class of issue is in fact endemic in attempts to interfere in the pathology of age-related disease at points that are distant from the root causes. The root causes of aging are limited in number, but spread out into a complex tree of descendant forms of damage and reactions to damage. If the approach to medicine takes the form of pruning the outer branches, as it were, then many of those branches (a) represent smaller individual contributions to dysfunction, and (b) are to some degree independent of one another. But further back towards the roots, an intervention might be much more effective, as it targets a form of damage that drives all of the smaller, downstream branches of damage and dysfunction.

That is the simple idealized model, and it is a very useful guide to thinking about strategy in medical research and development. Nothing is that neat and tidy in reality, sadly. Alzheimer's is a complex mix of what we might think of as fundamental damage, such as protein aggregation, and downstream changes resulting from many other forms of molecular disarray, such as inflammation and general vascular dysfunction. It all interacts. Even the fundamental types of protein aggregation appear to have some form of synergy with one another, with amyloid leading to tau aggregation, and the two being worse in combination than the individual contributions might lead one to expect. The only way to deal with Alzheimer's and other forms of late life dementia may be to fix it all: protein aggregation, inflammation, vascular dysfunction. This is actually a reasonable conclusion for any age-related disease when starting from the consideration of aging as damage accumulation and rejuvenation as damage repair.

Impact of the biological definition of Alzheimer's disease using amyloid, tau and neurodegeneration (ATN): what about the role of vascular changes, inflammation, Lewy body pathology?

The treatment of Alzheimer's disease (AD) is currently symptomatic and based on neurotransmitter manipulation, akin to what has been achieved in Parkinson's disease. Thus acetylcholine activity is being increased by cholinesterase inhibitors, and glutamatergic activity is being dampened by memantine action on NMDA receptors. A modest but clinically detectable response is present in many patients using such drugs alone or in combination. Unfortunately the next generation of drugs acting on AD core pathological factors such as amyloid deposition and phosphorylated tau aggregation has failed so far to delay disease progression, raising the issue of timing of these interventions along the continuum of AD neurodegeneration over time. This review wants to highlight the facts that other pathological factors are at play in AD, and deserve consideration in the full diagnostic assessment of the patients, and for treatment. These factors are vascular changes, Lewy body pathology, and neuroinflammation.

The clinical progression of AD is linked to specific neuropathological features, such as extracellular deposition of Aβ plaques, intracellular inclusions of tau protein in neurofibrillary tangles, and neuronal degeneration. Given that the presence of AD pathophysiology has been found across a broad clinical spectrum including individuals asymptomatic and with mild cognitive symptoms, biomarkers now play an important role in characterizing the trajectory of AD pathophysiology and have been incorporated in the AD diagnostic research criteria. These diagnostic research criteria recognize that the coexistence of abnormal Aβ and tau biomarkers better identify the preclinical and mild cognitive impairment (MCI) individuals who will progress to dementia over relatively short time frames of three to 5 years.

Based on histopathological and genetic evidences, fibrillar Aβ, the main constituent of Aβ plaques, has been postulated as the major driving force leading to AD dementia (Aβ cascade hypothesis). According to this hypothesis, all the resulting pathological processes are due to an imbalance between Aβ production and clearance, which would then potentiate the spread of tauopathy, leading to neurodegeneration and cognitive decline. However, the lack of consistent association between Aβ and clinical progression, and the fact that amyloid pathology has been found in cognitively normal elderly individuals challenge the Aβ hypothesis in its original form.

There is growing evidence that AD often coexists with cerebrovascular disease (CVD). They share many risk factors, leading to additive or synergistic effects on cognitive decline. Most AD patients have structural changes in their cerebral blood vessels. Imaging and pathological studies have demonstrated a high prevalence of arteriolosclerotic small vessel disease (SVD) in AD patients. Post-mortem and imaging studies demonstrate that arteriolar Aβ amyloid angiopathy, a sub-type of SVD, is more common in patients with AD than in elderly controls. The links between vascular factors and AD have been clearly confirmed both clinically and pathologically. However, there is a lack of high-quality therapeutic research to examine the extent to which vascular risk changes alter the course of AD. Further longitudinal mechanisms and therapeutic studies are needed, especially to determine whether the treatment of vascular risk factors can prevent or delay the onset of AD.

Although the accumulation of amyloid protein in plaques and tau protein in neurofibrillary tangles constitutes the core pathological feature of AD, the presence of abnormal brain aggregates of a third proteinopathy has been shown to be very prevalent in moderate and severe AD. Cytoplasmic inclusions of α-synuclein intraneuronally in Lewy bodies have been reported in up to 50% of sporadic AD cases and up to 60% of familial AD cases. Postmortem observations focusing on the influence of Lewy bodies have shown inconsistent results. However, it is worth mention that a well-powered multicenter study with a high sample size has reported that the onset of symptoms and death in AD individuals with Lewy bodies occurs at younger ages as compared to those without Lewy bodies, and that AD individuals with Lewy bodies have higher chance to be APOE ε4 carriers than AD individuals without Lewy bodies.

There is a growing body of evidence supporting neuroinflammation as an important player in the pathogenesis of AD. Neuropathological studies have shown the presence of activated microglia and inflammation related mediators in AD brains. Genetic studies show that several genes that increase the risk of sporadic AD encode factors that regulate microglial clearance of misfolded proteins and inflammatory reaction. Epidemiological studies further suggest that non-steroidal anti-inflammatory drugs (NSAIDS) can defer or prevent the onset of AD. Preclinical and post-mortem studies have consistently found that activated microglia colocalises with Aβ plaque, suggesting a close intimate relationship between microglia activation, Aβ and neuroinflammation. Several mechanisms have been hypothesised, including ongoing formation of Aβ and positive feedback loops between inflammation and amyloid precursor protein (APP) processing which compromise the cessation of neuroinflammation. Continued exposure to Aβ, chemokines, cytokines, and inflammatory mediators leads to microglia being chronically activated at the Aβ plaque site, which further contribute to Aβ production and accumulation in a vicious cycle.

Tauopathies are conditions in which accumulation of tau into neurofibrillary tangles causes dysfunction and cell death in the brain. Alzheimer's disease is the best known of these neurodegenerative conditions. Researchers here demonstrate an approach to reducing both tau aggregation and inflammation in mice, based on inhibition of leukotrienes. Mouse models of neurodegenerative conditions based on protein aggregation are highly artificial, as these forms of aggregation do not naturally occur in that species. This can produce misleading results, or at least results that have to be carefully assessed in the full understanding of the biochemistry involved, and how it might differ from that of humans. That said, the approach here does use an established pharmaceutical compound, meaning that there is a comparatively short path towards validation of the mechanism in human patients.

Researchers have shown, for the first time in an animal model, that tau pathology - the second-most important lesion in the brain in patients with Alzheimer's disease - can be reversed by a drug. The researchers landed on their breakthrough after discovering that inflammatory molecules known as leukotrienes are deregulated in Alzheimer's disease and related dementias. In experiments in animals, they found that the leukotriene pathway plays an especially important role in the later stages of disease. "At the onset of dementia, leukotrienes attempt to protect nerve cells, but over the long term, they cause damage. Having discovered this, we wanted to know whether blocking leukotrienes could reverse the damage, whether we could do something to fix memory and learning impairments in mice having already abundant tau pathology."

To recapitulate the clinical situation of dementia in humans, in which patients are already symptomatic by the time they are diagnosed, researchers used specially engineered tau transgenic mice, which develop tau pathology - characterized by neurofibrillary tangles, disrupted synapses (the junctions between neurons that allow them to communicate with one another), and declines in memory and learning ability - as they age. When the animals were 12 months old, the equivalent of age 60 in humans, they were treated with zileuton, a drug that inhibits leukotriene formation by blocking the 5-lipoxygenase enzyme. After 16 weeks of treatment, animals were administered maze tests to assess their working memory and their spatial learning memory. Compared with untreated animals, tau mice that had received zileuton performed significantly better on the tests. Their superior performance suggested a successful reversal of memory deficiency.

To determine why this happened, the researchers first analyzed leukotriene levels. They found that treated tau mice experienced a 90-percent reduction in leukotrienes compared with untreated mice. In addition, levels of phosphorylated and insoluble tau, the form of the protein that is known to directly damage synapses, were 50 percent lower in treated animals. Microscopic examination revealed vast differences in synaptic integrity between the groups of mice. Whereas untreated animals had severe synaptic deterioration, the synapses of treated tau animals were indistinguishable from those of ordinary mice without the disease. "Inflammation was completely gone from tau mice treated with the drug. The therapy shut down inflammatory processes in the brain, allowing the tau damage to be reversed."

Link: https://www.templehealth.org/News/TempleResearchersSuccessfullyReversebrCognitiveImpairmentsinMicewithDementia

A successful evolutionary theory of aging must explain how a mix of species with shorter and longer life spans can emerge from a common ancestor with a longer life span. Putting theories of programmed aging to one side for a moment, as in that case one only has to argue that a shorter life span is more optimal for the ecological niche in question, antagonistic pleiotropy is the most readily available explanation for shorter lifespans to arise from natural selection. The theory here is that evolution selects for mechanisms and systems that both (a) ensure reproductive success in early life and (b) damage health in later life. There are all too many examples of biological systems that work well in childhood and youth, but inevitably fail because they are not capable of comprehensive repair and therefore accumulate damage, or because they are otherwise limited in some important capacity, and that limit will eventually be reached.

Can the evolution of shorter life spans appear in models without employing the assumption of antagonistic pleiotropy, and without invoking programmed aging, however? The authors of this paper argue that it can, and arises as an inevitable consequence of the dispersion of a population over the landscape. Interestingly, the details of the explanation touch on some of the same group dynamics - such as resistance to population collapse due to resource contention - that at least one programmed aging theorist employs to argue that aging must be selected. This is far from the only line of thought to approach group selection, which is still very much out of favor, while not being group selection.

With only a few exceptions, organisms deteriorate as they age and consequently die, but large variation in longevity still exists among species. A comparative study of 107 bird species found that fatty acid characteristics of cellular membranes have a prominent causative role in the aging process: species with longer maximum lifespans have higher proportions of long and monounsaturated fatty acids in their membranes. The question then arises as to why high proportions of long and monounsaturated fatty acids have not evolved in all species, given that this would maximize their lifespan and should therefore be promoted by natural selection, as aging is clearly detrimental for the fitness of individual organisms. In other words, why has a variability of lifespans evolved among species?

Evolutionary theory is still based on the antagonistic pleiotropy hypothesis: high mortality rates promote rapid reproduction, and direct selection for rapid reproduction leads to indirect selection for shorter lifespan. While this hypothesis has sometimes been supported by data from wild populations of animals, other empirical studies have frequently called into question the claimed role of extrinsic mortality in promoting senescence and the evolution of short lifespan.

Maybe as a response to this incapacity of the antagonistic pleiotropy hypothesis to provide a general explanation for the evolution of lifespan variability, some theoretical models have appeared in the last years based on the idea of programmed aging, stating that organisms have a genetically fixed senescence rate that is favored by natural selection because senescence may be adaptive in certain circumstances. These models have the important limitation of dealing with group selection, as they assume that senescence benefits lineages by avoiding overpopulation and associated problems such as resource depletion and epidemics, and thus lack an evolutionary logic. In fact, no genes exist that promote aging.

Here we propose that the evolution of lifespan is based on the ecological process of dispersal and does not depend on extrinsic mortality nor assume any adaptive benefit of aging, thus avoiding the above-mentioned limitations of group selection. Dispersal has previously been proposed in a theoretical model as a determinant of aging assuming that shorter dispersal distances create more competition for resources and shorter lifespans are then favored under such conditions because it would be beneficial for the lineages, therefore carrying the problems of group selection and programmed aging. Here we first provide theoretical arguments by which a similar dependence of lifespan evolution on dispersal distance can be achieved with basic concepts of population dynamics without the need of assuming adaptive group benefits or a genetic aging clock.

Our model considers that limited dispersal can generate, through reduced gene flow, spatial segregation of individual organisms according to lifespan. Individuals from subpopulations with shorter lifespan could thus resist collapse in a growing population better than individuals from subpopulations with longer lifespan, hence reducing lifespan variability within species. As species that disperse less may form more homogeneous subpopulations regarding lifespan, this may lead to a greater capacity to maximize lifespan that generates viable subpopulations, therefore creating negative associations between dispersal capacity and lifespan across species.

Link: https://doi.org/10.1002/ece3.4073

Today I'll point out a few recent examples of research into Alzheimer's disease; they are representative of present shifts in emphasis taking place in the field. There is a great deal of reexamination of existing mechanisms, alongside a search for new mechanisms. This is prompted by the continued failure to obtain meaningful progress towards patient improvement via clearance of amyloid, which some are interpreting as a need to look elsewhere for a viable basis for therapy. I believe it probably has more to do with the condition arising from multiple processes that have similarly sized contributions to cognitive decline: amyloid, tau, immune dysfunction, and vascular aging. Partially address one, and it may be hard to prove that a useful difference was made in patients because the other mechanisms are still present, still causing harm.

The Alzheimer's-related portion of the broader field of aging research represents a sizable fraction of the output of the medical life science community these days. That is because much of the budget of the NIA has for some time been directed towards the study of Alzheimer's disease, and that in turn influences the strategy taken by larger private funding sources and research programs. The grant-seeking portion of the scientific world, which is to say most of it, sedately follows the availability of funds in much the same way as flowers follow the sun. Over time, the funding landscape shapes the endeavor of science just as much as the state of the science shapes availability of funding.

It has often appeared to me somewhat arbitrary as to which aspects of aging are considered an emergency, a priority. The modern public consensus on the need for a massive cancer research institution and a timeline for bringing cancer under medical control is in fact quite modern - it didn't exist much prior to the 1930s. Presentation of the various forms of dementia as a major public concern is a much more recent development. Yet these issues have long existed. We might view it as progress that at least a few pieces of degenerative aging have been pushed over time from the "way things are, cannot be changed" bucket into the "addressable, must fix" bucket. But most people have yet to take the necessary next step, which is to consider aging as a whole a medical condition with clear root causes, a state of ill health that the research community can work towards treating. The dominant conceptual approach of breaking down aging into named diseases has obscured the most important possibility, that aging as a whole can be repaired and reversed.

Research links Tau aggregates, cell death in Alzheimer's

Although scientists have studied for years what happens when tau forms aggregates inside neurons, it still is not clear why brain cells ultimately die. One thing that scientists have noticed is that neurons affected by tau accumulation also appear to have genomic instability. Previous studies of brain tissues from patients with other neurologic diseases and of animal models have suggested that the neurons not only present with genomic instability, but also with activation of transposable elements.

"Transposable elements are short pieces of DNA that do not seem to contribute to the production of proteins that make cells function. They behave in a way similar to viruses; they can make copies of themselves that are inserted within the genome and this can create mutations that lead to disease. Although most transposable elements are dormant or dysfunctional, some may become active in human brains late in life or in disease. That's what led us to look specifically at Alzheimer's disease and the possible association between tau accumulation and activated transposable elements."

The researchers began their investigations by studying more than 600 human brains. One of the evaluations is the amount of tau accumulation across many brain regions. In addition, researchers comprehensively profiled gene expression in the same brains. The researchers found a strong link between the amount of tau accumulation in neurons and detectable activity of transposable elements. Other research has shown that tau may disrupt the tightly packed architecture of the genome. It is believed that tightly packed DNA limits gene activation, while opening up the DNA may promote it. Keeping the DNA tightly packed may be an important mechanism to suppress the activity of transposable elements that lead to disease.

Brain cholesterol associated with increased risk of Alzheimer's disease

While the link between amyloid-beta and Alzheimer's disease is well-established, what has baffled researchers to date is how amyloid-beta starts to aggregate in the brain, as it is typically present at very low levels. "The levels of amyloid-beta normally found in the brain are about a thousand times lower than we require to observe it aggregating in the laboratory - so what happens in the brain to make it aggregate?" The researchers found in in vitro studies that the presence of cholesterol in cell membranes can act as a trigger for the aggregation of amyloid-beta.

Since amyloid-beta is normally present in such small quantities in the brain, the molecules don't normally find each other and stick together. Amyloid-beta does attach itself to lipid molecules, however, which are sticky and insoluble. In the case of Alzheimer's disease, the amyloid-beta molecules stick to the lipid cell membranes that contain cholesterol. Once stuck close together on these cell membranes, the amyloid-beta molecules have a greater chance to come into contact with each other and start to aggregate - in fact, the researchers found that cholesterol speeds up the aggregation of amyloid-beta by a factor of 20. "The question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol's role in Alzheimer's disease through the regulation of its interaction with amyloid-beta. We're not saying that cholesterol is the only trigger for the aggregation process, but it's certainly one of them."

Since it is insoluble, while travelling towards its destination in lipid membranes, cholesterol is never left around by itself, either in the blood or the brain: it has to be carried around by certain dedicated proteins, such as ApoE, a mutation of which has already been identified as a major risk factor for Alzheimer's disease. As we age, these protein carriers, as well as other proteins that control the balance, or homeostasis, of cholesterol in the brain become less effective. In turn, the homeostasis of amyloid-beta and hundreds of other proteins in the brain is broken. By targeting the newly-identified link between amyloid-beta and cholesterol, it could be possible to design therapeutics which maintain cholesterol homeostasis, and consequently amyloid-beta homeostasis, in the brain.

As mystery deepens over the cause of Alzheimer's, a lab seeks new answers

For more than 20 years, much of the leading research on Alzheimer's disease has been guided by the "amyloid hypothesis." But with a series of failed clinical trials raising questions about this premise, some researchers are looking for deeper explanations into the causes of Alzheimer's and how this debilitating condition can be treated. Among these investigators are researchers focused on axonal transport - the complicated, internal highway system that conveys precious, life-giving materials from one part of a nerve cell to another. Breakdowns in this transport system can lead to "traffic jams," and some scientists hypothesize that such blockages precede the formation of plaques in neurological diseases like Alzheimer's.

Using the neurons of fruit fly larvae, researchers have been investigating the role of presenilin - another Alzheimer's-linked protein - in axonal transport for several years. "We are looking at processes that occur before cell death, before you start to see plaques in the brain. A lot of the treatments being developed for Alzheimer's are targeting beta-amyloid, but maybe we should be targeting processes that happen earlier on, before plaques are formed."

The researchers' latest study provides details on how presenilin interacts with GSK-3β, and reports that a specific molecular structure within presenilin - a loop region - is necessary for proper traffic control. Presenilin has an important role in Alzheimer's: The protein aids in the production of beta-amyloid, which, when overproduced, causes plaques to form in patients' brains. But the latest work shows that presenilin may also have another role - this one positive - in regulating the flow of traffic within brain cells and preventing blockages that over time can lead to death of the cell and disease. "What does this protein normally do? As we learn more about presenilin, it's possible that our research will result in new, more targeted opportunities for treating or preventing Alzheimer's disease."

Ending Aging is an important book, a concise explanation of the SENS approach to the development of rejuvenation therapies. It is aimed at laypeople, but with enough depth for scientists to use it as a starting point for their own further reading as well. It covers the extensive evidence gathered by the research community over the decades to support the concept that aging is caused by the accumulation of a few classes of molecular damage to cells and tissues. It outlines proposed therapies that could, if fully developed, repair or work around that damage in order to remove its contribution to aging.

Since its publication in English, volunteers have translated Ending Aging into a number of other languages, and a Portuguese edition is now the latest to be published. Scientific translation is particularly challenging, and people who have both the requisite scientific knowledge and are multilingual do not exist in great numbers - so many thanks to the team who persevered to carry out this work.

Some months ago, we announced an initiative by Nicolas Chernavsky and Nina Torres Zanvettor to translate Ending Aging into Portuguese. As of today, the translated book is available in an electronic format on Amazon and is ready to reach millions more readers.

A classic book about the possibility of repairing the damage of aging is now available in the native tongue of hundreds of millions more people. The book Ending Aging, by the British biogerontologist Aubrey de Grey and Michael Rae, has been published in Portuguese on June 5th. The book presents a series of possible strategies to repair the cellular and molecular damage that occurs in the human body throughout life. With these strategies, age-related diseases, such as Alzheimer's disease, Parkinson's disease, cancer, cardiovascular diseases, and diabetes, could be avoided.

Since it was published in 2007 in its original English version, the book has become a classic of biogerontology and has already been translated into German, Spanish, Russian and Italian. With the additional 250 million people that speak Portuguese as their native tongue, the number of people that can access the book's content more easily continues to rise.

Link: https://www.leafscience.org/portuguese-edition-of-ending-aging-released-as-an-ebook/

How greatly does the onset of dementia depend on the age-related decline of the immune system? The most evident contributions to neurodegeneration are vascular aging and the accumulation of protein aggregates such as amyloid-β, tau, and α-synuclein. These are only indirectly connected to the aging of the immune system, in the sense that immune function influences in some way near all aspects of tissue function, and its progressive failure tends to make everything at least a little less functional. Chronic inflammation appears to play a direct and important role in the progression of most neurodegenerative conditions, however, and there at least we can point to the immune system as a primary issue.

The immune system is responsible for defending against pathogens such as bacteria, viruses, and fungi to eliminate broken and harmful cells, like senescent cells and toxic or allergenic substances. Immunosenescence is a term that describes a different state of the immune system in aged people, in association with detrimental clinical outcome, due to reduced ability to respond to new antigens. Although immunosenescence is a phenomenon present in the majority of individuals, factors like genetic, environment, lifestyle, and nutrition are responsible for their heterogeneity among individuals and cause a higher susceptibility to develop infections and progression of disease pathology.

The age-related dysregulation of immune responses impacts the resistance to infections, diminishes responses to vaccination, increases the susceptibility to autoimmunity and cancer, and promotes the development of an inflammatory phenotype. Researchers have introduced the term "inflammaging", related to the immunosenescence, to describe a low-grade, asymptomatic, chronic, and systemic inflammation, characterized by increased levels of circulating cytokines and other proinflammatory markers. The relationship between aging and chronic disorders, including atherosclerosis, dementia, neurodegeneration, and many others, has its bases in senescent remodeling of immune system.

The increased proinflammatory environment could be the major contributing factor to the development of aging-associated diseases. Given the well-established communication between the immune system and brain, the age-related immune dysregulation may bring neurodegeneration. Several studies have demonstrated that immunosenescence and inflammaging can induce an overactivation of central nervous system (CNS) immune cells, promoting neuroinflammation. In Alzheimer's disease patients, the microglial aging and dysfunction lead to amyloid-β accumulation and loss of peripheral immune response, contributing to disease pathogenesis. Furthermore, in Parkinson's disease, the interaction between aging and over time decreased immune response suggests a disease predisposition for neurodegeneration.

Recently, several studies have reported the relationship between delayed immunological aging and reduced expansion of senescent late-stage differentiated T cells and active lifestyle and has been suggested that aerobic exercise training might attenuate cognitive impairment and reduce dementia risk. Although it is unknown whether effects of exercise are direct, such as a targeted removal of dysfunctional T cells, or indirect, such as lower inflammatory activity, it may be hypothesized that these changes can provide benefits for health, including mitigate cognitive impairment.

New strategies to combat immunosenescence and neurodegeneration are focused on cellular and genetic therapies, such as genetic reprogramming and bone marrow transplantation, but cell reprogramming has still poor efficiency, and clinical translation shows several ethical and safety questions that may be answered. Thus, a better understanding of immunosenescence mechanisms will be necessary to develop new, unconventional, or pharmacological therapy strategies, for peripheral and CNS immunosenescence delay. Additional studies are required to determine the effectiveness and optimal conditions to improve the function of the aged immune system and undertake the challenges of immunosenescence.

Link: https://doi.org/10.1155/2018/6039171

In the SENS rejuvenation research view of atherosclerosis, a primary cause is the presence of oxidized lipids in the bloodstream. Rising levels of oxidative stress with aging, with mitochondrial dysfunction as a primary cause, means an increasing number of oxidized lipid molecules. Atherosclerosis begins when these lipids irritate the blood vessel walls, attracting macrophage cells to clean up the problem. The normal process involves macrophages ingesting the problem lipids and either breaking them down or handing them off to high-density lipoprotein (HDL) particles to be carried to the liver where they can be dealt with. Unfortunately, some species of oxidized lipid cannot be processed well by macrophages, and the cells become overwhelmed. They either die or become inflammatory foam cells, making the area of damage worse. The fatty plaques of atherosclerosis that narrow and weaken blood vessels are formed of dead macrophages and the lipids that they should have removed.

The SENS approach is to find ways to break down the problem oxidized lipids, remove them before they can cause harm to the macrophages that are critical to maintenance of blood vessel walls. Some progress in this LysoSENS program for atherosclerosis has been accomplished, mostly focused on 7-ketocholesterol, a particularly harmful species of oxidized lipid. Other groups are starting to pay attention to this line of research, which is a good thing. In the study reported here, scientists used antibodies to thin out a class of oxidized lipid from the bloodstream, and demonstrated that this slows the pace at which atherosclerosis progresses in a mouse model of the condition. This is important evidence that strongly supports the SENS position.

In atherosclerosis, lipids such as cholesterol move in a loop: from the liver to LDL particles, then into atherosclerotic lesions, then taken up by macrophages and passed off to HDL particles, then finally back to the liver. All of the available anti-atherosclerosis technologies interfere in the front half of that loop, the movement of lipids through the bloodstream in LDL particles. They globally reduce cholesterol levels, and that somewhat slows the advance of atherosclerosis. It doesn't do it well, however. Even extremely low cholesterol levels, such as those produced by PCSK9 inhibition, don't significantly reduce existing atherosclerotic plaque - they allow a little reduction, but that is about it. Thus other strategies are needed, and the work here is good evidence for approaches that in some way protect macrophages from oxidized lipids, a methodology that should allow those cells to better clear existing plaque.

Antibody Blocks Inflammation, Protects Mice from Hardened Arteries and Liver Disease

Some phospholipids - the molecules that make up cell membranes - are prone to modification by reactive oxygen species, forming OxPL. This event is particularly common in inflammatory conditions such as atherosclerosis, in which artery-blocking plaques form. Prior to this study, researchers were unable to control phospholipid oxidation in a way that would allow them to study its role in inflammation and atherosclerosis.

Researchers engineered mice with two special attributes: 1) they have a gene mutation that makes them a good model for atherosclerosis and 2) they generate a piece of an antibody called E06 that's just enough to bind OxPL and prevent their ability to cause inflammation in immune cells, but not enough to cause inflammation on its own. They fed the mice a high-fat diet.

Here's what happened: Compared to control mice, the mice with E06 antibodies had 28 to 57 percent less atherosclerosis, even after one year and despite having high levels of cholesterol. The antibody also decreased aortic valve calcification (hardening and narrowing of the aortic valves), hepatic steatosis (fatty liver disease) and liver inflammation. E06 antibody-producing mice had 32 percent less serum amyloid A, a marker of systemic inflammation. The E06 antibody also prolonged the life of the mice. After 15 months, all of the E06 antibody-producing mice were alive, compared to 54 percent of the control mice.

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes. Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL.

Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling.

Compared to Ldlr-/- mice, Ldlr-/-E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo.

Copy number variation is a type of genetic difference between individuals in which a section of DNA, usually one that is already duplicated multiple times in most people, has a different number of repeats. Researchers have studied copy number variation and relationships with longevity, both in general, in the sense of looking for correlations, and in specific, looking at copy number variations in a single gene. As is the case for most genetic correlations in the matter of human longevity, the vast majority of results suggest only tiny effects on mortality and fail to reproduce between study populations. That tells us that most naturally occurring individual genetic contributions to longevity are both small and highly conditional. The study here is representative of the type, and thus I would say that there is no great expectation that the results will be replicated in other data sets.

Human lifespan has long been observed as a complex trait with approximately 25% genetic contributions. To date, only very few genes have been shown consistently associated with it. Recent studies reported that copy number variation (CNV) may directly contribute to human lifespan. CNV is a general term for all the chromosomal rearrangements, such as deletions, duplications. CNVs can change gene structures, thus affecting gene expression and phenotypes. In human, CNVs have been implicated in numerous diseases, such as autism and diabetes. CNVs also contribute significantly to the genome instability of cancer cells.

A few studies have investigated the association of CNV with human lifespan using genome-wide approaches. One reported this association in 11442 human samples representing two cohorts. They found large deletions in 11p15.5 among the oldest people. Another study uncovered a deletion in the CNTNAP4 gene in a female group of 80 years of age, but not the male group. Recently, a study in Caucasians revealed an insertion allele of the CNTNAP2 gene in esv11910 CNV of males, but not females.

In this study, we investigated the association of CNVs and longevity in Han Chinese by genotyping 4007 individuals obtained from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) database. We have identified a few CNVs, and most of them were new. These CNV regions encode nineteen known genes, and some of which have been shown to affect aging-related phenotypes such as the shortening of telomere length (ZNF208), the risk of cancer (FOXA1, LAMA5, ZNF716), and vascular and immune-related diseases (ARHGEF10, TOR2A, SH2D3C). In addition, we found several pathways enriched in long-lived genomes, including FOXA1 and FOXA transcription factor networks involved in regulating aging or age-dependent diseases such as cancer.

Link: https://doi.org/10.18632/aging.101461

Raised blood pressure, hypertension, is an important mechanism involved in the transmission of age-related damage from low-level biochemical changes to high level structural damage and organ failure. The importance of blood pressure in this context is why significant reductions in mortality rate can be achieved by means of lowering blood pressure, by overriding cellular reactions or cell signaling, that fail to address any of the underlying root causes of hypertension. These root causes are largely the set of biochemical changes that act to stiffen blood vessels, as hypertension appears to be near entirely a consequence of loss of elasticity in the vascular system. They include cross-linking, cellular senescence, and a range of less well understood shifts in the capabilities and behavior of vascular smooth muscle cells. If reductions in blood pressure now can achieve useful results, imagine the far greater benefits that will result once rejuvenation therapies exist capable of repairing the low-level damage that causes vascular stiffness. Not only hypertension will be addressed, but also all of the other issues that this damage in cells and tissues gives rise to.

Treating high blood pressure in stroke survivors more aggressively, could cut deaths by one-third, according to new research. "The potential to reduce mortality and recurrent stroke is immense, because more than half of all strokes are attributable to uncontrolled high blood pressure." In the AHA/ACC guideline for hypertension, released in 2017, the threshold for stage 1 hypertension, or high blood pressure was changed to at or above 130 mmHg for the top number or 80 mmHg for the bottom number. The previous threshold for high blood pressure was, at or above 140/90 mmHg.

Overall, while many more people will be diagnosed with hypertension under the new guideline, there will be only a small increase in the percentage of people who require medication. However, blood pressure-lowering medications are recommended for all stroke survivors with blood pressures of 130/80 mmHg or higher, and additional drugs if needed to reduce blood pressure below that threshold.

In the new study, researchers used data from the National Health and Nutrition Examination Surveys to estimate the nationwide impact of applying that approach. The surveys, conducted between 2003 and 2014, included blood pressure measurement and asked participants about their stroke history and blood pressure treatment. If clinicians fully shift from the previous guidelines to the new ones, the researchers calculated the impact on stroke would be: (a) a 66.7 percent increase in the proportion of stroke survivors diagnosed with hypertension and recommended for pressure-lowering medication (from 29.9 percent to 49.8 percent); (2) a 53.9 percent increase in the proportion of stroke survivors already taking pressure-lowering drugs who will be prescribed additional medication to reach their target blood pressure (from 36.3 percent to 56 percent); and (3) a 32.7 percent reduction in deaths, based on the difference in death rates in stroke survivors above and below the 130/80 mmHg target blood pressure (8.3 percent vs. 5.6 percent).

Link: https://newsroom.heart.org/news/stroke-survivors-could-gain-the-most-from-new-blood-pressure-guidelines

It was only partially in jest that I recently noted Unity Biotechnology as a financial institution with a sideline in rejuvenation research, specifically the targeted destruction of senescent cells. The principals have raised a truly enormous amount of funding in the past year and a half, and recently filed for IPO. They have not yet presented even preliminary human data. Typically the ordering of these matters tends to be at least a little different; there are some raised eyebrows in the community. But if the Unity Biotechnology founders can raise the funds and use them well to advance the state of the art, then more power to them. From their SEC filings we know a little more than we did as to the specific classes of pharmaceutical developed at the company, or at least those they are prepared to talk about today. One is the line of development that started with Bcl-2 inhibitors such as navitoclax, and the other is a more novel approach to senescent cells, one that is as much about suppressing their harmful signaling as it is about destroying the cells.

In using pharmacological methods, Unity Biotechnology has an approach to senescent cell clearance that is objectively worse than, say, the programmable gene therapy pioneered by Oisin Biotechnologies. Pharmaceutical approaches are slow and expensive to tinker into better shape when they turn out to be overly tissue specific or have problematic side-effects. Nonetheless, it is entirely possible to build an enormous business on the back of a first generation senolytic pharmaceutical, because if it clears even 25% of senescent cells from just a few tissue types it will still be far more useful than any other class of medication for inflammatory, fibrotic, and other age-related diseases of those tissues. But the competition in the form of Oisin Biotechnologies will arrive in the clinic a couple of years later with a form of therapy that can destroy all senescent cells in all tissues, and that can be adapted quickly and at low cost.

The Unity folk know this, and the potential market is so very large (every human being much over the age of 40) that I think it probably won't dent their success all that much. There will be many enormous companies and many senolytic therapies coexisting in that market. It is plausible that the more interesting challenge for the Unity Biotechnology staff is to create a therapy that is meaningfully better than the dasatinib and quercetin combination, better enough to justify the very large cost multiple that the company will have to charge in order to keep their investors satisfied. Dasatinib is out of patent protection, its pharmacology is very well characterized in humans, and it runs to a $100-200 cost for a single dose that would be usefully taken perhaps once a year at most. Should the human studies, such as those running at Betterhumans, show it to be effective, that may cause issues for Unity or any other small molecule development concern. None of the other candidate drugs have yet done much better than dasatinib and quercetin in animal studies. The existence of dasatinib will drag down the prices it is possible to charge for anything that performs in the same class - which so far is everything, to a first approximation.

A Biotech Entrepreneur Aims To Help Us Stay Young While Growing Old

The idea behind Unity - preventing aging - sounds crazy, but it's backed by dozens of scientific papers. There are aging cells, called senescent cells, that build up throughout the body and contribute to what we think of as old age-things like achy joints, waning vision, even perhaps Alzheimer's. Kill those senescent cells with drugs, Nathaniel David reasons, and people might be able to grow old without becoming infirm. "Like, how awesome would it be? The problem is you have to take the first baby step to demonstrate it's possible. That's what chapter one is: demonstrate in a human being that the elimination of senescent cells takes a heretofore inescapable aspect of aging and can either halt it or reverse it." Unity's chief executive and chairman, Keith Leonard, 56, interrupts. "Just that. It's easier to talk to the FDA about treatment of a disease once it's diagnosed than it is to work really early and prevent disease. But prevention is what we'd love to get to."

It's an amazing goal, backed by great science, not to mention $222 million in venture capital and $85 million raised from a May initial public offering, which valued Unity at $700 million, flat with its last fundraising. When a medicine is just beginning human tests, the odds it will make it to market are 10%. But David's career has turned into a blueprint for success in biotech, transforming ideas from university laboratories into viable companies, investment gains and, maybe, drugs. David's five companies have raised $1.5 billion and made investors close to $2 billion without ever actually turning a profit. "He's probably the best person in the world at finding great academic science and shaping it into a fundable story and a sellable business plan," says Kristina Burow, managing director at Arch Venture Partners. She has known David since he was in graduate school and has backed four of his startups.

The idea for Unity arrived in David's email inbox in 2011, from multiple senders at the same time. Jan M. van Deursen had genetically engineered mice so that many types of senescent cells would die. The results of this experiment and of others that followed were striking. Van Deursen introduced David to Judith Campisi, at San Francisco's Buck Institute, who had helped establish the senescent-cell field. Arch founded Unity in 2011, with Van Deursen and Campisi as cofounders. For five years the company didn't even have offices; all the work was done at the scientists' labs.

There's a good reason for the skepticism, no matter how cool Unity's science is: Investors have been hoodwinked by antiaging science before. In 2007, a company called Sirtris went public based on the hype around antiaging compounds related to red wine. GlaxoSmithKline bought Sirtris for $720 million in 2008, but it never resulted in any drugs and was shut down in 2013. Unity needs to show that a medicine can have a clear effect in humans. Its first attempt, UBX0101, will target arthritis. Now, in the first human test, it will be injected into the knees of 30 patients, who will fill out surveys about how much pain they feel, have fluid removed from their knees and undergo MRI scans. They'll be compared with ten patients who will get a placebo injection. Any signs that the drug is making patients better will be seen as a reason to move into further studies. Unity expects to enter two more drugs into human studies by the end of next year. Candidate diseases include glaucoma, where killing senescent cells seems to lower the pressure that builds up in the eye, and lung diseases, where it may coax lung cells to stop making scarred, fibrous tissue.

Unity has raised so much money precisely because its executives know it may take multiple tries to find a medicine. It's not known what the risks of killing senescent cells are; it's possible they could include, for instance, slow wound healing. There's no way to know until human tests begin.

The medical nanorobots of decades to come will be a close fusion between natural and artificial molecular machinery. They will exist because it is possible to build worker devices that are more effective and efficient at a given task that evolved cells and cellular structures. Today, however, the state of the art involves melding simple cell structures with nanoparticles or other molecular machines. A great deal of innovation and experimentation is taking place, but it isn't always clear which of these many projects will make the leap into commercial development, versus serving as an inspiration or bridge to later efforts in the lab. In many ways this is still the barnstorming era of biotechnology, in which we should expect many strange feats, works of art, and dead ends along the way to the standard tools of the 2040s and beyond.

Scientists have developed tiny ultrasound-powered robots that can swim through blood, removing harmful bacteria along with the toxins they produce. These proof-of-concept nanorobots could one day offer a safe and efficient way to detoxify and decontaminate biological fluids. Researchers built the nanorobots by coating gold nanowires with a hybrid of platelet and red blood cell membranes.

This hybrid cell membrane coating allows the nanorobots to perform the tasks of two different cells at once - platelets, which bind pathogens like MRSA bacteria (an antibiotic-resistant strain of Staphylococcus aureus), and red blood cells, which absorb and neutralize the toxins produced by these bacteria. The gold body of the nanorobots responds to ultrasound, which gives them the ability to swim around rapidly without chemical fuel. This mobility helps the nanorobots efficiently mix with their targets (bacteria and toxins) in blood and speed up detoxification.

Researchers created the hybrid coating by first separating entire membranes from platelets and red blood cells. They then applied high-frequency sound waves to fuse the membranes together. Since the membranes were taken from actual cells, they contain all their original cell surface protein functions. To make the nanorobots, researchers coated the hybrid membranes onto gold nanowires using specific surface chemistry. The nanorobots are about 25 times smaller than the width of a human hair. They can travel up to 35 micrometers per second in blood when powered by ultrasound. In tests, researchers used the nanorobots to treat blood samples contaminated with MRSA and their toxins. After five minutes, these blood samples had three times less bacteria and toxins than untreated samples.

Link: http://jacobsschool.ucsd.edu/news/news_releases/release.sfe?id=2550

Alzheimer's disease might be argued to be a lifestyle condition, but it is not as much of a lifestyle condition as type 2 diabetes - it is not as reliably connected to lifestyle choices. Not everyone who lets themselves go, becoming fat and sedentary, winds up with a diagnosis of Alzheimer's disease, despite it being clear from the data and what is known of the mechanisms involved that both of those environmental circumstances are contributing risk factors. So why do only some people with the risk factors suffer Alzheimer's disease? Why do some people without the risk factors suffer from Alzheimer's disease? Is there anything useful to be learned at this stage from comparing the biochemistry of various groups with and without the condition?

These are questions very focused on how exactly the condition progresses, which stands a little in opposition to the strategy of attacking all of the known root causes of disease - in other words striving to remove all of the accumulated protein aggregates thought to cause the condition. In the case of Alzheimer's disease, that strategy hasn't been doing so well to date; the amyloid clearance field is a graveyard of failed clinical trials. Does this mean there is vital information yet to be discovered, or does it mean that the research community hasn't been clearing enough molecular waste, and both tau and amyloid must be reduced in the aging brain in order to see benefits? Arguments can be made either way.

The two primary histopathological changes to the brain due to Alzheimer's disease (AD) are the deposition of amyloid and tau. These two AD-related brain changes are the primary underlying causes of neurodegeneration and cognitive dysfunction which ultimately leads to dementia. As human longevity increases, and AD dementia increasingly becomes a major societal burden, finding pathways that lead to brain aging without AD pathologies (ADP) are critical.

Currently, much of the research has been focused on resilience or cognitive reserve, wherein the focus has been on discovering how and why individuals are able to remain clinically unimpaired or cognitively normal despite ADP. However, it is important to investigate, using surrogates of amyloid and tau pathologies via cerebrospinal fluid (CSF) and positron emission tomography (PET), why majority of individuals develop ADP as they age and how some oldest old individuals are able to age without significant ADP. The latter individuals are called "exceptional agers" without ADP.

There are three testable hypotheses. First, discovering and quantifying links between risk factors and early ADP changes in midlife using longitudinal biomarker studies will be fundamental to understanding why the majority of individuals deviate from normal aging to the AD pathway. Second, a risk factor may have quantifiably greater impact as a trigger and/or accelerator on a specific component of the biomarker cascade (amyloid, tau, neurodegeneration). Finally, and most importantly, while each risk factor may have a different mechanism of action on AD biomarkers, "exceptional aging" and protection against AD dementia will come from "net sum" protection against all components of the biomarker cascade.

While important strides have been made in identifying risk factors for AD dementia incidence, further efforts are needed to translate these into effective preventive strategies. Using biomarker studies for understanding the mechanism of action, effect size estimation, selection of appropriate end-points, and better subject recruitment based on subpopulation effects are fundamental for better design and success of prevention trials.

Link: https://doi.org/10.1186/s13195-018-0373-z

As I'm sure you are all aware, we humans do not exhibit a uniform pace of aging. Setting aside mortality caused by anything other than aging, the vast majority of recorded life spans at the present time fall within a range of three decades, 65-95. A comparatively tiny number of exceptional outliers age to death at younger or older ages. Some of this variation can be attributed to secondary aging, which is to say the way in which circumstances and lifestyle choices interact with the biology of aging. Visceral fat tissue and smoking cause greater chronic inflammation, accelerating all of the common age-related conditions, for example. On the other hand, calorie restriction modestly slows most aspects of aging. The rest is due to differences in primary aging, meaning intrinsic differences in genetics that lead to differences in the operation of cellular mechanisms that occur more independently of lifestyle and environment. Some human mutants have lower blood cholesterol, and thus slower onset of atherosclerosis, for example.

Most accelerated aging conditions take the form of a mutational malfunction in DNA repair - cells become damaged and dysfunctional much more rapidly than is the case in normal individuals. The present consensus, not unchallenged, is that stochastic mutation has a meaningful role in aging. This may be a matter of problematic acquired mutations in stem cells expanding widely throughout a tissue as a result of being inherited by daughter cells. If stochastic mutation is important in aging, then it may be reasonable to argue a role for variations in DNA repair mechanisms in the natural differences observed in human life span. Indeed, some past studies have done just that. It is very challenging to make a case for how large any given contribution to aging and longevity might be, however. Short of accurately and narrowly removing a specific contribution and watching to see what happens as a result, informed speculation is about the best that can be achieved.

Personally, I'm not convinced that there is all that much gold to be found in mining the causes of natural variation in human life span. Near all evidence to date (with one or two spectacular exceptions) suggests that individual genetic variations have at best modest effects, and more usually tiny and highly conditional effects. Variations correlated with longevity in one study usually don't appear in another, and "correlated" in this context might mean that it raises the odds of reaching the age of 100, while being so corroded by aging to a ghost of what you once were, to be 2% rather than 1%. This doesn't seem like a goal worth chasing when there are better options available. Instead of searching for ways to alter cellular metabolism in ways that would make more people live and age like today's centenarians, the research community should be finding ways to reverse the mechanisms of aging - to repair the damage, to restore the normal operation of youthful metabolism.

Genomic Approach to Understand the Association of DNA Repair with Longevity and Healthy Aging Using Genomic Databases of Oldest-Old Population

Longevity is usually defined as living until life expectancy that is typically over 85 years old. Exceptional longevity such as centenarians is considered when one is more than 95 years old with a healthy life. Several researchers have emphasized the importance of in-depth studies on longevity to cope with an aging society because such studies could suggest various biomedical clues for living a long and healthy life. Oldest-old individuals, often centenarians, represent an adequate model to investigate the complex phenotype of healthy longevity. Among enormous population-based studies on centenarians, one major focus is on people with exceptionally long lives without functional impairment. Several landmark studies on healthy centenarians have found that the progression of major diseases such as cancer, cardiovascular disease, and stroke is delayed in the oldest group compared to that in the other younger or same-aged control groups, suggesting a substantial relationship between healthspan and longevity.

Although successful longevity traits are modulated by various factors, such as environmental, behavioral, and/or endogenous causes, genetic factor might be a major factor that contributes to healthy aging. Within the past few decades, many researchers have tried to identify longevity-associated genes using diverse species, ranging from less complex organisms to higher organisms. With development in genomic technology, genetic factors associated with longevity have been suggested in human population studies and human genome-wide association studies. It has been found that variants of APOE and FOXO3A are highly associated with longevity. This finding has been consistently replicated in many different population-based studies. Despite the complexity of healthy longevity in human due to various influences, genetic factors are thought to be exceedingly important to understand the genetic basis of longevity.

Accumulation of DNA damage is associated with functional decline in the aging process. Thus, maintenance of genomic integrity might be a crucial factor for healthy life and longevity. Genome instability generally increases with age. DNA repair machineries control genome stability. Previous studies on centenarians have shown that oldest-old population have enhanced DNA repair activity with significant lower frequency in genomic and cellular damage compared to their younger counterparts. Thus, DNA repair plays an important role in understanding exceptionally long-lived individuals.

In this review, we focus on major DNA repair machineries associated with longevity. We also explored longevity-associated population studies using genome-wide approaches. With brief introductions of genomic databases in aging and longevity field, ample genomic resources of normal long-lived human population were utilized for DNA repair-focused approach. Herein, we suggest a new aspect of longevity study to investigate the complex interplay between DNA repair and longevity by processing human genetic variations based on previous studies, providing a brief interpretation of their molecular networks.

It seems that the research community has made some progress in recent years towards methods of rebuilding tooth enamel. This would in principle allow for reconstruction rather than replacement of damaged teeth, and let dental caries be regrown rather than drilled and patched. I noted one possible approach earlier this year, and the work here is the basis for another. These are fairly low-level methodologies, depending on the fine molecular details of mineralization in living organisms. The open access paper makes for interesting reading, albeit rather heavy going for anyone not up to speed on the chemistry involved. It remains to be seen how rapidly this approach can move towards the clinic.

Enamel, located on the outer part of our teeth, is the hardest tissue in the body and enables our teeth to function for a large part of our lifetime despite biting forces, exposure to acidic foods and drinks and extreme temperatures. This remarkable performance results from its highly organised structure. However, unlike other tissues of the body, enamel cannot regenerate once it is lost, which can lead to pain and tooth loss. These problems affect more than 50 per cent of the world's population and so finding ways to recreate enamel has long been a major need in dentistry.

Now a new approach can create materials with remarkable precision and order that look and behave like dental enamel. The materials could be used for a wide variety of dental complications such as the prevention and treatment of tooth decay or tooth sensitivity - also known as dentin hypersensitivity. "This is exciting because the simplicity and versatility of the mineralisation platform opens up opportunities to treat and regenerate dental tissues. For example, we could develop acid resistant bandages that can infiltrate, mineralise, and shield exposed dentinal tubules of human teeth for the treatment of dentin hypersensitivity."

The mechanism that has been developed is based on a specific protein material that is able to trigger and guide the growth of apatite nanocrystals at multiple scales - similarly to how these crystals grow when dental enamel develops in our body. This structural organisation is critical for the outstanding physical properties exhibited by natural dental enamel. Enabling control of the mineralisation process opens the possibility to create materials with properties that mimic different hard tissues beyond enamel such as bone and dentin. As such, the work has the potential to be used in a variety of applications in regenerative medicine.

Link: https://www.qmul.ac.uk/media/news/2018/se/scientists-develop-material-that-could-regenerate-dental-enamel-.html

Researchers here argue for enhanced levels of NAD+ to boost stem cell function through improved mitochondrial function. This is an area of metabolism that has gained increasing attention of late, a second pass at the whole topic of sirtuins, mitochondrial function, and metabolism in aging. I'd say the jury is still out on whether it is worth pursing aggressively in human medicine. One or two early trials seem promising, in the sense of obtaining benefits that look similar to those derived from exercise, but the magnitude and reliability of those benefits is the important question.

The bone marrow stem cell population responsible for generating blood and immune cells, hematopoietic stem cells, declines in activity with age, as is the case for other stem cell populations. Some of this is due to intrinsic damage, but the evidence to date suggests that, up until very late life, the majority of the loss of activity can be overridden - it is an evolved response to rising levels of damage, possibly arising because it reduces cancer risk, rather than the direct consequence of damage. Thus researchers are in search of ways to safely override this response, via a variety of means.

Mitochondria are generally characterized as the powerhouse of the cell, since this is the site where energy is produced from ATP. In addition to energy production, mitochondria play a key role in several important cellular processes, including growth, signaling, differentiation, reactive oxygen species (ROS) production, apoptosis, and cell cycle control. Interestingly, unlike other cellular organelles, mitochondria have their own DNA, mitochondrial DNA (mtDNA), and several studies have indicated an association between the accumulation of mtDNA mutations and mammalian aging.

Historically, mitochondria have not been considered important in restoring the functions of aged hematopoietic stem cells (HSCs); however, emerging studies on rejuvenating HSCs suggest an association between sirtuins (SIRTs) and mitochondrial activities. In addition, a study on the deregulation of the mitochondrial stress-mediated metabolic system demonstrated that SIRT7 strongly influences the regenerative capacity of HSCs. Although the functions of musculoskeletal stem cells (MuSCs) and HSCs are distinct, alteration of the SIRT1-associated nuclear/mitochondrial axis appears to be a common hallmark of aging in both cell types.

Recent research suggests the possibility of restoring the mitochondrial functions of aged stem cells, including MuSCs, nerve tissue stem cells (NSCs), and melanocyte stem cells (McSCs), by NAD+ supplementation without genetic manipulation. The remedial effect of the NAD+ precursor nicotinamide riboside (NR) enhances mitochondrial functions in stem cells, including respiration, membrane potential, ATP production, and the mitochondrial unfolded protein response (UPR); however, these effects are not observed in stem cells with a SIRT1 deficit. Moreover, NR was found to suppress the process of senescence in adult NSCs and McSCs.

These findings have reinforced the notion that NAD+ precursors can function as a pharmacological tool to enhance SIRT activities. This, in turn, paves the way for clinical translation of NAD+ precursor treatment through further investigations of hematopoietic tissues. We review evidence relating mitochondrial dysfunction to HSC aging, and propose a strategy for mitochondrial-targeted recovery as a potentially safe, effective, and non-invasive method for the control or prevention of aging-related hematopoietic diseases.

Link: https://doi.org/10.3343/alm.2018.38.5.395

Oisin Biotechnologies is one of a number of companies to have emerged from our community in recent years, from the network of supporters and researchers connected to the Methuselah Foundation and SENS Research Foundation. The Oisin principals are working with a platform capable of selectively destroying cells based on the internal expression of specific proteins. Their initial targets are senescent cells, one of the root causes of aging, and cancerous cells, one of the consequences of aging. They will be taking a therapy for cancer into clinical trials initially, as it is somewhat less challenging to move viable cancer treatments through the regulatory process than is the case for many other conditions. This will allow them to prove out and iterate on the technology in preparation for later trials of a senolytic therapy capable of clearing near all senescent cells in near all tissues. In this video, taken at the Undoing Aging conference hosted by the SENS Research Foundation and Forever Healthy Foundation earlier this year, Oisin Biotechnologies CSO John Lewis talks about their technology and recent results.

John Lewis, CSO of Oisin Biotechnologies, presenting at Undoing Aging 2018

Good evening everybody. It's a real pleasure to be here at this meeting; I really thank Aubrey de Grey and Michael Greve for the invitation to speak. I couldn't really have asked for a better sequence of speakers, as the prior presenter did a fantastic job of covering why senescent cells are important, and also why they are such a pain in the ass to work with scientifically. I'm a career academic scientist working in oncology and I'm relatively new to the senescence field, although I have a lot of experience in killing cells, and that's what I'd like to tell you about today: how Oisin Biotechnologies is working to develop very selective therapies to kill senescent cells and cancer.

I don't really have to give much of a background on what a senescent cell is, or what they do. These are cells that arise through programming in the body, a reaction to outside stresses - oxidative stress, genotoxic stress, and they basically prevent us from developing cancers. It is really important to note as well that as cells become senescent in the body, in response to these stresses, they also can send out factors that can spread. I'll reiterate the fact that we don't have great markers for identifying senescent cells. There are some common features we can use, scientifically, to identify them in this case, because of an accumulation of active enzymes in lysosomes. We can stain for active β-galactosidase. But really these are very heterogeneous populations, and they arise from a variety of different pathways. I don't want to go into detail about signaling, I just want to highlight the fact that the induction of this cell cycle arrest is mediated through a number of factors: p16, p53, p21. We've thought about this, and we've asked what are the common pathways that we could potentially target in order to create a selective therapy that can start to ablate these cells. Obviously, I don't need to go into the fact that while senescent cells have been implicated in aging and age-related processes, there are also very specific diseases that are consequences of aging and other phenotypes that an anti-senescence therapy could address clinically.

It was a really salient point in the last talk that p16 cells may not be the whole story. But you have to look at the data that has been shown in the past few years - and this is what really convinced me - that, sure, all senescent cells may not express p16, but it is very clear in a mouse model that if you engineer it such that you can selectively ablate all of the p16 expressing cells, you get dramatic changes in phenotype. For me, that was very impactful. In this case, Jan van Deursen's work, if you genetically engineer mice to express a suicide gene driven by a p16 promoter, using what is called INK-ATTAC, an inducable caspase-9 system, that allows them to then give a dimerizer that activates apoptosis in cells that have activated p16, that are putatively senescent, and these mice showed very dramatic changes in their phenotype. Significant improvements in healthspan, 25% median increase in lifespan, although some heterogeneity, 50% less cancer, and also functional phenotypes as well: delayed cataract formation, decreased frailty, decreased loss of hair.

I think that as a prelude to the next talk, some data that came out recently that really solidified for me that this was something worth going after as a therapy is Peter de Keizer's work, published last year, using a p53- and FOXO4-dependent mechanism. He was able to use an accelerated aging model, mice that are losing their hair, that are becoming frail, and show that treatment with an anti-senescence approach after these phenotypes have already manifested can reverse these phenotypes. This to me really solidifed the fact that this was a worthwhile development route to take for a therapy.

So that is the basis for Oisin's technology. As a team we thought that if we're going to develop a therapy that we can use for disease, then we were also thinking about the general anti-aging community and where this might be used some time in the future after it is proven clinically. So we wanted to utilize a strategy that is similar, leveraging successful animal models developed to date. Obvious we wanted to develop something that has a low toxicity profile, something that is well tolerated, and something that can be repeat dosed again and again. Something that is non-immunogenic, ideally didn't have overly off-target effects. Obviously many senescence phenotypes are tissue-specific, and the ability to target a therapy to different tissues would be a strength.

What I'm going to tell you about today is Oisin's technology that we developed. It is called the SENSOlytic platform. It is a lipid nanoparticle (LNP) platform that contains a non-integrating DNA plasmid. It is functionalized to be activated by a chemical inducer of dimerization that induces a very rapid and irreversible apoptotic response. Probably the most important part of this is the drug delivery system - the ability to deliver plasmid DNA systemically to many different tissues without significant toxicity. Oisin has developed a platform plasmid-based technology, and contrary to RNAi or delivery of messenger RNA, plasmids can be exquisitely engineered to only be activated in situations where specific pathways are activated, such as p16, p21, or p53. But they can also be engineered with enhancers or repressors and really tuned to specific tissues and diseases. We've created a system and a library of constructs that are active in various circumstances. The two I'm going to show you data on today are a version of the p16 promoter driving a suicide gene and a version of the p53 promoter driving a suicide gene.

We built a library of plasmids that are basically a specific selective promoter tied to an iCas9 inducable suicide gene that is then induced, or dimerized, through a chemical inducer of dimerization. Many of you may have seen this before, but iCas9 is a modified caspase, so it is truncated, the recruitment domain has been chopped off and replace with an FKBP dimerization domain. These domains interact very strongly with this chemical inducer of dimerization, AP20187, or its clinical analog, AP1903, that has already been shown to be safe in phase II clinical trials. What's really nice about this system is that you transiently express using a plasmid in the target cell, it is only expressed in cells with that pathway active, so p16 or p53 in our case. Then basically nothing happens until you add the dimerizer. The small molecule dimerizer is very well tolerated, goes systemic in a matter of minutes, and induces an irreversible apoptotic response. The iCas9 will then dimerize under these conditions, self-cleave, go to the apoptosome, and carry out a very rapid cell death with two to three hours. It is very hard from cells to escape from this. They can't evolve or otherwise get away from it. It is definitely final.

Some of our in vitro proof of concept experiments utilized placental lung myofibroblast cell line IMR-90. In this case we were inducing senescence using 10 grays of radiation and transfecting cells with a p16-driven iCas9. iCas9 is a little smaller than caspase-9 and can be detected with caspase-9 antibodies. In cells that haven't been treated with radiation, we don't see any expression of the iCas9. In cases where we cells are becoming senescent, expressing p16, we see induction of iCas9, and when we add a little bit of dimerizer to these cells, it is gone. It is very rapidly clearing from these cells. Then when we look at the ability for this to actually kill these cells, in viability assays, we see that every cell successfully transfected with the plasmid dies. We've shown through a number of other experiments, I'm just showing one example here, if we do flow cytometry, to look at the pathway of death, we confirm that we are inducing apoptosis in these cells.

So we have a plasmid that is very selective for p16-expressing cells. We can kill them very rapidly upon adding of the dimerizer. The question is how do we make this into a drug that works in people. It really is the delivery mechanism that is critical to making this both effective and safe. We opted to use a lipid nanoparticle platform. Lipid nanoparticles have been used for years and I'd say that mostly there's been a lot of promise and a lot of investment and very few successes. Alnylam Pharmaceuticals in Boston has just had a recent phase III successful trial with an RNAi drug, and the issue is that lipid nanoparticles tend to accumulate in the liver preferentially, and their mechanism of delivering nucleic acids into cells is a positive charge. It is a sort of a very simple technology. They've created lipids that have a positive charge. If you use a constitutive positive charge they punch holes in membranes very easily, so they associate and punch holes, disrupt endosomes, disrupt plasma membranes, so you can get stuff into cells very effectively, except they are really toxic. So there is a very low maximum tolerated dose in humans.

In response to this, several companies have developed what is called a conditionally cationic lipid. This is a lipid that is generally neutral in the bloodstream, gets taken up into endosomes, and becomes cationic in that acidic environment. These are the subject of the current clinical programs that are making their way through clinical trials for lipid nanoparticles. They work, but they are still quite toxic. The ideal delivery system is one that can use neutral lipids that are non-toxic, but use an alternative mechanism for cellular delivery of nucleic acids. I'm going to give you a tiny bit of background as to how we got to this this point. If you have a lipid nanoparticle and it has to get inside a cell, it has to get past an intact plasma membrane with all of its defenses. Viruses have evolved over millions of years to be able to solve this problem, and have evolved a variety of fusion proteins. Unfortunately, these fusion proteins are beautiful and gigantic and elegant and the way that they bring membranes together and create pores and mix lipids is really fantastic, but to attach this to a lipid nanoparticle is insane, because they are multi-protein, multi-subunit, they have gigantic active domains that are highly immunogenic.

Fortunately, there is a Canadian researcher who has been studying all his life these fusogenic orthoreoviruses and what he discovered in this particular class of viruses was that they don't use the fusion protein to enter cells, but once they enter cells in their reptilian or bird hosts, they cause all of the cells around them to rapidly fuse together. He spent his career characterizing this class of fusion-associated transmembrane proteins that are two orders of magnitude smaller than the smallest fusion protein produced by another virus, but are sufficient to induce cell-to-cell fusion, and most importantly, lipid nanoparticle to cell fusion.

While incorporating these proteins into a neutral lipid nanoparticle platform, you will find that neutral lipids by themselves are extremely poor at delivering things. In this example we're delivering an mCherry plasmid to cancer cells, and so without the fusogenic protein there is no delivery, with it we get fantastic delivery. So it increases delivery of a neutral lipid formulation by 80-350 times, and these are well tolerated in vivo. So this is an example, we're delivering an mRNA expressing luciferase, injecting into the tail vein. We get systemic expression of luciferase throughout the body. You get some accumulation in lungs and liver, but we get broad expression in many tissues including skin and soft tissues throughout the body.

This platform is what we are using to deliver the anti-senescence payload. The platform is called Fusogenix. It uses a neutral lipid formulation that is non-toxic and well tolerated. It uses these fusogenic proteins to deliver intracellularly. I'm not going to go into all the data. It actually took us three years to create an antibody against these proteins, they are really not immunogenic whatsoever. The reason for this is because most of it is a transmembrane domain. They are lipophilic, so they pack lipids around them, and they have a low profile to the immune system. We spent a lot of time working on these, engineering these fusogenic proteins to make them better. I'm not going to get into it all, but we're at the point now where we have a manufacturing platform to create these at scale, lypholize them even, and ship them around for use.

Let me show you data now taking the p16-activated caspase-9 and putting it in vivo in mice. In this case we've done an experiment now with 16 mice, an aged mouse cohort 80 weeks old. We've divided them into three groups, we're giving them a control LNP, we actually not giving them a dimerizer, or two doses, 5 and 10 mg/kg - and 10 mg/kg, if you know this field, is quite a huge dose. We treated these animals a single time by tail vein injection. We waited 96 hours, and then we gave them a single dose of dimerizer, also intravenously. Then we waited two more days, and we collected tissues, blood, and in this case we're doing a sensitive RT-PCR and controlling it with some housekeeping genes. We get a convincing dose-dependent reduction in p16 expression in a variety of tissues.

I'm going to show a couple of images where we spend a lot of time optimizing β-gal staining in mice. These are the prettiest images we've got, but we saw in multiple tissues a dose-dependent reduction in the expression of β-galactosidase. So very, very encouraging data. Obviously, creating data in the lab is great, but if we're going to translate this into humans, there's a lot of things that must be figured out. Toxicology is extremely important. It is important for a drug that you are going to deliver more than once to make sure that you don't create any neutralizing antibodies. So we've done a ton of studies looking at repeat dosing, and we don't produce any anti-drug antibodies whatsoever, so we can give this in repeated doses over time without any reduction in efficacy. CARPA assays are up there: CARPA is something that I learned about recently, complement activation-related pseudoallergy, an immune reactivity response that many patients who receive nanoparticle therapies like doxil can have. We've run all the assays for this, and it has a lower profile than doxil, so it is very well tolerated that way.

I'm happy to say that we've done some pilot non-human primate studies, giving ten times the maximum estimated human dose, and it was extremely well tolerated. We are just going through that information. Those monkeys actually got the treatment, both the p53 and p16 alone and in combination, and the dimerizer, so we will look at that and get some rich data. We're in the process of working through that now.

I'll keep coming abck to this point: the tolerability of these formulations is really important. I show this slide because it shows all of the efforts put into clinical trials of lipid nanoparticles and why they failed. If you look at the first three programs, these were really promising ten years ago, using cationic liposomes and lipid nanoparticles. If you can see by their maximum tolerated dose, way below 1 mg/kg, and these programs all failed due to liver-related toxicity. The second generation in the middle, conditionally cationic lipids, these were tolerated to a more or less better extent, and some of those programs have been successful and will result in approved drugs, but all of the targets are liver. Because the lipid nanoparticles preferentially accumulate in the liver, you're going to see dose-limiting toxicity if you don't use a neutral lipid formulation. Then you can see work using a neutral lipid formulation similar to ours, and they were not able to find a maximum tolerated dose in the one study. Based on our non-human primate studies, we expect our formulation to be equally as well tolerated.

We're currently evaluating a variety of constructs to see which one is the best to bring into humans, and - obviously it has been talked about at this conference - the creation of biomarkers that are viable endpoints for clinical trials, and also viable in animal models to look at efficacy. We're keen to talk to anybody who has a great biomarker. We have cohorts of mice in which we are looking at the life span and health span of these mice. We are thinking about the transition to the clinical stage where we're getting GMP manufacture going and doing our GLP toxicity analysis.

So I'm going to switch to cancer for a second because this is our route to the clinic. My day job is as a prostate cancer researcher. The one thing that really intrigued me about the crossover between senescence and cancer is the activation of the p53 pathway. p53 is the most mutated gene in cancer, and there are a lot of cancers that have a high burden of p53 mutation. I put prostate up there because it is actually relatively low, an average might be 10%, the vast majority of prostate cancers are low-grade. Once you get to metastatic disease, that mutation rate is well over 50%. So this is a viable target for cancers. While the p53 protein itself hasn't been a great target for oncology therapies, I think the pathway is great. If you think about p53, you can get two kinds of mutations. With all the stress cells have through replication and mutation burden, they will activate p53, to either resolve the damage or go through apoptosis. So cells either mutate or get rid of p53 to get around this. As a result the actual activation pathways that are driving this are highly upregulated. So can we exploit this activation to kill cancer cells?

I'm skipping over all the in vitro data as I only have three slides left, and I want to show you some in vivo data, as that's really important. In this case, we are using a very similar formulation to the one I showed before. There is an engineered p53 promoter driving this iCas9 suicide gene, wrapped in a neutral lipid nanoparticle. In this case we're growing gigantic prostate cancer tumors in an immunocompromised mouse. These are NOD/SCID mice. We're growing them up to over 500 mm^3, so big tumors. We're doing a single intratumoral injection of the nanoparticle, waiting three days, and then doing a systemic injection of the dimerizer. We saw most of the tumors reduced 90-95% in 48 hours - and this is not amazing for an intratumoral injection, but I was very pleased because this means we're successfully transfecting the plasmid into the majority of tumor cells, which I thought was very exciting.

The real proof is to be able to do with a systemic injection, and we've done those studies. This is just an example of four mice in that cohort. We've grown these same very large tumors, growing them to a size of 500 mm^3. In this case we're giving four daily tail vein injections of the LNP and on the fifth day we're giving them a single dose of the dimerizer, systemically. Again, we saw remarkable results, between 50-98% tumor reduction in just two days. This resulted in a significant prolongation of survival with a single dose in these animals. On average, six mice per group, almost a 70% reduction in tumor volume.

One thing that is really important as well: primary tumors don't kill patients in most situations. It is the metastatic disease, so we're really interested in seeing whether we can hit metastatic cancers. Obviously this will be the population we go into for the first clinical trials as well. So we have done a number of models looking at the ability of these LNPs to control metastatic disease, in this case we've got a prostate cancer systemic metastasis model, and an immunocompetent melanoma model. In both cases with a multiple dosing regimen, we were able to control this disease effectively.

We're on the path. Obviously, the long term goal of Oisin is to develop senescence-clearing therapies for aging and age-related diseases. But I think in the short term it is really important, not only for the nanoparticle technology, but also for this platform technology, to prove it in the clinic - safety and efficacy. So we've already got a phase I/phase IIb cancer trial designed, and we're right now gearing up for GLP toxicology that will be enabling for those studies. We're hoping to dose our first person in early 2019. We're excited about accelerating the translation of this technology. One thing I'll mention as well, there are many cancers in which this can work in. In Canada, we can actually do a phase I trial with all types of cancer, basically, so colorectal, prostate, lung, etc. We'll be looking for the biggest signal and most important cancer to be able to expand that cohort and then do the phase II.

Recent (and not yet fully accepted) evidence suggests that chimpanzees and dolphins might suffer Alzheimer's disease, or at least a condition that is similar enough to be comparable. Other than possibly those two species, humans are the only mammals to experience Alzheimer's, the aggregation of amyloid-β and tau proteins into solid deposits that alter brain biochemistry for the worse. Why is this the case? What is it about our particular evolutionary path that resulted in this outcome? Might that teach us anything that could be used to suppress the development of the condition?

In this article, Alzheimer's is painted as a consequence of antagonistic pleiotropy during the divergence of our species from other primates. Antagonistic pleiotropy is the name given to the theorized tendency for evolution to produce systems that are advantageous to young individuals but harmful to old individuals. Examples include systems that do not maintain themselves well, such as cells that lack enzymes to digest certain harmful forms of molecular waste, systems that have finite resources that run out, such as the adaptive immune system's capacity to remember past pathogens, and systems that interact poorly with the damaged environment of old tissues, causing further damage - which is just about everything else.

While granting human species some advantages over our primate cousins, recent genomic adaptations appear to have come at a cost. "I find the idea that genes that have been involved in the development of the human brain and in making the human brain different from the brains of great apes might also be genes that have the byproduct of raising the risk of Alzheimer's is one of those ironic twists that seem to be pretty common in evolutionary biology."

In 1957, evolutionary biologist George Williams proposed a theory: adaptations that made species more fit in the early years of life likely made them more vulnerable to diseases in the post-reproductive years. However, there has been little research to support his theory. As a test of this theory, researchers started by focusing on enhancers, pieces of DNA with the ability to boost the activities of certain genes, and therefore, the levels of resulting proteins. Previous research had identified enhancers as key to as key to human evolution after diverging from the last common ancestor with chimpanzees. Using FANTOM, an annotated database with information on expression levels of human-specific enhancers, researchers compared human data with that of primates to find the fastest evolving enhancers. Comparisons with primates including chimpanzee, gorilla, orangutan, and macaque genomes revealed 93 such enhancers expressed within neurons and neuronal stem cells that had evolved rapidly in humans.

Genes lying close to these enhancers, and therefore possibly under their control, were important for brain development. It is plausible that the enhancers were positively selected for during evolution because of their effects on these brain-related genes. However, they also found evidence of proximal associations between the enhancers and genes implicated in Alzheimer's, Parkinson's disease, type 2 diabetes, hypertension, and osteoporosis. According to Williams's theory, these aging-related diseases would manifest later in life and would go unnoticed during the Darwinian selection process because of the advantage they bestowed in the early years.

In order to see if there is indeed a functional (rather than merely correlative) connection between the enhancers and aging-related diseases, the team used the Cancer Genome Atlas and GTEx, both large databases, to draw up gene maps highlighting all the genes coexpressed with each enhancer. The researchers targeted one such enhancer associated with brain development and also with genes known to be linked to brain diseases. When the researchers used CRISPR to delete the enhancer in human cell lines, protein abundance from its related genes fell. Importantly, some of these genes are usually suppressed by a gene called REST, which keeps Alzheimer's at bay. However, in the presence of the functional enhancer, these genes are boosted. Thus, while this enhancer may be important for brain development, it seemingly opposes REST's protective function against Alzheimer's.

Link: https://www.the-scientist.com/?articles.view/articleNo/54716/title/Aging-Related-Diseases-May-Be-a-Negative-Outcome-of-Human-Evolution/

This interview with Jim Mellon opens with an update on some of the recent investment activities of Juvenescence, founded last year in order to participate in the enormous market opportunity afforded by the development of the first working rejuvenation therapies. It is in Mellon's self-interest to help educate the world about the size of this market, and draw in other, larger entities that will help to carry his portfolio companies to the finish line. So he is doing just that, and in doing so benefits us all. His advocacy will help all fronts in fundraising for research and development in this field.

That advocacy continues, as it remains the case that the investment community as a whole is slow to wake on the topic of treating aging as a medical condition. The more agile portions of it are starting to move, but the larger interests are still on the sidelines. Yet any viable rejuvenation therapy will be a bigger prospect that any blockbuster drug of the past few decades, and the first of these therapies are already either in development or even arguable available in the case of the first senolytic pharmaceuticals. The target market is every human being over the age of 40, for treatments that will have to be reapplied every so often, indefinitely. There won't be a bigger opportunity for gain until the orbital frontier opens up.

What's making you so optimistic that you and I will live to be 100 or 110?

The first book I wrote about biotech came out at the end of 2012. When the latest book came out, we were looking at just five years of a gap. And in those five years, artificial intelligence - which didn't exist in 2012 - is now very much in the frame for the development of new compounds. A cure for hepatitis C did not exist in 2012. Now, if you've got the money - and even if you don't have the money, because drugs are coming down in price - you can be cured of hepatitis C. Cancer immunotherapy did not exist in 2012, and is fast becoming the standard of care in blood cancers and will ultimately become as important in solid tumors as well, improving cancer survival rates by a dramatic amount. And lastly, most importantly, CRISPR gene editing did not exist in 2012. If you think about what's happened in the last five years, all remarkable technologies, just imagine what's going happen in the next five years.

How do you expect Juvenescence Ltd. will capitalize on this?

We are very early in this land grab. We are very hopeful that we can get at least two or three compounds into the clinic and out of the clinic within the next few years which will have indications beyond longevity, because it's very hard for anyone to say "I can keep you alive for 30 or 40 years" without hanging around to see if it works. I've done a few things in my life, but this is by far the most interesting and exciting. Rather than associating old people with being decrepit, people will be robust for a lot longer and will live a lot longer. I'm not a subscriber to Aubrey de Grey's view that the first person to be 1,000 is alive today. But I do absolutely believe that the first people who will live to be over 150 are amongst us now. That is just quite amazing. It's going to change everything in the world.

Not long ago I interviewed an actuary about how the financial assumptions underlying pensions or life insurance. He pointed out that gains in life expectancy are leveling off.

Every bit of our life expectancy increase in the last century or so has come from environmental factors. Better sanitation, lower infant mortality, better nutrition, less manual labor and therefore less accidents. None of it has occurred from biological change. It's only now that biological change is about to happen. The question then becomes: who benefits, and who doesn't? In the United States, you suffer from tremendous health inequality. New drugs like senolytics or rapalogs are probably going to have 10 years of patent life. Now if we have a long life, 10 years is not that long. So even if those drugs may expensive to begin with and therefore available only to so-called elites, they will in due course become rather like anti-ulcer drugs are today and available to everyone. In the 1980s, anti-ulcer drugs were extremely expensive prescription drugs. Now you can go into Walgreens and buy them for nothing, basically. That will apply to all these drugs.

Link: https://medium.com/neodotlife/juvenescence-jim-mellon-longevity-e9a415dd0569

Autophagy is the name given to the collection of cellular processes that recycle broken and unwanted proteins and cell structures. More autophagy is a good thing, and many of the methods demonstrated in the laboratory to modestly slow aging in flies, worms, and mice involve enhanced autophagy. You might look at a recent experiment demonstrating a 10% gain in mouse life span via a narrowly targeted method of increasing autophagy, for example. Calorie restriction, the gold standard in reliability when it comes to slowing aging, depends upon autophagy: it doesn't work when autophagy is disabled.

Unfortunately, autophagy declines with age. But why? There are undoubtedly many answers to that question, a layered set of mechanisms that directly or indirectly arise from the root causes of aging, the accumulation of molecular damage as outlined in the SENS rejuvenation research proposals. In the direct case, autophagy suffers because persistent metabolic waste accumulates in lysosomes, the structures responsible for disassembling proteins and cell components. They are packed full of enzymes capable of dismantling near all of what they encounter, but near all isn't good enough over the long term. Long-lived cells in older people contain dysfunctional lysosomes packed full of a mix of hardy waste compounds collectively known as lipofuscin.

Autophagy is a complicated multi-stage process, however. Function isn't just a matter of the state of lysosomes, but also of the mechanisms responsible for flagging proteins and structures for recycling, constructing membranes around that material, and delivering the membrane-wrapped packages to the nearest lysosome. If any of that falters, then the pace of autophagy declines. The open access research here reports on an example of issues in the transport portion of autophagy, and the authors make some headway into understanding why it happens, associating it with reduced levels of KIFC3. While pinpointing age-associated changes in the expression of a particular gene is a first step, it has to be said that this rarely leads to the root cause damage without a great deal of further work.

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Autophagy is a highly conserved catabolic process responsible for the delivery of cytoplasmic materials (proteins and organelles) into lysosomes for their degradation. Autophagy contributes to maintain cellular and tissue homeostasis by assuring protein and organelle quality control. A growing number of reports have linked malfunctioning of autophagy with aging, highlighting the role of autophagy as an anti-aging cellular mechanism. Furthermore, genetic inhibition of this degradative process recapitulates features associated with aging and age-related diseases. Loss of protein/organelle quality control is a universal hallmark of aging, and malfunctioning of autophagy with age contributes to this gradual accumulation of damaged proteins and dysfunctional organelles. However, the cellular and molecular mechanisms underlying this progressive decline in autophagy during aging remain unknown.

Delivery of cargo (material to be degraded) to lysosomes via macroautophagy, the most conserved and best characterized type of autophagy (hereafter denoted as autophagy), requires regulated trafficking of autophagic vesicles (AVs), the compartments where cargo is sequestered, for their fusion with lysosomes. Subcellular positioning of organelles is mainly determined by the microtubule network. Interaction of these vesicles with microtubules is mediated by motor proteins that provide the force necessary to move them along the tubulin tracks. Vesicle-associated motors are of two types depending on the direction in which the vesicle is transported: plus-end-directed motor proteins (N-kinesins) that transport vesicles toward the cellular periphery and minus-end-directed motor proteins (dynein and members of the C-kinesin family such as KIFC2 and KIFC3) that move vesicles to the perinuclear area.

The balance between active plus-end- and minus-end-directed motors bound to a vesicle's surface determines the directionality of its intracellular movement. In the case of autophagy, the balance of active motor proteins on the surface of autophagosomes has been proposed to prevent their premature or random fusion with lysosomes. In most cells, autophagosome-lysosome fusion occurs mainly in the perinuclear region where it is facilitated through both physical proximity of the organelle and slowing of vesicular trafficking. Consequently, efficient positioning of these degradative compartments in the vicinity of the nucleus in a microtubule-dependent manner is an essential step for the final completion of the autophagic process.

Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule-based minus-end-directed motor proteins, the well-characterized dynein, and the less-studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Interestingly, the motor defect seems to preferentially affect basal quality control autophagy whereas induction of autophagy by starvation restores in part association of specific motor proteins with autophagosomes and lysosomes. These findings highlight the feasibility of activating inducible autophagy in old organisms to compensate for their defective basal autophagy.

Hypertension, high blood pressure, is caused by arterial stiffness, which is in turn caused by a combination of mechanisms such as the accumulation of persistent cross-links that alter the structural properties of tissue, and chronic inflammation produced by senescent cells that alters the behavior of cells in blood vessel walls. Hypertension damages fragile tissues, causes the muscle of the heart to become larger and weaker, and ultimately interacts with the corrosive effects of atherosclerosis on blood vessel walls to produce a fatal rupture, leading to a stroke or heart attack.

The work noted here is representative of most efforts to safely lower blood pressure, in that it attempts to force cellular mechanisms in blood vessel walls into a more functional state without addressing the underlying causes of dysfunction - those that stiffen blood vessels. All too much of medical research has this focus: tinker with cell state in patients, but don't repair the damage that is causing those cells to run awry.

In the case of raised blood pressure, however, this condition directly causes a varied package of downstream harm, and is an important mediating mechanism between low-level molecular damage and high-level structural consequences to organs. So it is possible to make some progress, produce some degree of benefits to patients, by lowering blood pressure without addressing the causes of hypertension. That doesn't make it the best strategy, and it certainly shouldn't be the most effective approach. That most effective approach would have to involve repair of molecular damage that in turn reverses arterial stiffening.

Researchers have demonstrated that Galectin-1, a protein in our body, influences the function of another protein known as L-type (Cav1.2) calcium channel found on the arteries that normally acts to contract the blood vessels. By reducing the activity of these calcium channels, Galectin-1 is able to lower blood pressure.

Hypertension is a common problem worldwide. Importantly, age is a major risk factor for the development of hypertension. According to the World Health Organization, elevated blood pressure is estimated to cause 7.5 million deaths globally, which represents more than 12 per cent of the total of all deaths. This is because hypertension is associated with major killers like coronary heart diseases and stroke. In addition, hypertension can also cause renal impairment, retinal haemorrhage, and visual impairment.

As hypertension is a common denominator to many serious conditions described above, nipping the problem at its bud will significantly improve our health. Although patients with Stage I hypertension are mostly recommended to make lifestyle changes to reduce the risks of suffering other cardiovascular diseases, those with Stage 2 hypertension or above have to take anti-hypertensive medicines to control blood pressure.

Calcium channel blockers (CCB) are traditionally used in the clinics to lower blood pressure, but the use of such medications was reported to be associated with increased risk for heart failure in hypertensive patients particularly those with heart problems due to their bad side effects. Therefore, the development of drugs that could adjust the activity of L-type (CaV1.2) calcium channel, rather than blocking its normal function altogether, has emerged as a novel research direction for anti-hypertensive therapeutics. The discovery that Galectin-1 can perform such a desired function represents a pathway to control blood pressure. The good news is that Galectin-1 only targets L-type (CaV1.2) calcium channel in the blood vessels. It spares other types of calcium channels that are important for the general functions of our body.

"The reported effects of Galectin-1 protein, and of its analogues, on the blood pressure in various models of human arteries and the circulatory system are encouraging. The results suggest that there is a reasonable likelihood of fabricating an antihypertensive treatment-molecule, based on Galectin-1, which will consistently suppress, without negating, the Cav1.2 calcium channel in human arteries, so lowering the blood pressure in persons with pulmonary hypertension. The results from human pulmonary arteries suggest that the candidate treatment-molecule might also be useful in the condition known as pulmonary arterial hypertension, for which highly cost-effective drugs are lacking."

Link: http://nusmedicine.nus.edu.sg/medias/news-info/1810-nus-scientists-discover-a-new-way-to-control-blood-pressure

Risk factors associated with age-related disease and mortality tend to also associate with higher medical costs. Obesity, for example, both shortens life span and increases lifetime medical costs thanks to the impact it has on health. High blood pressure, the condition known as hypertension, is another measure that reliably predicts a higher risk of mortality and poor health in later life. Here researchers run the numbers to show that it also results in higher medical costs, much as expected.

Hypertension isn't too far removed from the root causes of aging. High blood pressure is a direct result of arterial stiffening, as that detrimental change disrupts the finely tuned feedback mechanisms that balance blood pressure. Stiffening of blood vessels is caused by a mixed bag of mechanisms from the SENS rejuvenation research portfolio, such as cross-linking of the extracellular matrix in blood vessel walls, and the presence of senescent cells producing inflammation that both encourages calcification and disrupts the function of the smooth muscle responsible for dilation and contraction of blood vessels.

Raised blood pressure harms sensitive tissue structures such as those of the brain and the kidneys. It causes an increased rate of rupture of capillaries on a day to day basis, each destroying a tiny area of tissue. In later life it interacts with atherosclerosis, which weakens and narrows blood vessels with fatty plaques, to increase the risk of a fatal structural failure, a stroke or heart attack. More subtly, hypertension also causes the heart to reshape itself for the worse, the muscle growing larger and weaker, leading to heart failure. All of this is why methods of forcing lower blood pressure can be beneficial, even when they don't address the underlying root causes of hypertension, as is the case for all of the present approaches available in the clinic. In the future, we would expect to see far better outcomes for patients result from rejuvenation therapies that reverse the causes of blood vessel stiffening, thereby turning back hypertension.

Adults with high blood pressure face $1,920 higher healthcare costs each year compared to those without high blood pressure, according to new research. Based on the U.S. prevalence of hypertension, researchers estimate the national adjusted annual cost for the adult population with high blood pressure to be $131 billion higher compared to those without the disease. It is important to note that this twelve-year study was conducted using previous hypertension guidelines - which defined high blood pressure as 140/90 mm Hg or higher. In 2017, the American Heart Association and the American College of Cardiology lowered the definition of high blood pressure to 130/80 mm Hg or higher. "The new lower definition of high blood pressure will increase the number of adults in the hypertensive population. This may decrease the average cost of hypertension for individual patients while increasing the overall societal costs of hypertension."

Compared to patients without high blood pressure, those with high blood pressure had: 2.5 times the inpatient costs; almost double the outpatient costs; and nearly triple the prescription medication expenditures. "While the increased cost for patients with high blood pressure remained stable from 2003-2014, the rising prevalence of hypertension will become an increasingly large burden on the U.S. population for hypertension expenditures. The better we can learn to recognize high blood pressure, treat it and manage it, the better we'll be able to address these costs." National statistics from the 2017 hypertension guidelines estimate that 46 percent of U.S. adults - 103 million people - have high blood pressure, but only about half of those have their blood pressure controlled despite improvements in diagnosing, treating, and controlling hypertension.

Link: https://newsroom.heart.org/news/adults-with-high-blood-pressure-face-higher-healthcare-costs