Fight Aging!

It is well known that females of many species live longer than males. Some fundamental aspects of gender roles in mating and reproduction tend to lead to this outcome. It isn't peculiar to our species, so it can't have anything to do with technology or the sociology that comes with intelligence. Thus the dominant arguments really have to be evolutionary in nature. It is less well known that, in our species at least, women have worse health than men in later life, despite a greater life expectancy. This also probably arises at root from fundamental aspects of gender roles, but there is a great deal of room to argue for any specific position on how exactly it is that evolutionary processes lead to the observed result.

In the paper noted here, researchers take a swing at explaining how we could arrive at the position of worse female health, invoking the selection of gene variants that benefit males in late life but harm females in late life. This is a sort of cross-gender antagonistic pleiotropy to complement the usual understanding of how genetic variants that harm individuals in later life might arise. The size of the effect may depend upon the existence of menopause, which is only observed in a few species, however, which makes it harder to support any theoretic position with solid data. The paper makes for interesting reading, as is the case for most such research.

That said, I disagree with the authors' assertion that we need to understand this and other similarly subtle evolutionary mechanisms in order to produce greater human longevity. Understanding is not a bad thing, mind, and science is a worthy goal, but here understanding is near completely orthogonal to progress in the treatment of aging as a medical condition. Both men and women age for same underlying reasons, the accumulation of molecular damage is the same in both genders. After the research and medical communities have built therapies that can repair that damage, then it won't matter in the slightest how evolution has handled or mishandled late life resilience to high levels of damage. No-one will have high levels of cell and tissue damage any more.

Study reveals why older women are less healthy than older men

Scientists have long wondered why older women are less healthy than older men, given that men at any given age are more likely to die than women (a puzzle known as the "male-female, health-survival paradox"). The answer, according to recent research, is "intralocus sexual conflict" - genes that benefit one sex but harm the other. The researchers used mathematical models and experimental data on flies to show that such genes can easily spread if they take effect after female reproduction stops.

"Shared genes tether the sexes together in an evolutionary tug of war. Selection is trying to push females and males in different directions, but the shared genome means each sex stops the other from reaching its optima. Basically, certain genes will make a good male but a bad female, and vice versa. However, after females reaches menopause, they no longer reproduce to pass on their genes which means selection (which is reproduction) on females is greatly weakened. So after that point, any genes that improve late-life male fitness will accumulate, even if they harm female fitness."

Intralocus sexual conflict can resolve the male-female health-survival paradox

While we broadly understand why mortality risk rises as fertility and general performance decline with age, it is less clear why the tempo and severity of these changes often differ between the sexes. In humans, survival, fertility, and performance show sex-specific patterns of decline with age. Strikingly, women stop reproducing decades before dying, while men can reproduce throughout their adult lives. Additionally, men are more likely to die than women in most age-classes, but are healthier than women late-in-life. To be clear, this is not just due to the selective loss of low quality males, as female mortality rates are lower than male rates at nearly all ages despite poorer female health. This sex difference has been termed the "male-female, health-survival paradox", and while its causes are not well understood, some resolution of it is needed if we are to ensure healthy aging as human lifespan increases.

Here we focus on the health aspect of the paradox and suggest that intralocus sexual conflict might explain why women are less healthy than men late-in-life. Intralocus sexual conflict occurs when the sexes have different optimal values for a shared trait with a common genetic basis. For example, male broad-horned flour beetles develop enlarged mandibles and males with larger mandibles have higher fitness. However, daughters of males with large mandibles have lower fitness because of the masculinisation of the body that occurs with these genotypes. This means that alleles associated with mandibles are subjected to an intersexual tug-of-war over optimal values, with high fitness male genotypes making low fitness females. This type of conflict means that the alleles encoding a high-quality male often produce low quality females and vice versa.

For intralocus sexual conflict to explain the health-survival paradox, male-benefit sexually antagonistic alleles with late-acting effects must accumulate. This is entirely feasible because women experience the menopause. This means that selection against any alleles with costly effects when expressed in females will weaken dramatically once women undergo the menopause and stop reproducing, because these alleles can only have indirect effects on female fitness. However, in men there will be selection for male-benefit alleles over the entire lifespan because men can keep reproducing until advanced ages. This would allow late-acting, male-benefit sexually antagonistic alleles to spread and accumulate in the human genome and reduce female health late-in-life, as females carrying late-acting male-benefit alleles express trait values closer to male than female optima.

To formally test this hypothesis, we assessed whether a male-benefit, sexually antagonistic allele could spread through a diploid population using an evolutionary modelling framework. We show theoretically that under biologically realistic assumptions of costs and benefits, such antagonistic alleles can accumulate. Using Drosophila model systems, we then assessed whether sexual conflict solutions are feasible by testing whether populations evolving with selection for late-life male reproduction, but with no direct selection on females (as is the case for post-menopausal women), developed late-life costs to females. Our data broadly support the predictions and suggest that intralocus sexual conflict could help explain the male-female, health-survival paradox.

Researchers here describe a novel form of cell damage that results from oxidative stress, one that has not yet been investigated in any meaningful way. Oxidative stress is the name given to raised levels of oxidative molecules (free radicals, reactive oxygen species, and others) and the damage that they cause inside cells, in the form of chemical reactions that disable protein machinery. That damage is constantly occurring and constantly repaired, even in young cells, but in old cells the damage outpaces the repair mechanisms. Oxidative damage was at one time thought to be a fairly straightforward cause of aging, but that is no longer the case. It seems fairly clear nowadays that raised levels of oxidative stress in old tissues are a downstream consequence of a broad mix of other issues.

As we age, neurons in our brains can become damaged by free radicals. Researchers have discovered that this type of damage, known as oxidative stress, produces an unusual pileup of short snippets of RNA in some neurons. This RNA buildup, which the researchers believe may be a marker of neurodegenerative diseases, can reduce protein production. The researchers observed this phenomenon in both mouse and human brains, especially in a part of the brain called the striatum - a site involved in diseases such as Parkinson's and Huntington's.

For this study, the researchers used a technique that allows them to isolate and sequence messenger RNA from specific types of cells. This involves tagging ribosomes from a specific type of cells with green fluorescent protein, so that when a tissue sample is analyzed, researchers can use the fluorescent tag to isolate and sequence RNA from only those cells. This allows them to determine which proteins are being produced by different types of cells.

n separate groups of mice, the researchers tagged ribosomes from either D1 or D2 spiny projection neurons, which make up 95 percent of the neurons found in the striatum. They labeled these cells in younger mice (6 weeks old) and 2-year-old mice, which are roughly equivalent to humans in their 70s or 80s. The researchers had planned to look for gene expression differences between those two cell types, and to explore how they were affected by age. To the researchers' surprise, a mysterious result emerged - in D1 neurons from aged mice (but not neurons from young mice or D2 neurons from aged mice), they found hundreds of genes that expressed only a short fragment of the original mRNA sequence. These snippets, known as 3' untranslated regions (UTRs), were stuck to ribosomes, preventing the ribosomes from assembling normal proteins.

The 3' UTR snippets appeared to originate from about 400 genes with a wide variety of functions. Meanwhile, many other genes were totally unaffected. The researches found that the activation of oxidative stress response pathways was higher in D1 neurons compared to D2 neurons, suggesting that they are indeed undergoing more oxidative damage. The researchers propose a model for the production of isolated 3' UTRs involving an enzyme called ABCE1, which normally separates ribosomes from mRNA after translation is finished. This enzyme contains iron-sulfur clusters that can be damaged by free radicals, making it less effective at removing ribosomes, which then get stuck on the mRNA. This leads to cleavage of the RNA by a mechanism that operates upstream of stalled ribosomes.

Link: http://news.mit.edu/2018/biologists-discover-RNA-aging-neurons-1127

Many people find there to be little distance between the questions "why live longer?" and "why live at all?" It makes it hard to have conversations about the great good that might be done through the development of rejuvenation therapies without tipping over the edge into nihilistic considerations of the meaning of life. Since life has only the meaning we grant it, these tend to be circular, pointless conversations. If you wish to live, then live.

I would say that the purpose of longevity, insofar as it has one, is to make the continuation of a life worth living a choice for those who presently have no choice, tyrannized by the their own cellular biochemistry. Rejuvenation biotechnologies, like all technologies, involve expanding the human condition by adding new choices where no such choice previously existing. Indeed, the very act of choosing itself is predicated on being alive and sound to make the choice and experience the results.

"The Purposes of Longer Lives" is the theme under which the Annual Scientific Meeting of the Gerontological Society of America (GSA) will convene in November 2018. Longevity and life span have been a core focus for GSA ever since the very first issue of the Journal of Gerontology in 1946 came bannered with the slogan, "To add life to years, not just years to life." Explicit here was the idea, dating deep into recorded history, that pro-longevity efforts should seek "not merely an increase in time per se but an extension of the healthy and productive period of life."

Today, academic units concerned with gerontology have been adding the term longevity to their titles - a center for longevity, a longevity institute. This provides organizations with a measureable outcome in a way that aging by itself cannot. At the same time, credit for gains in life expectancy is due to mortality reductions at all stages of the life course.

Longevity's purpose is a teleological question about goals and ends, about the value of extended survival. Ironically, evolutionary theory about aging tells us that longer lives for organisms are pointless beyond the stage of reproduction and perhaps the rearing of offspring. If we are to find meaning in outliving this biological design, it will need to come from human and cultural aspirations for more time alive. And more time can be valuable in at least three ways: as a personal good available for any sort of individual pursuit; as a public good that benefits the larger group; and as a resource for the scientific and scholarly study of life span - research on aging thrives on more aging.

Link: https://doi.org/10.1093/geroni/igy029

At the present time, the main focus of therapeutic development involving senescent cells is the safe, selective destruction of as many such cells as possible. The accumulation of senescent cells is an important cause of aging and age-related pathology, and removing even just a quarter or a half of them - and in only some organs and tissues - has been shown to significantly extend life and improve health in mice. The first human trials are underway and the results will be published over the next year or so.

While senescent cells do a good job of accelerating our demise, it is undeniably the case that these cells also serve quite useful purposes for a short time after their creation. They exist for a reason, and the problem is not their existence per se, but that they are not removed efficiently enough after the job of the moment is accomplished. Senescence cells secrete a potent mix of signals that is well adapted for those tasks, but if allowed to continue for the long term, this signaling is highly disruptive of tissue structure and organ function.

Cellular senescence as a process serves to help define the shape of tissues during embryonic development, but in adult life its primary positive roles involve suppression of cancer and guidance of wound healing. Since cells become senescent in response to damage, such as the mutational damage to DNA that can lead to cancer, countless potential cancers are avoided because the cells involved enter a senescent state in which they can no longer replicate. They then rouse the interest of the immune system via inflammatory signaling, to ensure destruction. In the case of wound healing, the signal molecules secreted by senescent cell encourage the activities needed for regrowth and restructuring.

In a near future in which senescent cells can be very efficiently destroyed, then it becomes possible to think about delivering senescent cells to patients, or selectively forcing patient cells into a senescent state. This could have applications in the treatment of cancer, in which provoking cancerous cells into senescence has long been a desirable goal for chemotherapy, or in acceleration of wound healing, for example. After the job is done, efficient senolytic therapies could be delivered to remove the senescent cells, preventing them from causing long-term harm to the patient.

Senescent cells: A new Achilles' heel to exploit for cancer medicine?

In response to various intrinsic and/or extrinsic stimuli, cells enter an essentially irreversible senescent state. Senescent cells are frequently implicated in multiple disorders, mainly through secretion of numerous bioactive molecules, a distinctive phenomenon found a decade ago and termed as the senescence-associated secretory phenotype (SASP). The full SASP spectrum comprises a myriad of soluble factors including pro-inflammatory cytokines, chemokines, growth factors, and proteases, whose functional involvement can be classified into several aspects including but not limited to extracellular matrix formation, metabolic processes, ox-redox events, and gene expression regulation. The SASP promotes embryonic development, tissue repair, and wound healing, serving as an evolutionarily adapted mechanism in maintaining tissue and/or organ homeostasis.

Although the SASP is beneficial to several health-associated events, more evidence has showed that it actively contributes to the formation of a pro-carcinogenic tumor microenvironment. Long-term secretion of the SASP factors by senescent cells can impair the functional integrity of adjacent normal cells in the local tissue, serving as a major cause of chronic inflammation which drives aging-related degeneration of multiple organs. Thus, senescent cells and their unique phenotype, the SASP, can be defined as a form of antagonistic pleiotropy, a property that is beneficial in early life and during tissue turnover, but deleterious over time with advanced age.

A new function of the SASP was recently discovered, which is linked with increased expression of stem cell markers and keratinocyte plasticity upon short term exposure of cells to the SASP in vitro and liver regeneration in vivo, thus raising the possibility that transient therapeutic delivery of senescent cells could be harnessed to promote tissue regeneration.

Interestingly, a study of spontaneous escape from cellular senescence found that cells released from senescence can re-enter the cell cycle with pronouncedly enhanced stemness and Wnt-dependent growth potential. Thus, senescence-associated reprogramming promotes cancer stemness (senescence-associated stemness, or SAS), a distinct property that has profound implications for cancer therapy and presents new mechanistic insights into cancer cell plasticity. Partially resembling cancer cells which pose substantial threat to human lifespan, senescent cells are functionally involved in tumor progression and can be viable targets for some reasons. Fortunately, senescent cells share common biochemical features, allowing use of a single therapeutic agent to eliminate them from the tissue microenvironment. Given that many chemotherapeutics induce collateral senescence, pharmaceutical agents targeting senescent cells can be a key component of advanced anticancer arsenal.

Cell biology is complicated, to say the least, and so the unexpected keeps occurring. Cell maintenance is carried our by a number of processes such as the ubiquitin-proteasome system (UPS) or the various forms of autophagy. Collectively these are responsible for clearing out broken structures and unwanted proteins within cells. There is plenty of evidence for the role of maintenance process of this nature in policing aggregates such as the amyloid-β associated with Alzheimer's disease. It is suspected that the faltering of autophagy that occurs with age is one the reasons why neurodegenerative conditions like Alzheimer's disease are a feature of late life only.

Here, researchers undertake a routine study of dysfunctional maintenance processes in Alzheimer's disease. They break the normal operation of proteasomal protein disposal via the use of mice with a mutant ubiquitin gene, and cross those mice with an Alzheimer's model lineage to obtain mice that exhibit both amyloid-β and broken clearance of molecular byproducts such as amyloid-β. The expected result was a much more rapid accumulation of amyloid-β, due to failure to clear unwanted protein aggregates, but in fact exactly the opposite occurred.

Sadly, the animal models of Alzheimer's disease are highly artificial constructs, as humans are near the only species in which this condition occurs. So it is hard to say whether this has any relevance to Alzheimer's disease in humans, or whether it is a peculiar artifact of the model. This has long been a major challenge in this field of research, the sizable gap between the animal models and the real thing, much larger than is the case for other conditions. It means that any new and promising result in animal studies should be only cautiously applauded, as all too many fail to go any further.

Deposition of extracellular amyloid plaques is one of the main pathological features of Alzheimer's disease (AD), the most common cause of dementia. These plaques are composed primarily of aggregated amyloid β-peptide (Aβ), which is generated through proteolytic processing of the amyloid precursor protein (APP) by β-secretases and γ-secretases. According to the "amyloid hypothesis", accumulation of Aβ in brain is the primary influence driving AD pathogenesis. Therefore, lowering Aβ is a major therapeutic goal in AD. This might be achieved by controlling the production, aggregation, or clearance of Aβ.

The ubiquitin-proteasome system (UPS) is a highly regulated mechanism for protein breakdown in cells. It has been put forward that impaired UPS-mediated proteolysis contributes to AD pathogenesis, but the significance of the UPS in Aβ metabolism remains largely unclear. To study the effects of a chronically impaired UPS on Aβ pathology in vivo, we crossed APPPS1 mice with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based UPS inhibitor. APPPS1 mice express a chimeric mouse/human mutant APP and a mutant human presenilin 1, mutations that both represent early-onset AD, in central nervous system neurons and develop β-amyloid deposits in brain. Unexpectedly, the APPPS1xUBB+1 crossbred mice showed a decrease in plaques during aging. Also, levels of soluble Aβ42 were reduced in brain, suggesting that lower levels of Aβ42 might contribute to the decreased plaque load.

To investigate the effects of UBB+1 expression on APP processing, we carried out secretase activity measurements on brain tissue samples from different mouse lines. In APPPS1 mice, a partial decrease in γ-secretase activity was found compared to wild-type mice, in agreement with disruption of normal γ-secretase function. Interestingly, in APPPS1xUBB+1 triple transgenic mice, γ-secretase activity was partially restored, specifically at 6 months of age. Onset of amyloid plaque pathology in the APPPS1 mouse model occurs at approximately the same age. How UBB+1 exerts this stimulating effect on γ-secretase is not clear, but a potential mechanism may involve regulation of presenilin expression.

Link: https://doi.org/10.18632/aging.101598

People who have undergone chemotherapy or radiotherapy suffer a reduced life expectancy and increased risk of suffering other age-related conditions even when the cancer is defeated. These cancer therapies produce large numbers of senescent cells, both as a result of their toxicity and because they force cancerous cells into senescence. It is quite likely that this is the primary mechanism by which successful cancer treatments nonetheless shorten later lifespan. This could be considered a true form of accelerated aging, as the accumulation of senescent cells is one of the root causes of aging. These cells secrete signals that meaningfully disrupt tissue structure and function even when present in relatively small numbers. The research noted here doesn't make the direct connection to cellular senescence, but the cell properties examined are strongly related to levels of senescence.

Treatments for breast cancer increase patients' risks for long-term and late toxicities, including persistent fatigue, pain, and cognitive dysfunction. Certain treatments, including radiation and some chemotherapeutic drugs, work by damaging the DNA of cancer cells, but they can also cause damage to DNA of normal cells, which can contribute to accelerated biological aging.

To examine whether indicators of biological aging are related to cognitive function in breast cancer survivors, researchers evaluated a group of 94 women who had been treated for breast cancer three to six years earlier. The indicators of biological aging included elevated levels of DNA damage, reduced telomerase enzymatic activity, and shorter telomere length in certain blood cells. (Telomerase is an enzyme that is important for maintaining the length of telomeres, repeat sequences of DNA at the ends of chromosomes that help maintain the health of cells and serve as a marker of cell age.)

The team found that women who had previously been treated for breast cancer who had both higher DNA damage and lower telomerase activity had lower executive function scores. In addition, lower telomerase activity was associated with worse attention and motor speed. Telomere length was not related to any of the neurocognitive domains.

Link: https://newsroom.wiley.com/press-release/cancer/cancer-treatments-may-affect-cognitive-function-accelerating-biological-aging

The Methuselah Foundation is one of the most important non-profits in our longevity science community. It was the original home of the first SENS rejuvenation research programs, and has used our philanthropic support to fund a range of important projects and startups. If you look at many of the advances and initiatives of the past twenty years in our community, behind the scenes you'll find that Methuselah Foundation CEO Dave Gobel was in some way involved. All communities are the sum of their connections, and at the center of ours you will find the Methuselah Foundation and the SENS Research Foundation that it gave rise to, as our community grew in size and scope.

Below find the latest update from the Methuselah Foundation on their progress in helping to cultivate an industry of startups to produce therapies to treat aging, and in advancing the state of tissue engineering for the creation of new organs. Many of us in the community have supported the Methuselah Foundation from the early days, from the days in which the Methuselah 300 was established, a group of people who pledged to donate $25,000 over a decade. There are still spaces for those who want to support an organization that truly makes a difference. Give it some thought.

What If You Could Turn Back The Clock At A Cellular Level?

Enter Turn Biotechnologies, a company we began supporting in August after meeting them in California in February. Turn Bio is on a clear mission: to extend the health span by reverting cellular age. By doing that, tissues and organs can rejuvenate so that the whole body can be healthier and live longer. To do this, Turn Bio developed a technology capable of safely reprogramming how the DNA functions epigenetically. This approach effectively returns cells to a younger state, improving their function without changing their identity. The team comes out from Stanford University and is comprised of the proven scientists Vittorio Sebastiano, Marco Quarta, and Jay Sakar. The new CEO, Gary Hudson, is well known to many of us. The scientific team is optimizing the therapy and will be looking for strategic partnerships soon. As you might have realized by now, this activity falls under two of our six mission strategies: Debug the Code and Restock the Shelves.

New Parts for People: Progress on 3D Bioprinting of Organs

Many of you know Methuselah has been able to fully develop the mission strategy of New Parts for People. With our Support of Organovo, Organ Preservation Alliance, and New Organ Alliance, we are happy to have helped create an environment that fosters innovation in the printing of 3D tissues. We know that the organ shortage will be a thing of the past once these technologies fully mature. Our desire to accelerate results has moved us to make progress in two needle-moving activities.

First, we held a Vascular Tissue Challenge at NASA Ames this past March to continue the road mapping efforts to solve the vascularity challenge. As you may know, while full organs can be 3D printed, lack of blood perfusion is a roadblock to their practical use. In other words, the 3D printed organs begin to die almost as quickly as they are being printed. We partnered up with NASA to create a sizeable prize that would entice world-class teams to join in solving this problem. We are happy to say that 13 teams from academia and the private sector are nearing the point of submission for winning the prize.

We also decided to support a new venture called Volumetric. This team is focused on facilitating 3D printed organs for us all. They are doing this by producing biomaterials that will be used as inks in stereolithographic bioprinting. They just graduated from the NSF I-Corps program designed to help academics translate their breakthroughs into products. In just a few weeks, they have been able to partner up with top 3D bioprinting companies and have started focusing on the production of a bioprinter. What is so exciting about this bioprinter is that it will allow far more academics around the world to own a 3D printer due to its significantly reduced expense compared with alternatives in the market. We think that this move will keep democratizing research in this sector, which will accelerate results.

Methuselah Fund Successfully Closes Its Founder's Round!

We are happy to declare victory as the M Fund is finally closed! As everyone knows, a sector becomes legitimized once investors are excited to put the money in it. We understand that enticing money beyond the research budgets is vital to accelerating results. We wholeheartedly believe in the translation of science to the clinic and know that companies are obligated to do so by coming up with products. That is why the M Fund is so vital to making 90 the new 50 by 2030. With the help of some of you, we successfully finished this Founder's round and raised the full amount we were after. The M Fund investigates several companies weekly, looking for the best ventures to support. We hope to keep pouring fire into this nascent investment sector.

Study: What does it mean to be 90 vs 50 years-old?

What defines an average 90-year-old scientifically? What defines a 50-year-old? How could we make 90 the new 50 by 2030? Clearly, this is something that was of paramount importance since we decided to have the self-imposed deadline of year 2030. We know it is important to understand these questions in order to find out if we succeeded or not by the time 2030 comes around. Since the M Fund has been created to accelerate results in this field by means of targeted investments, we decided early on to study hundreds of longevity-related papers to come up with answers that could point us that way. The study yielded the added benefits of giving us a significant advantage in understanding the investable science that is on the horizon, and is available at our website. We know that you will find this extremely interesting and hope it can add value to your lifestyle and direct investment goals.

Aging is a general process of deterioration, and any specific age-related disease, even one of the fatal conditions, is only a very narrow manifestation of that broad deterioration. It is a fantasy to think that any one specific age-related condition can be cured, entirely removed from the full spectrum of damage that is aging, in isolation, and without impact to the rest of aging. The only way to cure an age-related condition is to repair all of the forms of cell and tissue damage that cause it, and each type of damage has widespread effects beyond its contribution to any one named disease. Aging is treated all at once, or not at all, and is treated by addressing the root causes rather than the late disease state, in other words.

This explains how one can arrive at the results of the study noted here. Run the numbers on age-related mortality, remove the contribution of the few top causes of death, and the result is that life is extended by very little. Aged people will shortly die from other causes, given a hypothetical, fantastical way of absolutely preventing mortality attributed to one specific age-related disease in isolation of all of the others.

In the real world, there are ways of affecting, say, cardiovascular mortality to some degree while affecting the progression of other forms of mortality to a lesser degree: statins and antihypertensive medications, for example. But this is isn't the same thing. The reduction of specific forms of downstream damage (atherosclerotic lesions or high blood pressure) causes benefits to mortality that are spread across many age-related conditions, and are thus larger than the numbers in the study here. This is the way that the first rejuvenation therapies will also work, except that they will produce far greater benefits.

To curb the rising global burden of non-communicable diseases (NCDs), the UN Sustainable Development Goals (SDGs) include a target to reduce premature mortality from NCDs by a third by 2030. We estimated age-specific mortality in 183 countries in 2015, for the four major NCDs (cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes) and all NCDs combined, using data from WHO Global Health Estimates. We then estimated the potential gains in average expected years lived between 30 and 70 years of age (LE30-70) by eliminating all or a third of premature mortality from specific causes of death in countries grouped by World Bank income groups. The feasibility of reducing mortality to the targeted level over 15 years was also assessed on the basis of historical mortality trends from 2000 to 2015.

Reducing a third of premature mortality from NCDs over 15 years is feasible in high-income and upper-middle-income countries, but remains challenging in countries with lower income levels. National longevity will improve if this target is met, corresponding to an average gain in LE30-70 of 0.64 years worldwide from reduced premature mortality for the four major NCDs and 0.80 years for all NCDs. According to major NCD type, the largest gains attributable to cardiovascular diseases would be in lower-middle-income countries (a gain of 0.45 years), whereas gains attributable to cancer would be in low-income countries (0.33 years). Eliminating all deaths from the four major NCDs could increase LE30-70 by an average of 1.78 years worldwide, with the greatest increases in low-income and lower-middle-income countries. On average, eliminating deaths from all NCDs (compared with estimates for only the four major types) would lead to a further 25% increase in the gains in LE30-70.

Link: https://doi.org/10.1016/S2214-109X(18)30411-X

Calorie restriction, mTOR inhibition, and blockade of growth hormone interaction with its receptor all result in slowed aging and extension of healthy life span in mice. These interventions beneficially alter the operation of metabolism in humans, but do not enhance human life span to anywhere near the same degree; the current consensus suggests that an additional five years is probably the largest effect that could be expected to exist. The mechanisms involved overlap, and nutrient sensing plays an important role. Thus researchers looking for common epigenetic signatures shared by all of these interventions have found such shared signatures.

Long ago, the earliest organisms evolved to better maintain themselves in response to seasonal famine, extending their lives and raising the odds of successful reproduction later. That ability has been passed down over evolutionary time, and is present in near all species tested to date. The shorter the species life span, the greater the relative extension of life needed to pass through a season of famine. Thus mice that live only a couple of years can extend their lives by as much as 40% via stress triggers such as limited nutrient intake, while humans with a life span of decades do not exhibit a significant extension of life in this circumstance. Much of the same cellular machinery exists in both species, however, explaining why humans can obtain health benefits from the practice of calorie restriction.

Dietary, pharmacological, and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored.

We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation, and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation.

By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.

Link: https://doi.org/10.1371/journal.pgen.1007766

Today is Giving Tuesday, a day on which to ponder the change you wish to see in the world, and then help to make it a reality. For my part, I would prefer that no-one had to suffer and die because of the damage that accumulates in all of our bodies, through no fault of our own. Being born should not be accompanied by the guarantee of a slow, troubled, and painful decline and death, as it is today. We can do better than this limited human condition we find ourselves in. We can dig ourselves out of this pit. We can develop the means to repair the cell and tissue damage that causes aging, and build a world in which being old doesn't mean being diminished, sick, and at risk of imminent death.

The SENS Research Foundation tackles the lines of scientific development that are required for the first rejuvenation therapies to reach the clinic. The foundation staff unblock the work that has become stuck due to lack of tools, fund the work that has languished due to lack of interest from mainstream, highly conservative funding organizations, and tirelessly persuade the research community to take rejuvenation seriously. They and their allies, such as the Methuselah Foundation, have changed the face of aging research. They continue to produce results, and everything they have done has been powered by charitable donations, but the everyday philanthropy of people like you and I. To see this continue, we must continue to offer our material support.

Every one-time donation made today will be matched, and everyone who signs up as a monthly donor to the SENS Research Foundation will have the next year of their donations matched from the $54,000 SENS Patron challenge fund put up by Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! We believe in the value of the work done by the SENS Research Foundation, and want you to join us in supporting that work.

We, all of us, are the first people to be offered this chance. We are the first to be alive at a time in which medical biotechnology has advanced to the point at which rejuvenation is a practical, real, near term possibility. Every capable individual in the world should be leaping at the chance to fund this research and development. But the sad truth of the matter is that if you are reading this, then you are in a tiny minority. The vast majority of people have no idea that a revolution in health and aging could be just around the corner, if only given support and funding. They believe that the rest of their lives will look the same as those of their grandparents, that aging is set in stone and cannot be changed, that they will suffer and die on a schedule.

Without funding, without publicity, without large-scale development programs, that might even become true for our generation - there are no guarantees in development. Technologies do not become widespread just because they are possible; the realization of progress requires deliberate effort and a great deal of persuasion. Someone has to step up and sound the bell, to shine the lantern. Someone has to be first to tell their friends that rejuvenation therapies are nearly here, given funding. Someone has to take the step of making a charitable donation to help run research programs, rather than just hoping for a better future. If not you, one of the minority reading this missive, then who?

Autophagy is the name given to a collection of maintenance and recycling mechanisms responsible for removing damaged and unwanted proteins and structures from within cells. Many of the means of modestly slowing aging demonstrated in laboratory species feature increased levels of autophagy, in in some cases that increase in autophagy has been shown to be necessary for benefits to result. That autophagy is the most important means by which beneficial stresses such as exercise and calorie restriction improve health and longevity is by no means a novel argument. It has been made for decades, with increasing confidence.

Despite this, there has been comparatively little progress when it comes to the development of therapies that directly target the operation of autophagy, as opposed to calorie restriction mimetics that do so indirectly by targeting regulators known to be involved in the calorie restriction response. (We could argue about which side of that line mTOR inhibitors fall on, but their connection to aging arose out of work on calorie restriction rather than work on autophagy per se). In part this is because safely manipulating the state of metabolism is very challenging; metabolism is enormously complex and still comparatively poorly mapped.

Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age-related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidence suggests that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality.

Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy-dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise-induced TORC1 and autophagy signaling share common pathways with that of CR.

Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity.

Link: https://doi.org/10.1111/acel.12876

Researchers here demonstrate an association between reduced mitochondrial function and onset of sarcopenia in nematode worms. Muscle tissue requires a lot of energy for function and maintenance, and that energy is supplied in the form of adenosine triphosphate (ATP) by the roving herds of mitochondria found within muscle cells. Progressive failure of mitochondrial function is a feature of aging, and is thought to be a contributing cause of the loss of muscle mass and strength, known as sarcopenia, that is characteristic of late life physiology.

Sarcopenia is not exclusive to humans, and has been observed in non-human primates, dogs, rodents, and even the microscopic worm, C. elegans. These observations, therefore, suggest that sarcopenia is an evolutionarily conserved process and whilst some evidence suggests the underlying mechanisms might also be conserved, it remains an open question. There are several theories regarding the cause of sarcopenia, but we do not yet fully understand its aetiology, not least because of an absence of life-long, prospective studies.

Muscle architecture is highly conserved between C. elegans and mammals and the major signaling pathways and degradation systems are also present in both system. Thus, C. elegans is a good organism in which to investigate the molecular changes to muscle with ageing. Previous studies have shown that ageing in C. elegans muscle is characterized by altered structure and reduced function. This is displayed as progressive disorganization of sarcomeres and reduced cell size. Alterations to sarcomere structure have been associated with changes to locomotive ability. Alongside changes to muscle structure and function, mitochondrial defects such as increased fragmentation and reduced mitochondrial volume have also been observed in the body wall muscles of aged C. elegans.

Recently large scale studies using RNAi have been conducted to investigate how muscle health is maintained in C. elegans. These studies have examined the effect of knocking down more than 850 genes on sub-cellular muscle architecture. The results highlighted that in control animals sub-cellular components remained normal through early adulthood, however, after day three of adulthood, abnormal sarcomere and mitochondrial structures were observed. Furthermore, mitochondrial fragmentation appeared to arise earlier in the ageing process than the alterations to sarcomere structure. These data suggest that mitochondrial abnormalities precede other changes to muscles with age.

Here, we use C. elegans natural scaling of lifespan in response to temperature to examine the relationship between mitochondrial content, mitochondrial function, and sarcopenia. Mitochondrial content and maximal mitochondrial ATP production rates (MAPR) display an inverse relationship to lifespan, while onset of MAPR decline displays a direct relationship. Muscle mitochondrial structure, sarcomere structure, and movement decline also display a direct relationship with longevity. Notably, the decline in mitochondrial network structure occurs earlier than sarcomere decline, and correlates more strongly with loss of movement, and scales with lifespan. These results suggest that mitochondrial function is critical in the ageing process and more robustly explains the onset and progression of sarcopenia than loss of sarcomere structure.

Link: https://doi.org/10.18632/aging.101654

Aging is an accelerating process, in which new symptoms of degeneration appear ever faster as the decline progresses. This is characteristic of the aging of any complex system, in that damage to component parts - and the dysfunction that results - tends to produce further damage and dysfunction. To pick one example of many in human biochemistry, cross-linking in the extracellular matrix causes stiffening of blood vessels, which in turn causes hypertension, which in turn causes pressure damage to delicate tissues. Or accumulation of amyloid-β in the brain leads to accumulation of tau that in turn causes cell death and dementia. Thousands of such chains of cause and effect can be found in human aging, few of which are catalogued end to end and in all their detail. The roots of aging and the causes of mortality at the ends of aging are fairly well mapped, but the complexity in between is still a matter of a few paths through a dark forest.

The lack of understanding of the details of the progression of aging, how metabolism is disrupted, and how and why that produces the next form of damage and dysfunction in the chain of cause and consequence, is one of the reasons why it is a slow and expensive process to attempt to alter metabolism to be more resilient. That is true even given the easily established altered states of metabolism, such as that produced by calorie restriction, in which aging is modestly slowed. Metabolism is ferociously complex and incompletely understood. It is thus better to focus on the causes of aging, those forms of damage that arise in the normal operation of youthful metabolism, and are simply side-effects of that operation. If those initial, root cause forms of damage can be prevented or periodically repaired, then it doesn't much matter how they go on to cause aging.

The accumulation of senescent cells is one of the root causes of aging. Even if there were no other causes of aging, cellular senescence would still kill us given time. Senescent cells are constantly created when cells reach the Hayflick limit, or suffer mutational damage, or are exposed to other excessive stresses. Near all self-destruct, and near all that fail in that are instead destroyed by the immune system. A tiny minority remain, to generate a potent mix of signals known as the senescence-associated secretory phenotype. This generates chronic inflammation, disrupts the nearby structure of tissues, and, perhaps worse of all, encourages other cells to become senescent as well. This latter behavior makes sense given the tasks that senescent cells have evolved to carry out, meaning suppression of cancer by preventing at-risk cells from replicating further, steering embryonic growth, and regeneration of injuries, but it also makes their contribution to aging that much worse.

Cellular senescence is thus its own self-contained accelerating process of aging. The more senescent cells present in tissue, the more likely it is that other cells will become senescent in response to stresses or damage. This is yet another reason to prioritize the distribution and further development of safe and effective senolytic therapies capable of selectively destroying senescent cells. These errant cells are in effect actively maintaining a state of age-related dysfunction through their signaling. Removing them is a form of rejuvenation, demonstrated in animal studies, and in the process of being further demonstrated in human clinical trials.

The bystander effect contributes to the accumulation of senescent cells in vivo

Senescent cells accumulate in many tissues during aging. Genetic or drug-mediated specific ablation of senescent cells ameliorates a wide range of age-associated disabilities and diseases in mice. Cell senescence can be triggered by replicative exhaustion or stressors, specifically oncogenic and DNA-damaging stress. Moreover, pre-existing senescent cells in vitro are capable of inducing a senescent phenotype in surrounding bystander cells via integrated ROS- and NF-κB-dependent signalling pathways. It has been suggested that this senescence-induced bystander senescence might be a relevant trigger of senescent cell accumulation in vivo, based on focal clustering of senescent cells in old mouse livers and of SASP-mediated accumulation of senescent cells around pre-neoplastic lesions.

In accordance, autologous transplantation of senescent fibroblasts into healthy knee joints resulted in the development of an osteoarthritis-like condition in mice. Very recently, it was shown that intraperitoneal transplantation of relatively low numbers of senescent cells caused persistent physical dysfunction in mice, indicating that senescent cells can induce a deleterious bystander effect in vivo. However, direct evidence that transplanted or pre-existing senescent cells do induce senescence in surrounding tissues is still weak.

The impact of cell senescence for aging of skeletal muscle and the dermal layer of the skin has been questioned because the major cell types are slowly dividing (dermal fibroblasts) or not dividing at all (myofibres). However, the DNA damage response (DDR) induces a senescence-like phenotype in postmitotic cells like neurons or retinal cells. In the dermis, accumulation of fibroblasts with telomere dysfunction and other senescence markers has been observed in different mammalian species. In mouse skeletal (gastrocnemius) muscle, expression of various senescence markers increased with age and decreased after selective ablation of p16-expressing presumably senescent cells.

After observing increased frequencies of multiple senescence markers in aging myofibres, we xenotransplanted small numbers of senescent human fibroblasts into mouse skeletal muscle and skin. Bioluminescent and fluorescent labelling enabled tracking of the injected cells in vivo for at least 3 weeks as well as their identification in cryosections in situ. We found that mouse cells surrounding the injection sites showed increased frequencies of multiple senescence markers when senescent cells (but not non-senescent cells) were xenotransplanted. Comparing senescent cell accumulation rates in normal and immunocompromised mice under either ad libitum feeding or dietary restriction enabled separate estimations of bystander-dependent versus cell-autonomous senescent cell accumulation, indicating a significant and possibly major contribution of the bystander effect. Adjacent to injected senescent cells, the magnitude of the bystander effect was similar to the increase in senescence markers in myofibres between 8 and 32 months of age.

Forms of retinal degeneration are commonplace in later life, leading to progressive and presently irreversible blindness - though there are promising human trial results emerging from the tissue engineering community of late. The accumulation of senescent cells is a feature of aging found in all tissues. These errant cells should self-destruct or be destroyed by the immune system, but enough survive to linger and cause problems. They secrete an inflammatory mix of signals that disrupts normal tissue structure and function, and their presence is one of the root causes of aging. Thus it is not surprising to find evidence for senescent cells to contribute to retinal degeneration, such as that presented here.

It is good news for patients, and everyone else, whenever cellular senescence is associated with the progression of yet another age-related condition. Low-cost senolytic drugs capable of removing a significant fraction of senescent cells already exist, and numerous companies are working on the commercial development of further and better options. To the degree that we can all access senolytic treatments, and to the degree that those treatments are efficient in removing unwanted senescent cells, then we will age more slowly and the onset of age-related diseases will be postponed.

Regenerative medicine approaches based on mesenchymal stem cells (MSCs) are being investigated to treat several aging-associated diseases, including age-related macular degeneration (AMD). Loss of retinal pigment epithelium (RPE) cells occurs early in AMD, and their transplant has the potential to slow disease progression. The human RPE contains a subpopulation of cells - adult RPE stem cells (RPESCs) - that are capable of self-renewal and of differentiating into RPE cells in vitro. However, age-related MSC changes involve loss of function and acquisition of a senescence-associated secretory phenotype (SASP), which can contribute to the maintenance of a chronic state of low-grade inflammation in tissues and organs.

In a previous study we isolated, characterized, and differentiated RPESCs. Here, we induced replicative senescence in RPESCs and tested their acquisition of the senescence phenotype and the SASP as well as the differentiation ability of young and senescent RPESCs. Senescent RPESCs showed a significantly reduced proliferation ability, high senescence-associated β-galactosidase activity, and SASP acquisition. RPE-specific genes were downregulated and p21 and p53 protein expression was upregulated. Altogether, the present findings indicate that RPESCs can undergo replicative senescence, which affects their proliferation and differentiation ability. In addition, senescent RPESCs acquired the SASP, which probably compounds the inflammatory RPE microenvironment during AMD development and progression.

Link: https://doi.org/10.18632/aging.101624

The author of this open access commentary has long been a strong proponent of forms of programmed aging theory, as well as an outspoken advocate for mTOR inhibitors as an approach to treating aging. I don't agree with programmed aging, and I think mTOR inhibition - like all approaches to modestly slowing aging by mimicking calorie restriction - is of too little benefit to merit large-scale expenditure of research and development resources. The scientific and biotechnology communities should be able to do far better via the SENS-style approaches based on damage repair, and indeed that point is already being demonstrated in the case of senolytic therapies. This article, however, is more of a commentary on high level strategy and the effects of regulation, coupled with a desire to forge ahead rather than hold back in the matter of treating aging, thus I concur with much more of what is said than is usually the case.

For decades, one of the most debated questions in gerontology was whether aging is a disease or the norm. At present, excellent reasoning suggests aging should be defined as a disease - indeed, aging has been referred to as "normal disease." Aging is the sum of all age-related diseases and this sum is the best biomarker of aging. Aging and its diseases are inseparable, as these diseases are manifestations of aging.

What then is aging without diseases, so called "healthy" aging. "Healthy" aging has been called subclinical aging, slow aging, or decelerated aging, during which diseases are at the pre-disease or even pre-pre-disease stage. Diseases will spring up eventually. "Healthy" aging is a pre-disease state in which asymptomatic abnormalities have not yet reached the artificial definitions of diseases such as hypertension or diabetes. Instead of healthy aging, we could use the terms pre-disease aging or decelerated aging.

Currently, the term healthspan lacks clarity and precision especially in animals. Although the duration of healthspan depends on arbitrary criteria and subjective self-rating, it is a useful abstraction. In theory, a treatment that slows aging increases both healthspan (subclinical period) and lifespan, whereas a treatment that increases lifespan (e.g., coronary bypass, defibrillation) is not necessarily increase healthspan. The goal of both anti-aging therapies and preventive medicine is to extend healthspan (by preventing diseases), thus extending total lifespan.

The fact that aging is an obligatory part of the life of all organisms is not important. What is important is that aging is deadly and, most importantly, treatable. Consider an analogy. Is facial hair in males a disease? No of course, not. Still most men shave it, effectively "treating" this non-disease, simply because it is easily treatable. Is presbyopia (blurred near vision) a disease? It occurs in everyone by the age of 50 and is a continuation of developmental trends in the eye. It is treated as a disease because it is easily treatable with eye glasses. Unlike presbyopia, menopause in females is not usually treated because it is not easy to treat. Thus, the decision to treat or not to treat is often determined by whether it is possible to treat. It does not matter whether or not the target of treatment is called a disease.

It is commonly argued that aging should be defined as a disease so as to accelerate development of anti-aging therapies. This attitude is self-defeating because it allows us to postpone development of anti-aging therapies until aging is pronounced a disease by regulatory bodies, which will not happen soon. Aging does not need to be defined as a disease to be treated. Anti-aging drugs such as rapamycin delay age-related diseases. If a drug does not delay progression of at least one age-related disease, it cannot possibly be considered as an anti-aging drug, because it will not extend life-span by definition (animals die from age-related diseases).

Link: https://doi.org/10.18632/aging.101647

Giving Tuesday is just a few days away, the better sibling of earlier days of mandated commerce. Whatever your thoughts on top-down collectivism, there are worse things in the world than a successful movement to prompt people into thinking about the causes they support in principle, and encourage them to make that support material. Philanthropy is a very necessary part of our society, and particularly in the case of technological progress. Established sources of funding for medial research and development, even those we might think of as having an appetite for risk, such as venture capital funds, are in fact very conservative. The greater the pool of funds, the more conservative and risk-averse its controllers. But all new lines of research, all first attempts at development, are by nature highly risky endeavors, and thus there is very little funding for them.

The world is awash in money looking for a home, but next to none of those resources flow towards the high-risk, high-reward projects that will produce the next generation of medical technology. In the case we are interested in, that next generation means rejuvenation therapies capable of repairing and reversing the known root causes of aging. The foundation technologies for rejuvenation, those outlined more than fifteen years ago in the SENS proposals, still largely languish. Despite the successes that our broader community has achieved since then, such as the current excitement and investment in senolytic therapies to destroy senescent cells, most of these lines of work are still poorly funded. Few groups are focused directly on the production of therapies in these underfunded parts of the field.

The only way that lagging fields of research and development move forward in earnest is through philanthropy. Through people like us helping to provide the resources that can power organizations like the SENS Research Foundation and Methuselah Foundation, to give them the ability to fund the right programs, to bring that work up to the level at which the world will notice and large, conservative funding organizations start to join in. Our support has enabled initiatives that have been enormously successful in past years, given the modest size of our community. We have already changed the world by helping to seed research programs that will blossom into rejuvenation therapies - but there is much more yet to be accomplished. We have started. We must now continue towards to goal of a comprehensive toolkit of rejuvenation therapies that can repair all of the cell and tissue damage that causes aging.

So this Giving Tuesday, when you think about how you appreciate the work of the non-profit organizations in our community, then make that appreciation material. Make a donation to support continued progress towards working rejuvenation therapies, and longer, healthier lives for all.

The thymus is where T cells mature, the training ground for the footsoldiers of the adaptive immune system. As the thymus declines in size and function with age, the supply of new T cells falls. This constrains and distorts the existing population of T cells, resulting eventually in chronic inflammation and immunosenescence, the failure the immune response and resulting vulnerability to pathogens and cancer. Atherosclerosis, meanwhile, is a condition of the innate immune system, in that it is caused by macrophages - a type of innate immune cell with origins that have nothing to do with the thymus - flocking to try and fail to remove deposits of cholesterol from blood vessel walls. The resultant dysfunction and death of those macrophages generates growing plaques of fat and cell debris that narrow and weaken blood vessels.

Given these two quite separate sets of mechanisms, what is the link between the two? The answer is chronic inflammation. The processes of atherosclerosis respond strongly to inflammation, as inflammatory signaling changes the behavior of macrophages for the worse. Badly behaving macrophages do less to clean up cholesterol in blood vessel walls, and may even actively make the situation worse by propagating inflammatory signals themselves. That much is straightforward and well-explored by the research community. The novel speculation in the open access paper here is a link between low-density lipoprotein and decline in thymic function, making a feedback loop of sorts. This is the first time I've seen that put forward as a hypothesis, and I have no idea as to its plausibility.

Atherosclerosis is a complex disease characterized by smooth muscle cell proliferation, cholesterol deposition, and the infiltration of mononuclear cells. The formation and progression of atherosclerotic plaques result in the disruption of organ perfusion, causing cardiovascular and cerebrovascular diseases. It has been proved that immune responses participate in every phase of atherosclerosis. There is increasing evidence show that both adaptive and innate immunity tightly regulate the development and progression of atherosclerosis.

Atherosclerosis is considered as an immune inflammatory disease, and the T cell-mediated immune inflammatory response plays an important role in the pathogenesis of atherosclerosis. T cells mature in the thymus and are involved in the process of atherosclerosis induced by inflammation and immune response. Inflammatory mechanisms and immune system mechanisms are crucially involved in the pathophysiology of atherosclerosis and cardiovascular disease. T lymphocytes are involved and play an important role in both the inflammatory response and the immune response. An imbalance of the degree of activation of the protective Treg lymphocytes, the pro-inflammatory and cytotoxic macrophages and T-effector lymphocytes could thus be at the origin of the triggering or not of progression of vascular injury. However, all of these processes are closely associated with thymus function. In other words, changes in the function of thymus will be deeply affecting the process.

Based on previous research, we can speculate that the changes of thymus function may have an impact on the process of atherosclerosis. The mechanism of thymus involvement in the process of atherosclerosis is assumed as follows: Low density lipoprotein or cholesterol reduces the expression of the thymus transcription factor Foxn1 via low density lipoprotein receptors (LDLR) on the membrane surface and low density lipoprotein receptor-related proteins on the cell surface, which cause the thymus function decline or degradation. The imbalance of T cell subgroups and the decrease of naive T cells due to thymus dysfunction cause the increase or decrease in the secretion of various inflammatory factors, which in turn aggravates or inhibits atherosclerosis progression and cardiovascular events. NK T cell, dendritic cells, and macrophages can affect the process of atherosclerosis by affecting the production of naive T cells through the thymus. Furthermore, these cells can also participate in the progression of atherosclerosis via the direct secretion of cytokines or inducing other cells to secrete cytokines.

According to our hypothesis, various biotechnologies can be selected to improve aging thymus function in animal experiments. In the clinical treatment of atherosclerosis, and even other immune-related diseases, we may consider improving the expression of foxn1 in the human body, thereby improving or restoring aging thymus function and resisting the related-diseases caused by the decline of immunity. Further investigation on changes of thymus function will help to develop new therapeutic targets that may improve outcomes in atherosclerosis and cardiovascular disease and discover novel approaches in the treatment of atherosclerosis and vascular disease.

Link: https://doi.org/10.7150/ijms.27238

Significant progress has been made in the tissue engineering of intervertebral discs in recent years. Researchers here report on an initial study in larger animals, demonstrating that the implanted intervertebral discs exhibit the correct behavior and otherwise hold up well for at least a few months. Degeneration of intervertebral discs is universal to at least some degree in older people, with a sizable portion of the population suffering pain and loss of function, and the consequences of disc injury at any stage of life can also be lasting and severe. Thus approaches that can meaningfully address this issue are most welcome, whether they involve engineered replacement discs, or act through forms of regenerative therapy that can spur existing tissues to restore themselves.

The soft tissues in the spinal column, the intervertebral discs, are essential for the motions of daily life, such as turning your head to tying your shoes. At any given time, however, about half the adult population in the United States is suffering from back or neck pain, for which treatment and care place a significant economic burden on society - an estimated $195 billion a year. While spinal disc degeneration is often associated with that pain, the underlying causes of disc degeneration remain less understood. Today's approaches, which include spinal fusion surgery and mechanical replacement devices, provide symptomatic relief, but they do not restore native disc structure, function, and range of motion, and they often have limited long-term efficacy. Thus, there is a need for new therapies.

Tissue engineering holds great promise. It involves combining the patients' or animals' own stem cells with biomaterial scaffolds in the lab to generate a composite structure that is then implanted into the spine to act as a replacement disc. For the last 15 years, a team has been developing a tissue engineered replacement disc, moving from in vitro basic science endeavors to small animal models to larger animal models with an eye towards human trials. Past studies from the team successfully demonstrated the integration of their engineered discs, known as disc-like angle ply structures (DAPS), in rat tails for five weeks. This latest research extended that time period in the rat model - up to 20 weeks - but with revamped engineered discs, known as endplate-modified DAPS, or eDAPS, to mimic the structure of the native spinal segment. The addition of the endplates helped to retain the composition of the engineered structure and promote its integration into the native tissue.

MRI, along with histological, mechanical, and biochemical analyses, showed that the eDAPS restored native disc structure, biology, and mechanical function in the rat model. Building off that success, the researchers then implanted the eDAPS into the cervical spine of goats. They chose the goat because its cervical spinal disc dimensions are similar to humans' and goats have the benefit of semi-upright stature. Researchers demonstrated successful total disc replacement in the goat cervical spine. After four weeks, matrix distribution was either retained or improved within the large-scale eDAPS. MRI results also suggest that disc composition at eight weeks was maintained or improved, and that the mechanical properties either matched or exceeded those of the native goat cervical disc.

Link: https://www.pennmedicine.org/news/news-releases/2018/november/treating-spinal-pain-with-replacement-discs-made-of-engineered-living-tissue-moves-closer-to-reality

Klotho is one of the better known longevity-associated genes. More klotho improves function and slows measures of aging in mice, and there is suggestive evidence for the same to be true to some degree in humans. The effect on life span is likely to be smaller in our comparatively long-lived species, unfortunately. This is true of all of the approaches to slowing aging for which there is data in both mice and humans to directly compare. Changes to the operation of metabolism that influence the pace of aging are subject to a long history of evolutionary pressures that lead to much greater plasticity of lifespan in response to environmental circumstances in short-lived species. Consider seasonal famines for example; a season is a sizable fraction of a mouse life span, but not of a human life span, and so only the mouse evolves the ability to live much longer when subject to stresses of this nature.

Much of the recent work on klotho has focused on its positive influence on the function of the brain. Delivering klotho improves cognitive function in both young and old animals, and thus this approach to therapy isn't just a case of producing a tool to mitigate some of the mental declines of aging, even though it is very much the case that levels of klotho diminish in later life. Klotho therapies, once developed, might be an enhancement that could benefit all people.

Klotho doesn't just act in the brain, however. As the research noted here makes clear, klotho also plays an important role in the regeneration of muscle tissue. This is the result of long years of investigation into how klotho interacts with the rest of cellular biochemistry in muscles; it is a complex business. The open access paper below outlines evidence to suggest that mitochondrial function is the critical mechanism by which klotho provides benefits. Mitochondria are the power plants of the cell, providing energy stores needed for cellular function. Loss of mitochondrial function is implicated in numerous aspects of aging, particularly in energy-hungry brain and muscle tissues. So it may well be that a sizable fraction of klotho's benefits in the brain are also mediated by greater mitochondrial function.

'Longevity Protein' Rejuvenates Muscle Healing in Old Mice

One of the downsides to getting older is that skeletal muscle loses its ability to heal after injury. New research implicates Klotho, both as culprit and therapeutic target. In young animals, Klotho expression soars after a muscle injury, whereas in old animals, it remains flat. By raising Klotho levels in old animals, or by mitigating downstream effects of Klotho deficiency, the researchers could restore muscle regeneration after injury. "We found that we were able to rescue, at least in part, the regenerative defect of aged skeletal muscle. We saw functional levels of muscle regeneration in old animals that paralleled those of their young counterparts, suggesting that this could potentially be a therapeutic option down the road."

Suspecting that Klotho acts through mitochondria dysfunction, the researchers gave Klotho-deficient animals a mitochondria-targeting drug called SS-31, which currently is in phase III clinical trials. Treated animals grew more new muscle tissue at the site of injury compared to untreated controls, and their strength after recovery rivaled that of genetically normal mice. Similarly, injecting Klotho into older animals a few days after injury resulted in greater muscle mass and better functional recovery than their saline-treated counterparts. Normal, healthy mice did not benefit from SS-31 after injury. Clinically, these findings could translate to older adults who either sustained a muscle injury or underwent muscle-damaging surgery. Giving them Klotho at the appropriate timepoint could boost their muscle regeneration and lead to a more complete recovery.

Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration

In this study, we tested the hypothesis that age-related declines in α-Klotho drive dysfunctional muscle progenitor cell (MPC) mitochondrial bioenergetics, ultimately resulting in an impaired tissue regeneration. Our findings demonstrate that young skeletal muscle displays a robust increase in local α-Klotho expression following an acute muscle injury with transient demethylation of the Klotho promoter. However, aged muscle displays no change in Klotho promoter methylation and no increase in α-Klotho expression following injury.

Levels of α-Klotho in MPCs derived from aged mice are decreased relative to those of young animals, and genetic knockdown of α-Klotho in young MPCs confers an aged phenotype with pathogenic mitochondrial ultrastructure, decreased mitochondrial bioenergetics, mitochondrial DNA damage, and increased senescence. Further supporting a role for α-Klotho in skeletal muscle vitality, mice heterozygously deficient for Klotho (Kl+/-) have impaired MPC bioenergetics that is consistent with a defective regenerative response following injury, but the regenerative defect of Kl+/- mice is rescued at the cellular and organismal level when mitochondrial ultrastructure is restored through treatment with the mitochondria-targeted peptide, SS-31.

Finally, we demonstrate that systemic delivery of exogenous α-Klotho rejuvenates MPC bioenergetics and enhances functional myofiber regeneration in aged animals in a temporally dependent manner. Together, these findings reveal a role for α-Klotho in the regulation of MPC mitochondrial function and skeletal muscle regenerative capacity.

Alzheimer's disease begins with increasing amounts of amyloid-β in the brain, leading to solid aggregates that distort cell function and cause a comparatively mild level of cognitive impairment. Over time, this initial abnormal biochemistry sets the stage for the later, much more serious accumulation of an altered form of tau protein. Tau aggregates causes severe loss of function and cell death, with dementia as the result. The research community is divided over the deeper origins of Alzheimer's, the processes that cause only some people to exhibit raised levels of amyloid-β, but it seems clear that comprehensive, effective treatment strategies must in some way tackle both amyloid and tau aggregates. If one therapy can clear out both forms of aggregate, then all to the good, but unfortunately there are few examples capable of this outcome.

In the case here, the reduction in amyloid-β is achieved directly, while the reduction in tau is achieved indirectly. The particular form of amyloid-β targeted by the therapy is involved in altering tau in ways that encourage its aggregation. Whether this mechanism is important in humans to the same degree that it is important in the particular animal model used here is a question best resolved by moving to human trials. One of the challenges inherent in Alzheimer's disease research is that humans are one of the only species to exhibit anything even remotely resembling the condition. Thus the mice used for testing are altered in highly artificial ways to produce models of Alzheimer's. The fine details of how the models differ from human Alzheimer's biochemistry are of great importance, and one of the reasons for the lengthy catalog of failure in clinical trials over the past few decades.

A DNA vaccine tested in mice reduces accumulation of both types of toxic proteins associated with Alzheimer's disease. The vaccine is delivered to the skin, prompting an immune response that reduces buildup of harmful tau and beta-amyloid - without triggering severe brain swelling that earlier antibody treatments caused in some patients. "This study is the culmination of a decade of research that has repeatedly demonstrated that this vaccine can effectively and safely target in animal models what we think may cause Alzheimer's disease. I believe we're getting close to testing this therapy in people."

Although earlier research established that antibodies significantly reduce amyloid buildup in the brain, researchers needed to find a safe way to introduce them into the body. A vaccine developed elsewhere showed promise in the early 2000s, but when tested in humans, it caused brain swelling in some patients. The new idea was to start with DNA coding for amyloid and inject it into the skin rather than the muscle to produce a different kind of immune response. The injected skin cells make a three-molecule chain of beta-amyloid (Aβ42), and the body responds by producing antibodies that inhibit the buildup of amyloid and indirectly also of tau.

The latest study - consisting of four cohorts of between 15 and 24 mice each - shows the vaccine prompted a 40 percent reduction in beta-amyloid and up to a 50 percent reduction in tau, with no adverse immune response. If amyloid and tau are indeed the cause of Alzheimer's disease, achieving these reductions in humans could have major therapeutic value. The study is the latest contribution to decades of research focusing on clearing toxic proteins in hopes of preventing or slowing the progression of Alzheimer's disease.

Link: https://www.utsouthwestern.edu/newsroom/articles/year-2018/dna-vaccine-alzheimers.html

Researchers here demonstrate that MRI scans of white matter in the brain can be used to visualize a form of dysfunction that is strongly associated with the near term development of dementia in patients already showing some degree of cognitive decline. Given that low cost approaches to predicting the declines of neurodegeneration earlier rather than later are still thin on the ground, possibilities such as this one are valuable indeed. The earlier the determination that dementia is ahead, the more opportunities there are to enact preventative strategies.

Neurologists can get a ballpark estimate of a patient's risk of Alzheimer's dementia using the Mini-Mental State Examination questionnaire, or by testing for the high-risk form of the gene ApoE, which increases a person's risk of Alzheimer's by up to 12-fold. Both tests were about 70 to 80 percent accurate in this study. Other assessments, such as PET scans for plaques of Alzheimer's proteins in the brain, are good at detecting early signs of Alzheimer's disease, but available to few patients. PET scans are expensive and require radioactive materials not found in a typical hospital.

In a small study, researchers have shown that MRI brain scans predict with 89 percent accuracy who would go on to develop dementia within three years. MRI brain scans are widely available and give doctors a glimpse into what's going on inside a person's brain. The researchers used a technique called diffusion tensor imaging to assess the health of the brain's white matter, which encompasses the cables that enable different parts of the brain to talk to one another. Diffusion tensor imaging is a way of measuring the movement of water molecules along white matter tracts. If water molecules are not moving normally it suggests damage to white tracts that can underlie problems with cognition.

Researchers identified 10 people whose cognitive skills declined over a two-year period and matched them by age and sex with 10 people whose thinking skills held steady. The average age of people in both groups was 73. Then, the researchers analyzed diffusion tensor MRI scans taken just before the two-year period for all 20 people. The researchers found that people who went on to experience cognitive decline had significantly more signs of damage to their white matter. The researchers repeated their analysis in a separate sample of 61 people, using a more refined measure of white matter integrity. With this new analysis, they were able to predict cognitive decline with 89 percent accuracy when looking at the whole brain. When the researchers focused on specific parts of the brain most likely to show damage, the accuracy rose to 95 percent.

Link: https://medicine.wustl.edu/news/mri-scans-shows-promise-in-predicting-dementia/

I have long argued that reduction in average telomere length with age is a downstream measure of aging, not an upstream cause of aging. Telomeres are the caps of repeated DNA sequences found at the end of chromosomes. A little is lost with each cell division, and when telomeres get too short then the cell become senescent and is destroyed. This mechanism limits the number of times a cell can replicate. The vast majority of our cells are somatic cells that are limited in this way. A tiny number of stem cells can maintain lengthy telomeres via use of the telomerase enzyme and thus divide indefinitely. This is how near all multicellular species keep the risk of cancer low enough to survive long enough to reproduce - only a tiny minority of cells are privileged with unlimited replication capacity.

Average telomere length is thus a measure of how rapidly cells divide and die, combined with how rapidly stem cells divide to deliver new daughter somatic cells with long telomeres to make up the losses. Stem cell function declines with age, a result of both molecular damage direction and indirectly via a changing balance of signals that are reactions to that damage. Fewer daughter somatic cells with long telomeres means shorter average telomere lengths in tissues. Telomere length is thus a measure of declining function.

Nonetheless, many groups are very enthusiastic about using telomerase to artificially lengthen telomeres. This extends healthy life span in mice, despite the fact that it is a matter of putting damaged cells back to work. This outcome, alongside the fact that stem cell therapies are beneficial, suggests that evolution has not produced a fine balance between declining function and cancer risk. There is some room for cells to act more vigorously in later life than they will do naturally. This is not, however, a reversal of aging. It is pushing the damaged engine harder. If we can, then let us take the benefits offered, but cautiously.

The research here is most interesting, as it causally links loss of mitochondrial function to telomere attrition via a mechanism that doesn't appear to have to involve telomerase activity. Mitochondria are the power plants of the cell, vital in the sense that they produce the chemical energy store molecules needed to power cellular activity. Failing mitochondrial function is implicated in age-related diseases of the energy-hungry brain and muscles, for example, though the degree to which this decline results from inherent damage in mitochondria versus reactions to damage elsewhere in tissues is an open question. Being able to demonstrate that age-damaged mitochondria are responsible for some fraction of telomere attrition puts a different twist on benefits in mice that result from lengthening those telomeres again. I'd like to see a paper with more of a focus on stem cells and somatic cells in this context rather than cancer cells, however.

hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction

Here we report an epigenetic mechanism by which mitochondrial dysfunction plays a role in inducing telomere attrition through acetyltransferase activity of hnRNPA2. Our results show that hnRNPA2 mediated H4K8 acetylation is a signal for telomere shortening. Additionally we provide evidence that alterations in the telomere length in response to mitochondrial dysfunction is dependent on histone acetylation status because mutant hnRNPA2 proteins, which show vastly reduced histone acetylation activity, cause a rescue of telomere length. This is in agreement with previous reports in cancer cells where telomere histone acetylation has been shown to correlate with telomere length. While our results show the causal role of mitochondrial dysfunction in telomere length maintenance by a novel epigenetic mechanism, prior studies have reported mitochondrial dysfunction as the result of telomere attrition, providing evidence for the close association between mitochondrial functions and telomere dynamics.

Mitochondria are highly susceptible to damage from numerous factors including free radicals, environmental chemicals, radiation exposure, and lipid peroxides produced by defective electron transport chain, the hypoxic environment prevalent in solid tumors and defective mtDNA transcription and replication machinery. These cellular and environmental stressors can cause mitochondrial defects such as reduction in mtDNA copy number, mtDNA mutations/deletions and impaired electron transport chain activity. In fact, defects in OXPHOS and accumulating mtDNA mutations are associated with aging and age-associated cancers. A common pathological feature of both of these diseases is shortened telomere DNA leading to DNA damage.

The consequence of telomere shortening in aging and cancer remains unclear. The prevailing view is that in aging, telomere shortening continues until cells senesce and finally die, while in cancer, the attrition stops when the telomere DNA reaches a critical length, and cells continue to divide and proliferate. It is suggested that induced telomerase activity in cancer cells is a critical factor, which prevents cell senescence and promotes tumor proliferation. It may be seemingly contradictory that mitochondrial dysfunction in immortalized cancer cells induces a proliferative phenotype in spite of mitochondrial stress induced telomere attrition. In a recent study tested the telomerase activity in these cell lines and found that mitochondrial stress induced signaling simultaneously activates telomerase in these cells. This provides a plausible explanation for these cells to maintain the critical telomere length for resisting senescence. In support, in IMR-90 cells, which do not express telomerase, we show that induction of mtDNA depletion results in hnRNPA2 activation and telomere shortening resulting in senescence. This suggests that the rescue of telomere length is possibly attributable to the reduced telomere histone acetylation but not due to activation of telomerase.

The authors of this open access commentary paint a picture of Alzheimer's disease as a condition that starts in a variety of different ways, all of which lead to amyloid-β accumulation, and this is then the common gateway to pathology and dementia. Once an individual begins to accumulate raised levels of amyloid-β, then the characteristic degeneration of Alzheimer's proceeds from there. This is a slow burn over years or decades in which the biochemistry of the brain becomes ever more aberrant, culminating in the development of tau aggregates, inflammation, dementia, and cell death.

The question has always been why only a fraction of people with any given risk factor go on to develop raised amyloid-β levels and full blown Alzheimer's disease. A variety of explanations are presently in various stages of construction and proof, most of which propose a way in which elevated amyloid-β levels might arise in only a portion of the population. Examples include persistent viral infection and differences in the drainage of cerebrospinal fluid through the cribriform plate.

Postmortem data clearly shows that Alzheimer's disease (AD) pathology rarely occurs in isolation. Most AD patients harbor more than one pathology in the brain, with cerebrovascular disease being the most common coexisting pathology. Furthermore, the frequency of both cerebrovascular and Alzheimer's disease increases with age. However, in what way cerebrovascular disease and AD pathology act in synergy leading to downstream neurodegeneration and dementia is still unknown.

Cerebral amyloid angiopathy (CAA), a form of cerebrovascular disease resulting from amyloid deposition in vessel walls, may be the link between these two frequently coexisting pathologies. It is interesting that anti-amyloid therapy has been reported to increase the incidence of microbleeds, potentially due to removal of amyloid through vessel walls. The big question is whether CAA is just a passenger on the AD train. How does CAA interact with amyloid and tau pathology? For instance, does CAA come in early on in disease pathogenesis by affecting the spread of neurofibrillary tangles across the brain? Or is CAA an event occurring in later stages, acting downstream to amyloid and tau pathology thus mostly contributing to neurodegeneration and brain atrophy? All these questions remain largely unanswered.

We recently conducted a comprehensive characterization of these AD subtypes in terms of cerebrovascular disease. We concluded that CAA seems to make a stronger contribution to hippocampal-sparing and minimal atrophy AD, whereas hypertensive arteriopathy, another form of cerebrovascular disease, may make a stronger contribution to typical and limbic-predominant AD. Evidence suggests that neurodegeneration can be expressed differently across different AD subtypes. Future research will also have to answer why amyloid pathology starts, what is triggering the cascade, and whether this differs in the different subtypes. Current data shows that dementia in AD is a downstream event that can be reached along different pathways. These different pathways may necessitate their own specific therapeutic strategies.

Link: https://doi.org/10.18632/aging.101638

Numerous studies demonstrate that increased exercise in the elderly reduces mortality risk and improves many measures of health. The glass half empty view of these results is that most people in wealthy, technological societies are not exercising sufficiently, and thus sabotaging their health. This conclusion is supported by the reduced presence of many of the characteristic aspects of age-related decline observed in hunter-gatherer populations, despite comparatively poor access to medical support throughout life. Exercise too little, and the result is that the decline into frailty is faster and greater than it might be. No-one can yet choose to avoid aging, as that will require rejuvenation biotechnologies, but it nonetheless still possible to choose poorly in life, in ways that will make aging notably worse.

The people participating in this research participated in a controlled, personalised programme of strength, balance, and walking exercises adapted to their possibilities, even during the acute phase of their diseases. Depending on the status of each patient, training intensity ranging between 30% and 60% of their muscular capacity was specified, so they did leg and arm exercises. These sessions lasted twenty minutes twice a day (morning and afternoon), over between five and seven consecutive days (including weekends and public holidays) under the individual supervision of experts in the field of physical exercise for the elderly.

The results of the study show that when discharged from hospital, the group that had participated in the prescribed programme of exercise achieved, in comparison with those who had not done it, a total of 2.2 points above the average on a maximum score of 12 in the SPPB (Short Physical Performance Battery) functional assessment tool, which measures balance, walking speed and leg strength, and 6.9 points above the average score in the Barthel Functional Index for Activities of Daily Living, which has a maximum score of 100 points. "Until now, no one had suggested that patients of this type (elderly people with a range of diseases) could benefit in just five days from a personalised exercise programme far removed from the usual message of 'get up and walk along the corridor a little' or 'rest in bed or in an armchair.´"

Significant benefits of the intervention from the cognitive and life quality perspective were also found. These improvements were achieved without any side effects or increase in hospital stay. "Nevertheless, this intervention did not change the rate of re-admittance or mortality three months later. In such an elderly population as those in the study and with a theoretically short life expectancy following hospitalisation, the aim of our intervention was not to increase the quantity but the quality of life. Sometimes we believe that improvements in technologies or the latest innovative treatment can provide all the solutions for our problems, but we are not aware that disability generated by hospitalisation may exert a greater impact than the very disease that prompted admittance in the first place. In this respect the hugely positive effect that physical exercise can have on disease prevention and treatment is reiterated."

Link: https://www.eurekalert.org/pub_releases/2018-11/ef-apo111918.php

The thymus atrophies with age, and since its primary function is to support the maturation of T cells, this means that the supply of new T cells, fresh and ready for action, also declines with age. This contributes greatly to immunosenescence, the progressive age-related failure of the immune system to respond to pathogens and destroy damaged or malfunctioning cells. Numerous research groups are attempting to restore the thymus to youthful size and activity, and thus also restore the supply of T cells, and reverse loss of immune function. A wide variety of approaches are under development, from gene therapies and small molecules aimed at the controlling proteins of thymic activity to tissue engineering and cell therapies.

Thymic rejuvenation is only one aspect of comprehensive restoration of youthful immune function. The hematopoietic stem cell population in bone marrow that generates immune cells becomes damaged and declines in function with age. These calls must be replaced in a manner that is far safer, more reliable, and cost-effective than current hematopoietic stem cell transplants. The accumulated debris of years of malfunctioning, damaged, and senescent immune cells must be safely destroyed. Further, of late the compelling argument has been made that lymph nodes become so dysfunctional with age that they will block the benefits of raised numbers of effective immune cells. Lymph nodes play a vital role in the immune response, acting as a sort of coordination point for immune cells to talk to one another. Thus regeneration of lymph nodes appears to be on the agenda as well.

Each of those tasks is big enough to build a company around, but all need to be accomplished at the end of the day. The way in which these compound development projects typically work is that every company involved works on achieving success in one line of work, even though the scope of benefits is reduced by the absence of the other programs. That success can then be used to generate interest and funding enough to start tackling those other programs. Sometimes this takes an industry and many companies collaborating, sometimes a single company can work its way through over the years. The way forward is at least fairly clear.

The open access paper here is effectively a call to arms on the lymph node dysfunction issue, the formally published results from scientific work publicized last year. The researchers use one of the weaker approaches to thymic rejuvenation in order to demonstrate that raised amounts of new T cells emerging from the thymus fail to help the immune response to infection when lymph nodes are dysfunctional in older animals. In this respect, the proposition is that there are three limiting factors here, that arise at differing times and to differing degrees across the course of aging, rather than only two: (a) hematopoietic stem cell output of immune cells, (b) thymic activity to allow those immune cells to mature, and (c) the integrity of lymph nodes to allow immune cells to coordinate and act.

One of the more interesting aspects of lymph node aging is that it involves significant amounts of fibrosis, the replacement of correct tissue structure with scar-like structures. In recent years fibrosis has been strongly connected with cellular senescence and the detrimental effects these cells have on regeneration and the extracellular matrix in their surroundings. Removal of senescence cells is a going concern, shown to improve many measures of function in older animals. So when approaching the lymph node challenge the first thing to try is probably the established senolytics, drugs that can selectively destroy a fraction of senescent cells. I believe that no-one in the senescence community has yet earnestly looked into what happens in the lymph nodes of animals treated with senolytics, but that will change soon enough.

Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates

The thymus undergoes age-related involution, that includes progressive loss of thymic epithelial and hematopoietic lineage cellularity, an increase in adiposity, and reduced T-cell output. In the periphery, fewer naïve T cells are available, and the old T-cell compartment is less able to respond to infections and cancer. This is believed to contribute to increased vulnerability of older adults to emerging and reemerging infections. More recent evidence suggests that secondary lymphoid organ (SLO) organization and structure also undergo changes with increased age, and the impact of these changes upon naïve T-cell survival and function is beginning to be understood.

A "holy grail" of T-cell aging research is to achieve functional rejuvenation of T-cell function. Early experiments with surgical castration have shown that transient thymic rejuvenation is possible, as measured by increased thymic volume and cellularity. Similar results have since been obtained using pharmacological sex steroid blockade as well as injection of growth factors. While some of these studies have shown some improvement in peripheral immune function in treated mice, the ultimate tests of functional immunity in the face of microbial challenge were not performed. Therefore, the question remains how well thymic rejuvenation improves the peripheral T-cell pool with aging, and whether it confers improved protection against infection.

To address this question, we examined the effects of (a) keratinocyte growth factor (KGF) administration in mice and nonhuman primates, or (b) sex steroid ablation (SSA) in mice using an antagonist of the luteinizing hormone-releasing hormone receptor, degarelix (Firmagon). Despite robust thymic rejuvenation in response to both interventions, we found no evidence of improved peripheral T-cell maintenance. KGF-treated old mice were not more effective at mounting CD8 T-cell responses to, or clearance of, Listeria monocytogenes. Similarly, degarelix did not improve CD8 T-cell responses to, or survival of old mice following challenge with, West Nile virus (WNV).

While rejuvenated thymi produced substantial numbers of recent thymic emigrants (RTE), these RTE did not significantly contribute to T-cell populations in the SLO of old mice compared to adults. We further found that old lymph nodes exhibited considerable fibrosis and degeneration of structure. These data indicate that restoration of thymic function by itself may not be sufficient to improve the immune response in elderly and suggest that interventions to simultaneously alleviate defects in aging SLO may need to be considered when designing strategies to improve immune response in older organisms.

A great deal of present day research is in one way or another focused on forms of lowered calorie intake. There are those who seek to fully map the mechanisms by which calorie restriction and intermittent fasting improve health and extend life significantly in short lived species. There are those who are trying to sufficiently quantify the benefits to be able to produce robust calorie-specific medical diets. There are those who are trying to find pharmaceuticals that partially replicate the changes induced by nutrient sensing regulators of metabolism, and thus improve health without eating less.

Any investigation of the mechanisms of calorie restriction and intermittent fasting is a complex business: a lower calorie intake produces sweeping changes in the behavior of cells and systems in the body, and metabolism is far from completely understood. The research community will only understand the fine details of exactly how eating less increases life span when they understand the fine details of cellular metabolism as a whole: how variations in metabolism determines variations in pace of aging. The achievement of that challenging goal lies decades in the future, which is one good reason not to bet on calorie restriction and fasting mimetic drugs to produce large gains in human life span any time soon.

The worldwide increase in life expectancy has not been paralleled by an equivalent increase in healthy aging. Developed and developing countries are facing social and economic challenges caused by disproportional increases in their elderly populations and the accompanying burden of chronic diseases. The primary goal of aging research is to improve the health of older persons and to design and test interventions that may prevent or delay age-related diseases. Although environmental quality and genetics are not under our direct control, energy intake is. Both hypo- and hypernutrition have the potential to increase the risk of chronic disease and premature death. Manipulation of a nutritionally balanced diet, whether by altering caloric intake or meal timing, can lead to a delay of the onset and progression of diseases and to a healthier and longer life in most organisms.

An emerging area of research is the investigation of the independent consequences of variations in meal size (through the control of energy intake) and meal frequency (by controlling the time of feeding and fasting) on the incidence or amelioration of multiple age-related diseases, including cardiovascular disease, diabetes, cancer, and dementia. These studies are starting to reveal that health-span and life-span extension can be achieved by interventions that do not require an overall reduction in caloric intake.

We discuss four experimental strategies aimed at altering energy intake or the duration of fasting and feeding periods that result in improved aspects of health in mammals. These are (i) classical caloric restriction, in which daily caloric intake is typically decreased by 15 to 40%; (ii) time-restricted feeding (TRF), which limits daily intake of food to a 4- to 12-hour window; (iii) intermittent or periodic full or partial fasting, that is a periodic, full- or multiday decrease in food intake; and (iv) fasting-mimicking diets (FMDs) that use a strategy to maintain a physiological fasting-like state by reducing caloric intake and modifying diet composition but not necessarily fasting. We also summarize the metabolic and cellular responses triggered by these feeding regimens and their impact on physiology, focusing on studies in rodents, monkeys, and humans.

Although the specific mechanisms are far from being fully understood, this periodic absence of energy intake appears to improve multiple risk factors and, in some cases, reverse disease progression in mice and humans. Thus, the time is ripe to add to our understanding of the molecular mechanisms of action and efficacy of these dietary interventions to the foundation for future clinical trials. We expect that these dietary interventions combined with classical pharmacology and clinical practice will yield interventions that will improve human health and enhance health span and quality of life as we grow old.

Link: https://doi.org/10.1126/science.aau2095

The snakeskin (Ssk) gene joins the short list of genes that can be manipulated to either reduce and extend life span in a short-lived laboratory species, flies in this case. Loss of Ssk causes intestinal dysfunction, and in flies the intestine is probably the most important organ in late life decline and mortality, much more so than is the case in mammals. Increasing Ssk in old flies reduces all of the features of intestinal dysfunction normally associated with aging, and the flies live longer as a result. The composition of gut microbial populations appears to be important in this effect, but it is unclear as to how exactly Ssk is mediating those populations, even given a fair amount of research linking changes in microbial populations with the cellular mechanisms that Ssk is known to be involved in.

Occluding junctions play critical roles in epithelial barrier function, restricting the free diffusion of solutes between cells, as well as in the regulation of paracellular transport. In vertebrates, the occluding junctions are called tight junctions and their functional roles are well characterized. A functionally analogous structure, called the septate junction (SJ), exists in invertebrates, such as the smooth SJs (sSJs) of Drosophila, which are found in endodermally derived epithelia, such as the midgut.

Age-related alterations in intestinal epithelial junction expression and localization have been observed in flies and mammals, yet the causal relationships between changes in occluding junction function, intestinal homeostasis, and organismal aging are only beginning to be understood. Age-onset microbial dysbiosis is tightly linked to intestinal barrier dysfunction in both flies and mice. Critically, however, the question of whether manipulating intestinal occluding junction expression can delay age-onset dysbiosis and/or positively affect lifespan has not been addressed in any organism.

In this study, we show that Snakeskin (Ssk), an sSJ-specific protein, plays an important role in controlling the density and composition of the gut microbiota and that upregulation of Ssk during aging can prolong Drosophila lifespan. More specifically, loss of intestinal Ssk in adults leads to rapid-onset intestinal barrier dysfunction, changes in gut morphology, altered expression of antimicrobial peptides (AMPs), and microbial dysbiosis. Critically, we show that these phenotypes, including intestinal barrier dysfunction and dysbiosis, can be reversed upon restored Ssk expression.

Consistent with a critical role for intestinal junction proteins in organismal viability, loss of intestinal Ssk in adult animals leads to the rapid depletion of metabolic stores and rapid death. Importantly, restoring Ssk expression in flies showing intestinal barrier dysfunction prevents early-onset mortality. Moreover, intestinal upregulation of Ssk in normal flies protects against microbial translocation, limits age-onset dysbiosis, and prolongs lifespan. Our findings support the idea that occluding junction modulation could prove an effective therapeutic approach to prolong both intestinal and organismal health during aging in other species, including mammals.

Link: https://doi.org/10.1016/j.isci.2018.10.022

Today's open access paper is, I think, chiefly interesting for the later section in which the authors ponder future directions for the treatment of aging via means of destroying or manipulating the activity of senescent cells. The accumulation of senescent cells is one of the root causes of aging. The creation of senescent cells happens constantly in the undamaged and fully functional tissues of young people, a tiny fraction of these senescent cells manage to evade destruction and linger to cause issues, and given enough time that fraction will grow large enough to kill you. Cellular senescence isn't the only harmful cause of aging, of course. As things stand, senescent cells speed the death that emerges from other forms of damage, and never have the chance to be the cause of death in and of themselves. Aging is a collaborative murder, carried out via the interaction of many distinct processes.

Selective destruction of senescent cells appears to work well as an approach to remove their contribution to aging. There are comparatively few such cells, no-one has yet found a population of senescent cells that is sufficiently vital to keep around, and numerous methods of destruction either already exist and are under development. By all measures assessed so far, old mice are greatly improved following removal of even a fraction of their senescent cells. To my eyes at least, the path to the future of the senescence field is the very simple one of finding ever more efficient ways to remove these errant and unwanted cells. The first approaches, even as they produce outstanding results in animal studies, are far from perfect. Removing only half of the senescent cell burden leaves half of the job undone, half of the benefits left to be claimed.

Some researchers disagree with the sole focus on destruction, however. They wish to pursue modulation of the bad behavior of senescent cells, or find ways to undo the transition into senescence. I have to think that this is a much harder road to more limited benefits, as well as offering greater risks to patients as damaged cells are pushed into renewed labors. Cellular senescence serves a purpose, in that it is protective against cancer, aids in regeneration from injury, and is a vital part of the replication limit imposed on most cells. In all such cases, the requirement for senescence and its characteristic behaviors is brief and the senescent cells can and should be removed afterwards. If a cell has become senescent due to DNA damage, with the accompanying risk of cancer, then better to remove it than to try to restore it, at least at our present level of technological sophistication.

The senescent cell epigenome

When cellular senescence was first characterized in in vitro cell culture, links to tissue and organismal aging were proposed. Critics of cellular senescence questioned its relevance to in vivo aging, their possibility of being an artefact and the inevitable lack of senescence despite normal aging in lower organisms. Senescence as a pro-aging phenomenon gained popularity with the discovery of biomarkers such as p16 and beta-galactosidase in multiple aged tissues. Mechanistically, the idea of senescent cells being causal in chronic inflammation characteristic of aging, also gained momentum with the discovery of the senescence-associated secretory phenotype (SASP).

The senescence field came of age with four major milestones, (a) two proof-of-concept studies showed major improvement in healthspan and lifespan in mice by the targeted ablation of senescent cells, (b) development of small molecule senolytics as a therapeutic strategy for clearing senescent cells, (c) demonstration that senolytics improve physiological function and lifespan in aged mice and (d) the success of senolytics in pre-clinical studies of a range of age-related conditions. Below, we discuss potential alternatives to senolytics that can deploy epigenetic proteins as "switches" to turn on/off specific pathways in senescent cells for their effective elimination.

SASP inhibitors

Despite the overwhelming success of senolytics, fundamental concerns about specificity and safety prevail. Additionally, the potential benefit of senolytics in treating age-related disease remains to be tested. A second class of molecules that have shown promise in anti-aging rejuvenation therapies is SASP inhibitors. The concept of annihilating the pro-aging arm of senescent cells while preserving the anti-tumor arm is a very attractive treatment option in the elderly who have a high incidence of cancer. Both rapamycin and metformin have shown anti-SASP effects and are on the road to clinical trial for aging. Alternatively, epigenetic enzymes that play a key role in turning on SASP genes (MLL1 and BRD4) can be inhibited by small molecules to prevent its deleterious effects.

Autophagy activation

Autophagy is a self-degenerative process that clears and recycles damaged cellular components. In a seminal publication, it was reported that basal autophagy is essential to maintain the stem-cell quiescent state while preventing senescence of muscle satellite cells in mice. Furthermore, autophagy declines during aging, calorie restriction activates autophagy, and dysfunctional autophagy is evident in Alzheimer's disease pathology. Thus, boosting general macroautophagy (non-selective) is a viable anti-aging avenue. The challenge of autophagy-promoting strategies however comes from observations that autophagy of "nuclear" substrates might in fact contribute to senescence, aging, and inflammation.

Immune-mediated clearance

Senescent cells are naturally cleared by innate immune mechanisms with the macrophage playing a central role. However, immune cells themselves undergo progressive decline in function (termed immunosenescence) that actively contributes to senescent cell accumulation. Furthermore, it has been proposed that subsets of senescent cells become resistant to immune-mediated clearance. Therefore, epigenetic interventions that boost immune surveillance in aged tissues or antibody-based therapies that revert the immune-resistance of senescent cells may also be future rejuvenation strategies.

Rejuvenation therapy

The principles of regenerative medicine can be applied in aging and age-related disease. Expression of pluripotency factors in senescent cells have been shown to allow cell cycle entry with reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism. Additionally, their expression in mice has also shown amelioration of a panel of age-related phenotypes. Epigenetic factors that can potentiate reprogramming can be used to rejuvenate senescent/aged cells. However, it is important to be cautious with regenerative therapy in the elderly because of its potential to be pro-tumorigenic.

Other potential epigenetic therapies

The emerging conceptual themes that arise from the observations are (a) a gradual euchromatinization of the genome, (b) loss or disorganization of constitutive heterochromatin due to (c) breakdown of the nuclear lamina and changes in nuclear morphology and (d) loss of spatial organization of the genome. These large-scale changes manifest in profound transcriptional alterations that ultimately activate programs such as SASP and contribute to transcriptional noise. Systematic screens for epigenetic factors will likely yield potential candidates that can be targeted to prevent or reverse the detrimental effects of senescence.

Given enough data from enough old people, to what degree could modern approaches to information processing be used to derive useful information about the underlying mechanisms of aging? Such as which of the varied collection of causes and consequences involved in the biochemistry of aging are more important, how they are connected to one another, and so forth. On the one hand it seems plausible that something can be learned here, but on the other hand it seems unlikely to be as effective an approach as selectively interfering in specific mechanisms in order to observe the outcome in animal studies.

So far near all of the demonstrated approaches capable of slowing aging have involved upregulation of stress responses, something that changes near all aspects of metabolism and influences near all aspects of aging. That makes it hard to draw conclusions about the structural makeup of aging, how its distinct processes are weighted, and how they interact. But with the advent of narrow approaches such as senolytic drugs that destroy senescent cells, it becomes possible for the first time to easily affect just one aspect of aging. It will be interesting to observe the data resulting from analytical studies as they arrive in the years ahead.

Aging in most species, including humans, manifests itself as a progressive functional decline leading to the exponential increase in death risk from all causes. The mortality rate doubling time is approximately 8 years. Age-independent mortality mostly associated with violent death and infectious diseases has been progressively declining over the last century, mainly due to universal access to modern medicine and sanitation. The risks of death associated with the most prevalent age-related diseases remain very low at first, increase exponentially and dominate after the age of about 40. The incidence rates of the specific diseases, such as cancer or stroke, also accelerate after this age and double at a rate that closely tracks mortality acceleration. It is therefore, entirely plausible to think there is a single underlying driving force behind the progressive accumulation of health deficits, leading to the increased susceptibility to disease and death. This force is aging.

Although we have come to expect that physical decline is a natural consequence of aging, there is no natural law that dictates the exponential morbidity and mortality increase we observe among human populations. It is possible for death risks to increase very slowly, stay constant for extended periods, or even decline with age. Naked mole rats and the growing number of bat species are now recognized as examples of mammals that exhibit the lack of detectable mortality acceleration, or negligible senescence. Formally, this means that the mortality rate doubling time could be arbitrarily large.

We have suggested that the mortality acceleration may vanish depending on modifiable parameters, such as DNA repair or protein homeostasis maintenance efficiency, and should be, in principle, subject to manipulation. We propose to combine big data from large prospective observational studies with analytical tools borrowed from the physics of complex dynamic systems to "reverse engineer" the underlying biology behind the Gompertz law of mortality variables. This approach may yield mechanistic predictive models of aging for systematic discovery of biomarkers of aging and identification of novel therapeutic targets for future anti-aging therapies.

Link: https://doi.org/10.3389/fgene.2018.00483

As one of many continuations of recent efforts to quantify the benefits of various forms of exercise, researchers here find an association between resistance training and reduced risk of cardiovascular disease. The association is fairly binary; people undertaking any meaningful degree of resistance training show the benefit, and the size of the benefit doesn't increase with more resistance training. That might make us suspicious regarding the direction of causation. If the association exists because only more robust older individuals tend to undertake resistance training, then the absence of a curve of increasing benefits for greater time spent in training is the expected outcome. The important determinant in that case is the capacity for resistance training. That said, there is plenty of other evidence to suggest that resistance training does in fact provide benefits, a situation analogous to that for aerobic exercise.

Lifting weights for less than an hour a week may reduce your risk for a heart attack or stroke by 40 to 70 percent, according to a new study. Spending more than an hour in the weight room did not yield any additional benefit, the researchers found. The results - some of the first to look at resistance exercise and cardiovascular disease - show benefits of strength training are independent of running, walking, or other aerobic activity. In other words, you do not have to meet the recommended guidelines for aerobic physical activity to lower your risk; weight training alone is enough.

Reseaerchers analyzed data of nearly 13,000 adults in the Aerobics Center Longitudinal Study. They measured three health outcomes: cardiovascular events such as heart attack and stroke that did not result in death, all cardiovascular events including death and any type of death. Resistance exercise reduced the risk for all three.

Much of the research on strength training has focused on bone health, physical function and quality of life in older adults. When it comes to reducing the risk for cardiovascular disease, most people think of running or other cardio activity. Weight lifting is just as good for your heart, and there are other benefits. Using the same dataset, researchers looked at the relationship between resistance exercise and diabetes as well as hypercholesterolemia, or high cholesterol. The two studies found resistance exercise lowered the risk for both. Less than an hour of weekly resistance exercise (compared with no resistance exercise) was associated with a 29 percent lower risk of developing metabolic syndrome, which increases risk of heart disease, stroke and diabetes. The risk of hypercholesterolemia was 32 percent lower. The results for both studies also were independent of aerobic exercise.

Link: https://www.news.iastate.edu/news/2018/11/13/resistancecvd

The Milken Institute has published a set of interviews with a variety of scientists and non-scientists on topics of human longevity. A few these are of interest to those of who would like to see a fast path to rejuvenation therapies unfold in the years ahead. Some of the others illustrate a point I made last week, which is that while all that really needs to happen in this field is for the biotechnologies of rejuvenation to be developed, and as quickly and directly as possible, there are those who feel that the sociological aspects of human longevity must be talked to death in advance. Thus broader advocacy initiatives tend to pull in all sorts of figures who have nothing useful to say about the practical challenges of funding and developing rejuvenation therapies, but who are instead more concerned with how people feel about the topic, or the reaction of the endless rolling bane that is politics, or good health practices in the absence of rejuvenation therapies, or other line items that really, truly, do not matter at the end of the day.

If the therapies are built, the peoples of the world will quickly adapt, just as they have for any number of past revolutionary advances, and no-one will give much thought to all who felt that there should have been more discussion beforehand. If the therapies are not built, then we all suffer and die, and no-one will give much thought to all who felt that there should have been more discussion beforehand. The primary focus should be on the building, not the talking. This, of course, is not a popular point of view. One counterargument is that the sort of broad advocacy that involves a lot of talk that I'd consider largely irrelevant to the task at hand is in fact necessary in order to win the support of the public, or at least the largest and most conservative sources of funding, organizations that follow the tide of opinion makers rather than striking out in the right direction regardless. Whether or not this is the case is an interesting question, but larger advocacy initiatives all tend to proceed as though it were, and are arguably led by people who know a lot more about advocacy at scale than I do.

My impression of the past few decades of progress is that we started moving a lot faster once the first rejuvenation therapies were robustly demonstrated in the laboratory, but the details of that progress may or may not support my suggested view of the world above. In any case, I'll draw your attention here to the interviews with Laura Deming and Jim Mellon, both investors in the field of rejuvenation biotechnology, and the former a scientist who has studied aging in addition. As people who are helping to fund the research and development, they are among those who have interesting things to say on the topic. But do glance at the other interviews as well; you may find them interesting regardless.

Laura Deming: Healthspan, Not Lifespan

How can we make longevity an essential topic for potential investors?

I think that problem is actually already solved. People in the financial community, at least right now, are rapidly investing or interested in the space. That's the complete opposite of eight years ago, when nobody wanted to put capital into it. One thing that's been helpful is that companies either get access to the public markets or get started with less capital from well-earned means, and these two events have really raised the profile with the field. Going forward, I think what will be helpful is for longevity researchers to make better strides in science. I think the most important thing will be getting that first longevity-specific drug into the hands of patients. Once we see a drug from this area of science that actually produces a measurable benefit to patients that they could not have gotten otherwise, that will be the largest invite to new investors.

What do you think are the main reasons for scientists focusing on increasing healthy lifespan?

One big driver has been that nobody wants just to increase lifespan. It's nobody's idea of a good plan. It's kind of fascinating, because I think in the early days of the field, we didn't really understand what it was that we wanted to optimize for. But now it's very clear to everyone that we should be focusing on increasing the healthy part of the life, not just maximum lifespan in an old, decrepit state.

Jim Mellon: Investing in the Growing Longevity Market

Can you assess the current climate of longevity science? Is the market ready for this opportunity?

The market is now ripe for development. The excitement over rapalogs and senolytics, in particular, is helping, as is the prospect of the metformin trial, TAME. I expect that in the next year a lot of venture capital and possibly public funding will flow the way of longevity science. I think we are at about the internet of 1995 in terms of development.

How does the message of Juvenescence apply to nations that have yet to confront the challenges of population aging?

This will be one of the challenges of our age. Africa is the only place in the world where populations continue to grow rapidly. There is no reason why the life expectancy of Africans on average won't reach at least 100 within 30 years. Policymakers really need to drill down into this.

Are there other ways, besides taking your view of aging as a disease, that might increase government and corporate-funded research into aging?

Yes, we must improve our collective lobbying. The best way to do this is to point out the inevitability of pension scheme failures if governments don't recognize the ultra-longevity that is coming soon - and quickly.

How are younger workers affected when older employees remain on the job past the traditional retirement age?

The nature of work will have to change. As Joan Ruff of the AARP has said, older workers will not only be hired, they will be required. I believe that there will be plenty of work for all, it will just be different. Don't get caught up in the gloom of automation. Just be observant of trends.

Many age-related conditions are associated with solid aggregates in tissues that are formed of altered, damaged, or misfolded proteins. Protein aggregates are thought to be an important contributing cause of these diseases. In most cases the proteins involved in aggregate formation can and do appear in lesser amounts in young tissues, but we can point to underlying problems that might explain why aggregates only appear in significant amounts in old tissues. Failure of clearance via fluid flow or the actions of immune cells for intracellular aggregates, or failure of clearance via autophagy within cells, for example. Near all processes in cellular metabolism falter with age, and increasing amounts of molecular waste is one of the many detrimental consequences.

Aging is in some ways a garbage catastrophe, and removal of aggregates is an important strategy for the treatment of aging as a medical condition. This has unfortunately proven to be a challenging task, particular for those aggregates that form primarily in the brain. The Alzheimer's research community required decades and a great deal of funding to get to the point of even preliminary success in the removal of amyloid-β via immunotherapies, for example. In the case of Parkinson's disease and α-synuclein aggregates, the situation is much the same: slow progress. Thus all novel possibilities for the removal of aggregates associated with neurodegenerative disease should be warmly welcomed.

A defining feature of Parkinson's disease is the clumps of alpha-synuclein protein that accumulate in the brain's motor control area, destroying dopamine-producing neurons. Natural processes can't clear these clusters, known as Lewy bodies, and no one has demonstrated how to stop the build up as well as breakdown of the clumps - until perhaps now. A team of neurologists has found through studies in mice and human brains that one reason Lewy bodies develop is that a molecule, USP13, has removed all the "tags" placed on alpha-synuclein that mark the protein for destruction. Toxic heaps of alpha-synuclein accumulate, and are never taken away. The findings show that inhibiting USP13 in mouse models of Parkinson's disease both eliminated Lewy bodies and stopped them from building up again.

The "tag" that USP13 removes is called ubiquitin, which labels alpha-synuclein for degradation. Parkin is one of a family of ubiquitin ligase enzymes. Ubiquitination is a process in which molecules are labeled (or tagged) with ubiquitin and directed to cellular machines that break them down. USP13 is known as a de-ubiquitinating enzyme, which removes ubiquitin tags from protein. USP13 renders parkin ineffective via removal of ubiquitin tags (de-ubiquitination) from proteins. Loss of parkin function leads to genetically inherited forms of Parkinson's disease.

The study began with postmortem autopsies of individuals who donated their brains to research, including 11 with Parkinson's disease and a control group of 9 without Parkinson's. The autopsies, which occurred 4 to 12 hours after death, found that the level of USP13 was significantly increased in the midbrain in Parkinson's disease patients, compared to the control participants. Studies in mouse models of Parkinson's disease then demonstrated that knocking out the USP13 gene increased alpha-synuclein ubiquitination and destruction. Researchers also saw that USP13 knockdown protected the mice against alpha-synuclein-induced dopamine neuron death. The mice had improved motor performance; parkin protein was increased and alpha-synuclein was cleared.

Link: https://gumc.georgetown.edu/news/Researchers-Find-Inhibiting-One-Protein-Destroys-Toxic-Clumps-Seen-in-Parkinsons-Disease

Researchers here report on two new senolytic compounds identified in the existing library of approved drugs, based on screening work in cell cultures. It is worth bearing in mind that drug candidates that demonstrate good results in cell culture quite often fail to show promise when tested in animals, so it is wise to be patient as new senolytics work their way through the research and development pipeline.

There will be a lot more of this sort of thing in the years ahead, as ever greater amounts of funding pour into finding new ways to selectively destroy senescent cells. Any senolytic approach that removes a significant fraction of these cells will produce a degree of rejuvenation in older patients, and so the hunt for mechanisms has taken on something of the air of a gold rush. So far at least four different mechanisms for prompting the self-destruction of senescent cells are targeted by a dozen or more drug candidates, while immunotherapy and suicide gene therapy approaches also exist. This will be a very busy industry a few years from now, and that bodes well for the future of our health and longevity.

Senescence is a clear hallmark of normal chronological aging. Senescence involves potentially irreversible cell cycle arrest, via the induction of CDK-inhibitors, such as p16-INK4A, p19-ARF, p21-WAF and p27-KIP1, as well as the onset of the SASP (senescence-associated secretory phenotype), and the induction of key lysosomal enzymes (e.g., Beta-Galactosidase) and Lipofuscin, an established aging-pigment. Interestingly, SASP results in the secretion of a wide array of inflammatory cytokines, such as IL-1-beta and IL-6, allowing senescent cells to "contagiously" spread the senescence phenotype from one cell type to another, systemically throughout the body, via chronic inflammation. Such chronic inflammation can also promote the onset of cancer, as well as drive tumor recurrence and metastasis.

Using the promoter of p16-IN4KA as a transgenic probe to detect and mark senescent cells, several research groups have now created murine models of aging in which senescent cells can be genetically eliminated in a real-time temporal fashion. Although this cannot be used as an anti-aging therapy, it can give us an indication whether the removal of senescent cells can potentially have therapeutic benefits to the organism. Results to date show great promise, indicating that the genetic removal of senescent cells can indeed prolong healthspan and lifespan.

As a consequence of this exciting genetic data, a large number of pharmaceutical companies are now actively engaged in the discovery of "senolytic" drugs that can target senescent cells. However, we believe that many FDA-approved drugs may also possess senolytic activity and this would dramatically accelerate the clinical use of these senolytic drugs in any anti-aging drug trials. Here, we have used controlled DNA-damage as a tool to induce senescence in human fibroblasts, which then can be employed as an efficient platform for drug screening.

Using this approach, we now report the identification of two macrolide antibiotics of the Erythromycin family, specifically Azithromycin and Roxithromycin, as new clinically-approved senolytic drugs. In direct support of the high specificity of these complex interactions, the parent macrolide compound - Erythromycin itself - has no senolytic activity in our assay system. Interestingly, Azithromycin is used clinically to chronically treat patients with cystic fibrosis, a genetic disease of the chloride-transporter, that generates a hyper-inflammatory state in lung tissue. Azithromycin extends patient lifespan by acting as an anti-inflammatory drug that prevents the onset of lung fibrosis by targeting and somehow eliminating "pro-inflammatory" lung fibroblasts. Therefore, the efficacy of Azithromycin in cystic fibrosis patients provides supporting clinical evidence for our current findings, as these lung fibroblasts are pro-inflammatory most likely because they are senescent.

Link: https://doi.org/10.18632/aging.101633

Today's good news is that investor Jim Mellon has provided a sizable charitable donation to the SENS Research Foundation in support of their advocacy and rejuvenation research programs. The foundation is currently running their year end fundraiser, and this certainly helps to move the needle towards the goal: I hope that other high net worth individuals take note. The rest of us should also take note! The SENS Research Foundation has succeeded in the past, has helped to advance the field, change the public debate on aging, and move important research from academic lab to clinical development, all as a result of our material support. Collectively, we provided the fuel to power this engine. If we want to see more and better progress towards human rejuvenation in the years ahead, then we must continue to put our shoulders to the wheel and provide the resources needed. Nothing in this world happens without effort, and that effort requires funding.

Accordingly, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! are matching the next year of donations made by any new SENS Patrons who sign up to make a monthly donation to the SENS Research Foundation. Two thirds of our $54,000 matching fund remain to be claimed. Donate today!

The SENS Research Foundation staff and the researchers in laboratories supported by SENS Research Foundation grants are presently hard at work on a range of ways to repair the molecular damage that causes aging, focusing on important areas that are are languishing, both poorly funded and given too little attention by the broader research community. Until comparatively recently that category included work on senescent cells, but now the development of senolytic therapies to destroy those harmful, unwanted cells in order to produce rejuvenation is a rapidly growing, very exciting area of medical biotechnology.

There are many other portions of aging research that could just as readily bloom into sizable medical industries, and just as rapidly given the technology and the proof of concept studies. The goal of the SENS Research Foundation is to enable those starting conditions for each and every one of the known root causes of aging, the forms of cell and tissue damage that ultimately lead to disability, disease, and death. There is tremendous potential in aging research, but all too little of the field is given the resources it merits, when considering the scale of the benefits that can result from the advent of real, actual, working rejuvenation therapies.

That so much of the potential for rejuvenation biotechnology is poorly funded and ignored means that we must step up to do our part. It means that all of the earliest and most important medical research is funded by philanthropy: the radical new directions; the high risk / high reward chances; the promising work for which the tools are lacking. In all such cases the established and very conservative sources of funding shirk their duty. Only philanthropists with a vision for a better future are willing to step up to make the difference. Everything starts with philanthropy, with charitable donations made to those organizations like the SENS Research Foundation that have a proven track record of doing the right thing.

Don't stand on the sidelines. Step up and help us to build a future in which the suffering and death of aging can be prevented or turned back, in which the old are hale and healthy and productive.

The best epigenetic clocks correlate well with chronological age, and when the measure departs from chronological age, that difference correlates well with risk or incidence of age-related disease. A higher epigenetic age is seen in people known to have higher age-related morbidity and mortality. The tantalizing potential offered by these clocks is the ability to quickly determine whether or not a putative rejuvenation therapy actually works, and to what degree it works. A true, rapidly assessed, cheap marker of biological age would greatly accelerate research and development. Unfortunately, this goal remains elusive because it is very unclear as what exactly the clocks are measuring. Yes, they measure changes in specific epigenetic markers, but which of the myriad processes involved in aging cause those epigenetic changes? If researchers cannot answer that question, then it is very hard to derive any useful information from epigenetic clocks.

The open access paper here is a good illustration of this point. Researchers checked the epigenetic age of hypertensive patients, both those using antihypertensive medication and those who did not use the medication. One would expect to see a reduction in epigenetic age, given that (a) the raised blood pressure that occurs with aging is highly damaging to delicate tissues, and (b) even blunt pharmaceutical means of reducing blood pressure, that fail to address the root causes and instead forcefully override cellular reactions, reduce mortality and incidence of age-related disease. Instead, researchers found that patients using antihypertensive medications had a higher epigenetic age. What are we to make of this result? The challenge, again, is that there is no good answer to that question.

DNA methylation, a major form of epigenetic modification, is known to play an important role in aging and the development of age-related health outcomes. Recently, a DNA methylation-based biological age predictor, "DNA methylation age (DNAmAge)", has been established and found to be highly associated with chronological age. The discrepancy between this epigenetic-based indicator and the chronological age has been termed age acceleration (AA), which was found to be heritable and has been used as an index of accelerated biological aging.

Several aging-related factors, including inflammation, neurohormonal disorder, and endothelial dysfunction, have been found to play key mechanistic roles in the development of hypertension, the most common long-term medical condition among older adults that could lead to various forms of age-related health outcomes, such as cardiovascular diseases (CVD), kidney failure, and dementia. Relationships of hypertension and blood pressure with biological aging have also been studied since the introduction of DNAmAge. In 2016 it was found that people with hypertension had a higher AA (0.5 - 1.2 years) in comparison to controls.

The use of antihypertension medication (AHM) reduces the risk of adverse age-related health outcomes caused by hypertension. Specifically, observational studies, clinical trials, and systematic reviews mostly suggested that effective antihypertensive therapy greatly reduces the risk of CVD in patients with hypertension, and may also be associated with a decreased risk of cognitive decline and incident dementia. As DNA methylation is a durable and reversible modification, we hypothesized that the use of AHMs might also be able to influence the biological aging reflected by the epigenetic AA. Therefore, we assessed the associations of AHM use with AA and further determined whether the change of AHM use could modify the change rate of AA (ΔAA).

After the fully adjusting for potential covariates including hypertension, any AHM use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased ΔAA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher ΔAA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality.

Link: https://doi.org/10.18632/aging.101626

A geroprotector is a drug or supplement that either slows the underlying causes of aging or produces a greater resistance to the damage of aging. In either case health is prolonged and mortality decreased. Calorie restriction mimetics are the best example of the type, but the category is expansive enough to include well known drugs such as aspirin. As you might imagine of a class of treatments that includes aspirin, the size of effect when it comes to additional years of life is fairly small, even in those cases in which the benefits are reliable. Geroprotectors largely work through upregulation of stress responses, something that has much larger effects in short-lived species, such as mice, than in long-lived species, such as our own.

Nonetheless, there is a growing interest in developing these compounds and bringing them to the clinic. Far more interest than is warranted, I'd say. If all of that attention was instead devoted to the SENS portfolio of approaches to rejuvenation, classes of therapy that are based on repair of the molecular damage that causes aging, then we might be moving a lot more rapidly towards reversal of aging and large gains in healthy life span, rather than towards the very modest, incremental slowing of aging that most research groups are aiming for. Repair and reversal will always be a much better approach to improving the function of complex machinery than a mere slowing of damage.

To confuse the nice neat line between two approaches to aging that I've drawn above, in the research here, the scientists are treating the senolytic compound fisetin as a geroprotector. It may well have effects that involve upregulation of stress responses, thus slightly slowing aging, but it would be hard to argue that those are large in comparison to its ability to destroy senescent cells, and thus reverse that cause of aging. That said, the senolytic dose is much larger than the usually explored dose, and so there may well be multiple mechanisms of interest involved.

Old age is the greatest risk factor for many diseases, including Alzheimer's disease (AD) and cancer. Geroprotectors are a recently identified class of anti-aging compounds. New research has now identified a unique subclass of these compounds, dubbed geroneuroprotectors (GNPs), which are AD drug candidates and slow the aging process in mice. "The argument for geroprotectors is that if one can extend the lifespan of model organisms, such as mice, and translate this effect to humans, then you should be able to slow down the appearance of many diseases that are associated with aging, such as Alzheimer's, Parkinson's, cancer and overall frailty."

The team started with two chemicals found in plants that have demonstrated medicinal properties: fisetin, a natural product derived from fruits and vegetables, and curcumin, from the curry spice turmeric. From these, the team synthesized three AD drug candidates based upon their ability to protect neurons from multiple toxicities associated with the aging brain. The lab showed that these three synthetic candidates (known as CMS121, CAD31 and J147), as well as fisetin and curcumin, reduced the molecular markers of aging, as well as dementia, and extended the median lifespan of mice or flies.

Importantly, the group demonstrated that the molecular pathways engaged by these AD drug candidates are the same as two other well-researched synthetic compounds that are known to extend the lifespan of many animals. For this reason, and based on the results of their previous studies, the team says fisetin, curcumin and the three AD drug candidates all meet the definition of being geroneuroprotectors. The group is now focusing on getting two GNPs into human clinical trials. The fisetin derivative, CMS121, is currently in the animal toxicology studies required for FDA approval to start clinical trials. The curcumin derivative, J147, is under FDA review for allowance to start clinical trials for AD early next year. The group plans to incorporate biochemical markers for aging into the clinical trials to assay for potential geroprotective effects.

Link: https://www.salk.edu/news-release/researchers-report-new-methods-to-identify-alzheimers-drug-candidates-that-have-anti-aging-properties/

Today, I'll point out an analysis from the SENS Research Foundation that covers the approach to selective destruction of senescent cells taken by one of the newly formed biotech startups in the space, Senolytic Therapeutics. This field is hot because it is now well proven that senescent cells are the enemy. They are one of the root causes of aging, accumulating with age to degrade tissue function via the secretion of inflammatory signal molecules. Senescent cells actively maintain an aged, inflamed state of metabolism, resulting in the development of age-related disease and increased mortality.

Senescent cells do serve useful functions when they arise temporarily in response to injury or cell damage, so senescence as a phenomenon cannot be safely suppressed. Since the problems only begin when these cells both fail to self-destruct and evade the immune system's policing of tissues, however, finding ways to periodically destroy all lingering senescent cells is a very viable approach to rejuvenation. When they are removed from old tissues, aged metabolism is quite quickly restored to an incrementally younger state. This point has been quite adequately demonstrated in mice in recent years.

Roughly speaking, there are two approaches to the selective destruction of senescent cells. The first approach is to target a mechanism that is only significant in senescent cells, such as the fact that they are primed for self-destruction via apoptosis, and only held back by the thinnest of threads. A nudge to the apoptotic protein machinery that a normal cell will ignore will tip a senescent cell over the edge. The present crowd of senolytic pharmaceuticals fall into this category. The second approach is to use a therapeutic that will definitely kill any cell, senescent or not, and then limit its application to senescent cells only. Forms of immunotherapy and suicide gene therapy currently under development are examples of the type.

The staff at Senolytic Therapeutics are undertaking an interesting approach to the delivery of a standard chemotherapeutic means of killing cells in which nanotubes are used to ensure that only senescent cells are exposed to the toxin. The hollow nanotubes are filled with chemotherapeutic and capped with a molecule that only senescent cells will remove. Or at least only cells that express large amounts of senescence-associated beta-galactosidase, which might not be exactly the same thing, but the overlap is quite large. This is similar to a wide variety of approaches to targeting of specific cell populations developed in the cancer research community, and most of those are probably also applicable in principle to the task of clearing senescent cells from old tissues.

Smart Bombs Against Senescent Cells

When Dr. de Grey and colleagues proposed ablation of senescent cells (ApoptoSENS) as the "damage-repair" strategy of choice for this kind of aging damage in 2001, you'd've been hard-pressed to find the idea even mentioned (let alone advocated) in the scientific literature - and certainly no one was actively working to develop such therapies. This approach remained largely ignored until a powerful proof-of-concept study in 2011. Soon after that, researchers developed an ingenious drug-discovery strategy that led to the identification of the first two of a new class of "senolytic" drugs - that is, drugs that selectively destroy senescent cells.

In the three short years since the initial breakthrough discovery of the first senolytic drugs, the progress in ApoptoSENS has been astonishing. A torrent of scientific reports have now shown that ablating senescent cells has sweeping rejuvenative effects - wider-ranging, in fact, than we ourselves had predicted. Drugs and gene therapies that destroy senescent cells can restore exercise capacity, lung function, and formation of new blood and immune precursor cells of aging mice to nearly their youthful norms. Senolytic drugs and gene therapies have also ameliorated the side-effects of chemotherapy drugs in mice, and prevented or treated mouse models of diseases of aging such as osteoarthritis; fibrotic lung disease; hair loss; primary cancer and its recurrence after chemotherapy; atherosclerosis; and age-related diseases of the heart itself - as well as preventing Parkinson's disease and (very recently) frontotemporal dementia, a kind of cognitive aging driven by intracellular aggregates of tau protein, which are also an important driver of Alzheimer's dementia.

Scientists use a range of different cell markers to identify senescent cells: no one marker is infallible, and different senescence markers are more dominant in different senescent cell types. But the best-established and perhaps most universal sign of all is the activity of an enzyme called senescence-associated beta-galactosidase, or SA-beta-gal. To create a system that would release of cell-destroying drugs selectively in cells with senescent-cell levels of SA-beta-gal, chemists and nanotechnologists turned to an established platform for the selective delivery of drugs: mesoporous silica nanotubes, or MSNs. What makes MSNs so useful as drug-delivery systems is that their constituent tubes can be packed with any number of different drugs, and their openings on the surface of the nano-balls "capped" with molecular stoppers that keep the drug sealed inside until the MSN encounters chemical or other conditions that can break open the seal. So the trick is to identify a molecular stopper that is sensitive to chemical or physical conditions that are found in the type of cell that you want to target, and not found in innocent cells that you want to leave alone.

SA-beta-gal's actual function in the cell is to breaks down the sugar galactose: senescent cells just produce a whole lot more of it than normal cells. So to target MSNs to senescent cells, the team used galactooligosaccharide (GOS) as the stopper molecule - that is, a series of galactose molecules strung together in a chain. The researchers predicted that with their overabundance of SA-beta-gal, senescent cells would whittle down the chain of galactose molecules until they uncapped the MSNs and released their payload, while the same MSNs would pass through normal cells with their contents still safely sealed up. To test this, the team first drove several lines of cancer cells senescent using palbociclib, a cancer drug that works by shutting down genes that cancer cells require for cell division. They loaded up their GOS-MSN with doxorubicin, a toxic chemotherapy drug that is lethal to normal, cancerous, and senescent cells alike. An additional useful feature of doxorubicin is that it's intrinsically fluorescent, allowing the scientists to easily see where it was released.

GOS-MSN loaded with doxorubicin (DOX-GOS-MSN) passed harmlessly through three non-senescent cancer cell lines, and only released their payload in a small percentage of cells of the same lines that were exposed to palbociclib too briefly to induce widespread senescence. But when cancer cells were exposed to palbociclib for long enough to force them into senescence en masse, they lit up with doxorubicin fluorescence, and programmed cell death raged through the population.

Previous research had already shown that a variety of ApoptoSENS strategies can prevent or reverse idiopathic pulmonary fibrosis (IPF) in mouse models of the disease, as well as reversing the "normal" loss of lung function with age. The team wanted to see if DOX-GOS-MSN could similarly restore lung function in mice with a model of IPF. After first confirming that GOS-MSN distributed evenly across normal and senescent lung tissue they treated mice with either straight doxorubicin or DOX-GOS-MSN for two weeks, starting two weeks after inducing model IPF. Lung dysfunction scores remained stubbornly high in animals treated with plain doxorubicin, but DOX-GOS-MSN restored the lung function of the IPF model mice levels equivalent to young mice not subjected to lung damage. DOX-GOS-MSN also reduced the amount of fibrotic tissue in the animals' lungs, which untargeted doxorubicin was again unable to do.

With those exciting results in hand, the researchers have launched a biotech startup to turn GOS-MSN into a human rejuvenation biotechnology. Senolytic Therapeutics projects that that their therapies will be efficacious in treating multiple disorders which are caused and driven by the accumulation of damaged cells - that is, exactly the conditions that GOS-MSN treated so successfully in their recent proof-of-concept scientific report.

For the vast majority of patients, type 2 diabetes is caused by the presence of excess visceral fat tissue, and can be reversed even at a late stage by losing that fat tissue. The degree to which one needs to abuse one's own body in order to become diabetic falls with advancing age, however. Aging makes type 2 diabetes more likely to occur, all other factors being equal. Looking at the relationship from the other direction, the chronic inflammation and other forms of metabolic dysfunction characteristic of type 2 diabetes accelerates the progression of aging. The condition shortens life expectancy and is associated with greater incidence of the other common age-related conditions.

Researchers here consider mTORC1 as an important regulator of this two-way relationship between aging and type 2 diabetes. The complexes of mTOR, mechanistic target of rapamycin, have become well studied in recent years as a result of research into calorie restriction. mTOR is a master regulator of metabolism, involved in nutrient sensing and most of the subsequent processes that must adapt to varying levels of calorie intake. Inhibition of mTOR, or preferentially only the mTORC1 complex, is a way to partially mimic some of the beneficial results of calorie restriction. It provokes increased activity in stress response mechanisms, and the outcome, in animal studies at least, is improved health and extended healthy life span. Both aging and type 2 diabetes give rise to greater mTORC1 activity, and thus move things in the opposite, undesirable direction.

It is well known that insulin signaling is involved in the control of longevity in a wide spectrum of organisms including worms, flies, and mice. In addition, the use of rapamycin or knocking down mTOR can promote life extension in several species. During aging or under a hypercaloric diet exists an mTORC1 hyperactivity, which derives into a disruption in autophagy and, concomitantly an increase in endoplasmic reticulum (ER) stress. The overactivation of mTORC1 signaling specifically in pancreatic β cells leads to an augmented in β cell mass, which are related to hyperinsulinemia and hypoglycemia. However, chronic overactivation of mTORC1 signaling pathway develops a progressive hyperglycemia and a diminished islet mass.

Type 2 diabetes mellitus (T2DM) is a very complicated disorder. It is a progressive disease including insulin resistance, β-cell hyperplasia and/or β cell hypertrophy, that mediates a compensatory insulin secretion and subsequently hyperinsulinemia and pancreatic β cell dysfunction. At the insulin resistant prediabetic stage, mTORC1 is a key effector for the growth and survival of pancreatic β cells. However, if mTORC1 remains chronically overactivated, pancreatic beta cell death occurs and the compensatory insulin secretion mechanism it is compromised. Then, mTORC1 is a double-edged sword in the progression to T2DM.

Diabetes is a multifactorial and progressive disease with two phases; firstly, a prediabetic stage, with an insulin resistance and hyperinsulinemia, and secondly as manifest diabetes associated with hypoinsulinemia and hyperglycemia. Then, it is crucial to understand the transition from prediabetes to type 2-diabetes status and the underlying molecular mechanisms of disease. At this stage, chronic overactivation of mTORC1 signaling pathway in β islets from prediabetic patients leads to on one hand to the expansion of the pancreatic beta cell mass and, on the other to the inhibition of autophagy as protective mechanism of beta cells against the attack of several stressors, making these cells more prone to trigger apoptosis. Thus, the maintenance of a functional autophagy it is an essential component to protect and prolong pancreatic β cell life span precluding chronic hyperglycemia.

Link: https://doi.org/10.3389/fendo.2018.00621

Klotho is one of a number of well-known longevity-associated genes. The amount of klotho observed in tissues declines steadily with advancing age. Interventions that increase levels of klotho have been shown to slow measures of aging to some degree in animal studies. Beyond life span, klotho is also strongly associated with cognitive function. More klotho is better in this case as well. Artificially raised levels of klotho might one day be used as a form of enhancement therapy, capable of improving cognitive function even in younger people.

In the research noted here, scientists uncover one of the mechanisms linking falling levels of klotho to the impact of aging on the brain. Klotho helps to protect the brain from the activities of the immune system in the rest of the body, and when that protection falters, chronic inflammation can result. Inflammation is important in near all forms of neurodegeneration. In the view of aging as an accumulation of molecular damage, loss of klotho is a downstream consequence of that damage. Finding ways to deliver klotho to older individuals, boosting the amount in circulation, may well help with this one narrow outcome resulting from rising levels of cell and tissue damage. It remains the case that it would be far more effective to repair the damage, and thus remove all of the varied downstream consequences.

Curiously, within the brain, one structure contains vastly higher levels of klotho than all the others. This structure is the choroid plexus, which comprises a complex assembly of cells that produce cerebrospinal fluid and form an important barrier between the central nervous system and the blood. In a new study, researchers showed that klotho functions as a gatekeeper that shields the brain from the peripheral immune system. "We discovered, in mouse models, that klotho levels in the choroid plexus naturally decrease with age. We then mimicked this aging process by reducing levels of klotho in this structure experimentally, and we found that depleting this molecule increases brain inflammation."

The researchers further investigated the impact of this phenomenon on other brain regions. They discovered that in mice with less klotho in the choroid plexus, innate immune cells in an important memory center reacted more aggressively when other parts of the body were exposed to immune challenges that mimic infections. "The barrier between the brain and the immune system seems to break down with low levels of klotho. Our findings indicate that klotho helps keep that barrier closed. When levels of this molecule are depleted in the choroid plexus, the barrier becomes more porous and allows immune cells and inflammatory molecules to get through more easily."

"The molecular changes we observed in our study suggest that klotho depletion from the choroid plexus might contribute to cognitive decline in elderly people through brain inflammaging. It could help explain, at least in part, why we often notice deteriorations in cognitive functions in hospitalized seniors when they have infections, such as pneumonia or urinary tract infections. This complication tends to be particularly prominent in patients with Alzheimer's disease, in which inflammation has emerged as a major driver of pathology."

Link: https://gladstone.org/about-us/press-releases/new-insights-aging-brain

How much of the natural human variation in longevity and pace of aging has its roots in genetics, and how much is determined by lifestyle and environment? Some gene variants result in beneficial metabolic alterations such as lower cholesterol or a greater resilience in the face of the molecular damage of late old age. Lifestyle choices such as calorie intake and exercise clearly influence long term health and mortality. Similarly, exposure to pathogens and pollutants can accelerate the pace of aging via their interaction with the immune system. The consensus of the past few decades had come to be that the split is around 25% due to gene variants versus 75% due to choice and environmental factors.

Large vaults of familial history data have been created since the advent of the internet, one of the many consequences of ubiquitous, low-cost channels of communication. Data of all varieties is more easily collected, stored, and analyzed. More rigorous analysis of this historical data of human lineages is now suggesting that the genetic contribution to longevity is much smaller than thought. The study here can be compared with a similar effort published last month. That both came to roughly the same conclusions, via quite different methods of analysis, is worth bearing in mind when balancing this against earlier, higher estimates of the degree to which genes determine life expectancy.

Our goal for the next few decades is, of course, to make all of this analysis a quaint curio that is only of interest only as part of a vanished past - a consideration of how the human system worked in the absence of rejuvenation therapies, to be placed next to work on the spread of smallpox and tuberculosis through populations lacking any effective treatment. When aging can be controlled through medical technology, and when those therapies are universally available, there will be only academic interest in how aging functions in people who have no access to rejuvenation therapies. Even the first, crude rejuvenation therapies that are now available, the pharmaceutical senolytics that selectively destroy a fraction of senescent cells in old tissues, will have a greater effect on human life span than near all genetic variants found in the wild.

Family tree of 400 million people shows genetics has limited influence on longevity

Calico Life Sciences and Ancestry teamed up to use publicly available pedigree data to approach the problem of figuring out the genetic contributions to human longevity. The heritability of life span has been well investigated in the literature, with previous estimates ranging around 15-30%. But some of these studies found that it wasn't just blood relatives who shared similar life spans - so did spouses. This suggested that the heritability estimates might have been confounded by shared environments or assortative mating (the tendency to choose mates who have similar traits to ourselves). Starting from 54 million subscriber-generated public family trees representing six billion ancestors, Ancestry removed redundant entries and those from people who were still living, stitching the remaining pedigrees together.

The data set, called the SAP for "set of aggregated and anonymized pedigrees," included almost 500 million individuals (with a single pedigree accounting for over 400 million people), largely Americans of European descent, each connected to another by either a parent-child or a spouse-spouse relationship. The scale of the data allowed the researchers to get accurate heritability estimates across different contexts; they could stratify the data by birth cohort or by sex or by other variables without losing the power needed for their analyses.

Running the numbers, the team initially found heritability estimates to be between 15-30% - similar to the reported literature. But genetics aren't the only thing that can be passed down between generations: sociocultural factors can also influence certain traits, and these too can be inherited. The combination of genetic heritability and sociocultural heritability is the total transferred variance, that is, the total amount of variability in a trait that can be explained by inheritance. Researchers looked not only at siblings-in-law and first cousins-in-law but also examined correlation in both types of co-siblings-in-law. None of these relationship types generally share household environments, and yet their life spans showed correlation.

If they don't share genetic information and they don't share household environment, what accounts for the similarity in life span between individuals within these relationship types? Going back to their impressive dataset, the researchers were able to perform analyses that detected assortative mating. In other words, people tend to select partners with traits like their own - in this case, how long they live. Of course, you can't easily guess the longevity of a potential mate, but the basis of this mate choice could be genetic or sociocultural - or both. For a non-genetic example, if income influences life span, and wealthy people tend to marry other wealthy people, that would lead to correlated longevity. By correcting for these effects of assortative mating, the new analysis found life span heritability is likely no more than seven percent, perhaps even lower.

Estimates of the Heritability of Human Longevity Are Substantially Inflated due to Assortative Mating

Human life span is a phenotype that integrates many aspects of health and environment into a single ultimate quantity: the elapsed time between birth and death. Though it is widely believed that long life runs in families for genetic reasons, estimates of life span "heritability" are consistently low (∼15-30%). Here, we used pedigree data from Ancestry public trees, including hundreds of millions of historical persons, to estimate the heritability of human longevity.

Although "nominal heritability" estimates based on correlations among genetic relatives agreed with prior literature, the majority of that correlation was also captured by correlations among nongenetic (in-law) relatives, suggestive of highly assortative mating around life span-influencing factors (genetic and/or environmental). We used structural equation modeling to account for assortative mating, and concluded that the true heritability of human longevity for birth cohorts across the 1800s and early 1900s was well below 10%, and that it has been generally overestimated due to the effect of assortative mating.

Given what we know of the relationship between hypertension and dementia, in which increased blood pressure damages the fragile tissues of the brain, causing loss of function over time, it is reasonable to consider that other disruptions of blood flow could have a similar relationship with the onset of dementia in later life. Researchers here investigate the association between atrial fibrillation and dementia, in search of specific disruptions in blood flow and brain tissue that could explain this relationship in terms of greater structural damage to the brain.

Researchers enrolled 246 patients in the study: 198 with atrial fibrillation and 48 without atrial fibrillation. They then obtained plasma samples and tested them for the circulating levels of four biomarkers associated with brain injury: glial specific GFAP and S100b; GDF15, a stress response marker; and neuron-specific tau protein. They found that levels of three of those biomarkers - tau, GDF15, and GFAP - were significantly higher in patients with atrial fibrillation. "We think patients with atrial fibrillation experience chronic, subclinical cerebral injuries. It becomes absolutely critical to identify the early markers of this injury and help these patients who are at higher risk of having subsequent neurodegenerative problems, such as cognitive decline and dementia."

Atrial fibrillation is an irregular and sometimes rapid heartbeat that can lead to blood clots, stroke, heart failure, and other heart-related problems. If people with atrial fibrillation are indeed suffering from ongoing brain injuries, they can also be at higher risk of developing everything from depression to neurodegeneration, which is the deterioration or death of the body's nerve cells, especially neurons in the brain, which could cause losses in mental function. That could be because atrial fibrillation alters blood flow through the body, including to and from the brain, which could lead to cerebral injury and disruption of the blood-brain barrier, which filters blood to and from the brain and spinal cord. If it's not working correctly, neuro-specific molecules like GFAP and tau get into the bloodstream, which was seen in this study.

The next step is to carry out the same kind of analysis on a larger group of patients. Recent results from the Swiss Atrial Fibrillation Cohort Study also point in the same direction - that atrial fibrillation causes brain injury. In the study, researchers performed MRIs on atrial fibrillation patients and found that 41 percent showed signs of at least one kind of a silent brain damage.

Link: https://www.eurekalert.org/pub_releases/2018-11/imc-rff110618.php

Checkpoint inhibitor therapies are a demonstrably successful approach to cancer immunotherapy. They suppress a mechanism that normally restrains immune cells from attacking other cells. This mechanism is abused by cancers, alongside a variety of other ways in which the immune system can be subverted or quieted. Any advanced tumor tends to have evolved into a state in which it is ignored or even helped by the immune system. Checkpoint inhibitor therapies are an improvement on chemotherapy when it comes to the trade-off between harming the cancer and harming the patient, as well as in the odds of success, but still present risks to patients. Immune checkpoints exist to prevent autoimmunity, and rampant autoimmunity can be just as deadly as any cancer.

Our usual defence against disease is our immune system. It does an excellent job of sorting out what doesn't belong in the body and attacking it - except when it comes to cancer. The checkpoint inhibitor breakthrough was the realisation that the immune system wasn't ignoring cancer. Instead, cancer was taking advantage of tricks that shut down the immune system. When stimulated, the T cell protein CTLA-4 acted like a circuit breaker on immune response. These brakes, which he called checkpoints, kept the cell killers from going out of control and trashing healthy body cells. Cancer took advantage of those brakes to survive and thrive.

In 1994, researchers developed an antibody that blocked CTLA-4. When they injected it into cancerous mice, the antibody jammed behind CTLA-4's brake pedal and prevented the T-cell attack from being stopped. Instead, the T-cells destroyed the tumours and cured the cancer. In 2011, that anti-CTLA-4 drug would gain approval as ipilimumab for use treating melanoma; it has since been approved to treat kidney and colorectal cancer. As a drug, it has saved many thousands of lives. Blocking the brakes on the immune system turned out to cause serious toxicities in some patients, but as a proof of concept, the success of ipilimumab proved that the immune system could, in fact, be weaponised against cancer. It also kicked off the search for newer, better immune checkpoints.

The first to be discovered was called PD-1. PD-1 is part of a sort of secret handshake that body cells give a T cell, telling it: "I'm one of you, don't attack." Cancers co-opted this secret handshake, tricking T cells into believing they were normal, healthy body cells. But that handshake could be blocked, creating a more precise cancer-killing machine with far fewer toxic side-effects than blocking CTLA-4. For many people, the anti-PD-1 drug pembrolizumab, approved in 2015 and sold as Keytruda, was the first and only thing they'd heard about cancer immunotherapy. Keytruda is currently one of the most widely used of the new class of drugs, approved for use against nine different types of cancer in the US, and a smaller number in the UK, and that list is growing rapidly.

Seven years after the approval of that first checkpoint inhibitor, there are reportedly 940 "new" cancer immunotherapeutic drugs being tested in the clinic by more than half-a-million cancer patients in more than 3,000 clinical trials, with over 1,000 more in the preclinical phase. Those numbers are dwarfed by the number of trials testing immunotherapy combinations or using them in concert with chemotherapy or radiation, which essentially turn the dead tumour into a cancer vaccine. It's hoped that, with checkpoint inhibitors releasing the brakes, the immune system can effectively finish up what the chemotherapy starts.

Link: https://www.theguardian.com/science/2018/nov/04/a-cure-for-cancer-how-to-kill-a-killer-revolutionary-immune-system-immunotherapy

In autoimmunity, the immune system becomes dysregulated and mistakenly attacks portions of the patient's own biochemistry. The broad variety of autoimmune conditions are differentiated from one another on the basis of exactly which structures and cells come under attack. Some autoimmune conditions are highly disabling or lethal, while others are comparative mild, but even lesser autoimmune conditions such as rheumatoid arthritis still shorten life expectancy. To the degree to which autoimmunity results in increased inflammation, a shorter life is the expected outcome, even when the tissues targeted by the immune system are less vital. Chronic inflammation is a major downstream mechanism of aging, and speeds the development and progression of all of the common fatal age-related conditions.

Most autoimmune disorders are comparatively poorly understood. The immune system is enormously complex, and far from completely mapped. Many of the autoimmune conditions in which etiology remains obscure may turn out to be collections of distinct conditions with varied causes and a similar outcome. Further, numerous forms of autoimmunity tend to arise with age as the immune system becomes worn and dysfunctional, and are presently lumped in with the other serious consequences of a failing immune system. These age-related autoimmunities are even less well understood than their more widely recognized counterparts, and it is very likely that many more remain to be discovered in the first place, let alone comprehensively investigated. Consider that the prevalent late life condition of type 4 diabetes was only cataloged a few years ago, for example.

Why does autoimmunity shorten life spans? Cardiovascular disease is the obvious candidate, and inflammation is the obvious link to investigate wherever there is a raised risk of cardiovascular mortality. Researchers here narrow down the connection to the inflammatory cytokine interleukin-17, and show that it is possible prevent the increased cardiovascular disease risk by blocking interleukin-17, at least in mice. This in turn suggests that existing drugs targeting this cytokine, used to treat some autoimmune conditions, might reduce cardiovascular disease risk in older people without autoimmunity. This is one of many examples to suggest that sophisticated control over inflammation could slow the progression of aging to some degree.

Link between autoimmune, heart disease explained in mice

People with psoriasis and lupus are two to eight times more likely to suffer a heart attack than people without these diseases. For young and middle-aged adults with rheumatoid arthritis, cardiovascular disease is the top cause of death. Psoriasis is characterized by patches of red, thickened, scaly skin. The thickening is partly due to an excess of collagen, the main protein in connective tissues such as skin and blood vessel. Researchers suspected that the walls of blood vessels also might be webbed with too much collagen. They created a light-sensitive form of high-density lipoprotein (HDL) - the molecular carrying case for cholesterol - that fluoresces when hit with a laser beam, and inserted it into mice. The researchers then induced a psoriasis-like disease in the mice.

By following the fluorescent cholesterol carrier, the researchers could see that HDL cholesterol was delayed in getting out of the bloodstream in the mice that received the compound. This was true not only in the skin, but in internal arteries near the heart. In addition, the skin and blood vessels were more densely interlaced with collagen and more resistant to stretching. Further, when the researchers fed mice a high-cholesterol diet for three weeks, the mice in the experimental psoriasis group developed significantly larger cholesterol deposits in their blood vessels.

An immune cell type called Th17 cells multiplies robustly in autoimmune diseases such as psoriasis, lupus, and rheumatoid arthritis, releasing copious amounts of the immune molecule IL-17. When the researchers neutralized IL-17 in mice with psoriasis-like disease, using an antibody, collagen density went down and cholesterol deposits shrank. "It'll take a few years before we know for sure, but we predict that the anti-IL-17 antibodies that already are being used to treat autoimmune diseases will be effective at reducing risk of cardiovascular disease."

Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis

Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit was rescued by depleting CD4+ T cells, neutralizing interleukin-17, or inhibiting lysyl oxidase that crosslinks collagen. Experimental psoriasis also increased vascular stiffness and atherosclerosis via this common pathway. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen.

Current enthusiasm for the development of means to boost levels of NAD+ in older people is driven in part by research such as the open access paper noted here, in which the authors show a clear decline with age in NAD+ outside cells. Inside cells, NAD+ is an important component in the machinery that allows mitochondria to generate chemical energy store molecules to power all cellular functions. Importantly, there is evidence that comparatively straightforward approaches to increase NAD+ levels can produce beneficial effects, such as improved mitochondrial function leading to lowered blood pressure via reduced dysfunction of smooth muscle cells in blood vessels, reducing blood vessel stiffness.

None of this is damage repair, rather a matter of putting damaged cells back to work, overriding one of the less helpful evolved responses to rising levels of molecular damage present in old tissues. The size of benefits is thus necessarily limited in comparison to approaches that can successfully repair the underlying damage that leads to reduced NAD+ levels and many other consequences. If the costs are low enough, then even limited benefits are worth chasing, however. It remains to be seen whether the cost-benefit considerations work out favorably in this case.

In the last decade, there has been growing interest in the role of redox active nucleotides in the metabolism. Nicotinamide adenine dinucleotide (NAD+) represents one of the most important coenzymes in the hydride transfer reactions. NAD+ is the precursor of the pyridine nucleotide family, including NADH, NADP+, and NADPH, and is the end product of tryptophan metabolism via the kynurenine pathway. It has been well established that NAD+ is a substrate for major dehydrogenase enzymes involved in nutrient catabolism. As well, NADH, which is the reduced form of NAD+, preferentially provides electrons to power mitochondrial oxidative phosphorylation. Apart from its roles in fuel utilization, NAD+ also serves as an exclusive substrate for nuclear repair enzymes.

NAD+ has also been shown to be the sole substrate for a new class of NAD-dependent histone deacetylase (HDAC) enzymes known as sirtuins. Increasing histone acetylation is associated with age-related pathologies, whereas gene silencing by upregulation of sirtuins has been shown to extend lifespan in yeast and small organisms. HDACs are also being found to interact with a variety of nonhistone proteins and to thereby change their function, activity, and stability by post-translational modifications. Accurate determination of the NAD+ metabolome is of major interest due to its potential association with cognitive decline, including AIDS dementia complex, cancer, aging, and a plethora of age-related disorders.

While it is thought that NAD+ is predominantly an intracellular nucleotide, emerging evidence suggests that extracellular NAD+ crosses the plasma membrane and replenishes intracellular NAD+. Accurate monitoring of the plasma NAD+ metabolome is necessary and may provide valuable information regarding the effect of various lifestyle and dietary factors, pharmacological and nutraceutical supplementation of NAD+ and/or its metabolites. We quantified changes in the NAD+ metabolome in plasma samples collected from healthy human subjects across a wide age range (20-87 years) using liquid chromatography coupled to tandem mass spectrometry. Our data show a significant decline in the plasma levels of NAD+, NADP+, and other important metabolites such as nicotinic acid adenine dinucleotide (NAAD) with age. Our data cumulatively suggest that age-related impairments are associated with corresponding alterations in the extracellular plasma NAD+ metabolome.

Link: https://doi.org/10.1089/rej.2018.2077

The scientific and medical communities have over recent years lowered the threshold of raised blood pressure that defines hypertension. This has happened due to increasing evidence for even lesser degrees of increased blood pressure to be notably harmful over the long term. There is apparently no such thing as a safe rise in blood pressure over the course of aging - any increase is damaging, and the greater the increase the greater the damage. The high blood pressure of hypertension harms delicate tissues, such as those of the kidney and brain, through mechanisms such as the rupture of capillaries. It also acts to accelerate the progression of atherosclerosis, and thus raise the risk of cardiovascular mortality via stroke and heart attack. The research noted here should not be surprising in this context, as it reveals that even the a pre-hypertensive state of somewhat raised blood pressure correlates with increased organ damage and dysfunction.

Hypertension is exacerbated by the usual problems of excess weight and poor diet, and that contribution at least is well within our ability to control, but even the best lifestyle choice can only slow the progression of molecular damage that stiffens blood vessels. When blood vessels cannot respond to circumstances by contracting or dilating to the appropriate degree, the evolved system of pressure regulation runs awry. Cross-links that form in the extracellular matrix impair elasticity; the elastin required for that elasticity diminishes with age; calcification takes place in old blood vessel walls; the smooth muscle cells become dysfunction for a variety of reasons. Therapies to address these issues lie somewhere in our future. Once introduced, they will have a sizable impact on human life expectancy via the prevention and reversal of hypertension.

Hypertension is a well-known risk factor for a variety of cardiovascular and renal diseases. Nowadays, it is estimated that more than 1 billion people have hypertension around the world. Furthermore, the prevalence of pre-hypertension, which is defined by a systolic blood pressure (SBP) from 120 to 139 mm Hg or a diastolic blood pressure (DBP) from 80 to 89 mm Hg, has also been dramatically increasing in recent decades. The Prospective Studies Collaboration, which included data from 61 observational studies, shows that for every 20/10 mm Hg increase in SBP and DBP, the risk of cardiovascular disease and mortality is increased two-fold, and this relationship extends to a BP level of 115/75 mm Hg. These data together imply that treatment of pre-hypertension should be beneficial for reducing target organ damage and cardiovascular events.

Arterial stiffness is a pathophysiological process of vascular ageing, and prior observational studies suggest that arterial stiffness is highly prevalent in subjects with hypertension. Nevertheless, the prevalence of arterial stiffness in subjects with pre-hypertension is unclear, and whether arterial stiffness is associated with target organ damage in subjects with pre-hypertension is also less well studied. Using data from a cross-sectional study, we evaluated the prevalence of arterial stiffness in subjects with pre-hypertension and potential risk factors for pre-hypertension. Moreover, whether arterial stiffness was independently associated with the prevalence of target organ damage including left ventricular hypertrophy and albuminuria in pre-hypertensive subjects was also evaluated.

The principal findings of our current study include four aspects. First, the prevalence of pre-hypertension in patients who came to the outpatient clinic for screening potential hypertension is 17.5% and the prevalence of target organ damage including left ventricular hypertrophy and albuminuria in subjects with pre-hypertension is not low. Second, compared to subjects without arterial stiffness, those with arterial stiffness are more likely to have left ventricular hypertrophy and albuminuria. Third, ageing and presence of arterial stiffness are two major potential risk factors for pre-hypertension. Fourth, in subjects with pre-hypertension, increased carotid-femoral pulse wave velocity is associated with higher prevalence of target organ damage such as left ventricular hypertrophy and albuminuria.

Link: https://doi.org/10.5114/aoms.2017.69240

The raised blood pressure of old age is known as hypertension, and it is predominantly caused by dysfunction in blood vessel walls: cross-links, calcification, and loss of elastin cause reduced elasticity, while smooth muscle cells lose their capacity to act for a variety of other reasons. When blood vessels can no longer correctly react to circumstances by contracting and dilating to an appropriate degree, then the whole system of pressure control is thrown off, and higher blood pressure is the result.

Atherosclerosis, on the other hand, is the progressive formation of fatty plaques in blood vessel walls. This narrows and weakens blood vessels. Atherosclerosis interacts with hypertension in the obvious way: weakened blood vessels and fragile plaques are more likely to suffer catastrophic structural failure in a high pressure environment, leading to a fatal stroke or heart attack. Just considering this interaction, it is clear that hypertension raises the risk of death and shortens life expectancy. This isn't the only interaction, however, just the most direct one. In addition, hypertension accelerates the growth of atherosclerotic plaques, and the reasons for this are not fully understood.

In the research materials noted here, the authors report on an association between a particular subset of cases of hypertension and the pace at which immune cells known as monocytes arrive at atherosclerotic plaques in order to try to clean them up. Once embedded into the blood vessel wall, monocytes transform into macrophages. Plaques grow because these macrophages become overwhelmed by oxidized lipids, fail in their task of rescue, and die. Worse, many become inflammatory, senescent foam cells that linger to secrete signals that call in more of their peers. The bulk of a plaque is cell debris, and atherosclerosis is really a form of runaway garbage catastrophe. Once things get to the tipping point, the end is inevitable. In some cases, hypertension moves that tipping point in an undesirable direction by causing the production of more monocytes.

Neural driven blood pressure accelerates atherosclerotic cardiovascular disease through over production of monocytes

Atherosclerotic cardiovascular disease is a build-up of cholesterol plaque in the walls of arteries, causing obstruction of blood flow. Scientists have found that high blood pressure caused by specific signalling from the brain promotes heart disease by altering stem cells within the bone marrow. The results demonstrate how an overactive sympathetic nervous system that causes elevated blood pressure can instruct bone marrow stem cells to produce more white blood cells that clog up blood vessels.

"We now know that changes in the immune system contribute significantly to heart disease. We aimed to determine how the sympathetic nervous system through the brain directly promotes atherosclerosis in the setting of hypertension. We have discovered that this form of high blood pressure, often associated with stress, causes changes within the bone marrow leading to increased white blood cells circulating though our vessels. This is significant as the general view of hypertension is that it is mainly a disease of the blood vessels, which means other heart damaging events are missed." The team is now exploring the specific molecules involved, which may shed light as to why some current therapies are ineffective.

Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis

Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E deficient background. When mice were placed on a western type diet for 16 weeks we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms.

With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells, and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.

Researchers here describe the character of fibroblasts in old skin as a loss of characteristic function and identity. The fibroblasts begin to take on aspects of other cell types, and thus the character of skin changes for the worse. In the publicity materials this decline in cell function is described as a cause of aging, but that should probably be taken to mean that the researchers consider it a contributing cause to age-related pathology rather than a root cause of aging per se. Dysfunction of this nature has all the signs of being a downstream consequence in aging, cellular misbehavior that is a reaction to earlier processes, such as the accumulation of molecular damage within and between cells, or the changes in cell signaling that results from that damage.

With age, our tissues lose their function and capacity to regenerate after being damaged. The main conclusion drawn from recent findings is that these fibroblasts lose their cell identity, as if they had "forgotten" what they are, and consequently their activity is altered, thus affecting tissue. The new study reveals the cellular and molecular pathways affected by ageing and proposes that they could be manipulated to delay or even reverse the skin ageing process.

Dermal fibroblasts are key for the production of collagen and other proteins that make up the dermis and that preserve the skin's function as a barrier. The activity of these cells is also crucial for the repair of skin damage. As we age, the dermis loses its capacity to produce collagen, and consequently its capacity to repair wounds is also significantly impaired. A single-cell analysis confirmed the loss of fibroblast identity in aged animals. Using sophisticated computational tools, scientists observed that aged fibroblasts show a less defined molecular conformation compared to young fibroblasts and come to resemble the undefined cell states observed in newborn animals.

"The elderly face many problems in this regard because their skin does not heal properly and its barrier properties are decreased, thus increasing the risk of skin infections and systemic infections. The notion that the loss of cell identity is one of the underlying causes of ageing is interesting and one that we believe hasn't been considered before."

Link: http://www.crg.eu/en/news/skin-ages-when-main-cells-dermis-lose-their-identity-and-function

In flies, the declining state of the intestine is a critical aspect of aging, the strongest determinant of mortality. This central position of the intestine in aging is not the case in mammals, but loss of integrity of the intestinal wall is still a major driver of chronic inflammation. That inflammation in turn accelerates progression of all of the common age-related diseases; it is a major aspect of aging, and control of inflammation is a goal well worth chasing. The practice of calorie restriction has been shown to slow down near all measurable aspects of aging, and the aging of the intestinal wall is no exception, as researchers demonstrate here. The noteworthy aspect of this research is the demonstration that the microbes of the gut do not seem to be all that involved in the pace of decline, which is not what one might expect based on recent years of work on the role of the gut microbiome in aging.

Flies eating a Spartan diet are protected from leaky gut and the systemic inflammation associated with it as they age. Conversely, flies on a rich diet are more prone to developing intestinal permeability, a condition linked to a variety of human conditions including inflammatory bowel disease. Researchers have shown that gaps in the intestinal barrier are caused by an age-related increase in the death of intestinal epithelial cells, also known as enterocytes.

The researchers zeroed in on dMyc, a gene involved in cell proliferation. They observed that levels of dMyc act as a barometer of cellular fitness in enterocytes, post-mitotic intestinal cells. They found that cells that have too little dMyc get eliminated by neighboring cells through a process termed cell competition in an attempt to maintain gut health. Levels of dMyc naturally decline with age in enterocytes, leading to excessive cell loss and thus a leaky gut. This decline in dMyc was enhanced by a rich diet, while dietary restriction maintained dMyc level in the flies, preventing leaky gut and extending the lifespan of the animals.

The researchers also looked at the role of dysbiosis, an imbalance in the intestinal bacteria or microbiome of the flies, as a potential contributor to leaky gut. Even though dysbiosis has been proposed as a leading cause of leaky gut, researchers found that removing intestinal bacteria with antibiotics conferred only minimal protection to the animals and did not prevent age-related damage to enterocytes. "The intestinal epithelium is affected by everything that moves through the gut. It would make sense that diet would have major impact on the health of those cells, especially over a lifetime of eating. While we understand the interest in the role of the microbiome, we think that diet may ultimately be the primary driver in cellular changes leading to leaky gut."

Link: https://www.buckinstitute.org/news/does-dietary-restriction-protect-against-age-related-leaky-gut/

Researchers have identified a marker for a small population of smooth muscle cells in blood vessel walls that show up in larger numbers in cases of vascular disease, such as atherosclerosis. These cells may be dysfunctional in the sense that they (a) appear to be involved in inflammatory signaling and (b) lose the normal behavior of smooth muscle tissue. My first thought on reading the abstract of the paper was that this may be a senescent population, as inflammation and disruption of tissue function are quite characteristic of the bad behavior of senescent cells. On closer reading that sounds less likely, however. These may well be cells that are engaged in repair and regrowth activities, which also tend to involve at least short term inflammation alongside significant changes in cell activities.

Are these cells harmful, or are they responding in a beneficial way? That may depend on context; it might be the case that they are initially beneficial, but in the later stages of disease progression they become a problem, and contribute to the disease state. The discovery of a marker allows technologies such as the Oisin Biotechnologies suicide gene therapy platform to target these cells for destruction. Evaluating the outcome in mice is the fastest way to determine whether or not the cells are harmful, and whether or not this varies with disease progression. This is the case for the removal of a broad range of other potentially harmful cell populations found in older individuals. Most of these projects are easy to describe, and all of the necessary preliminary work of identifying the cells has been accomplished, but still no-one is even thinking about undertaking the work. The challenge here is that there is too little philanthropy, too few entrepreneurs, and too little venture funding to carry out anywhere as much as many projects as should be underway right now.

Observation of blood vessel cells changing function could lead to early detection of blocked arteries

The muscle cells that line the blood vessels have long been known to multi-task. While their main function is pumping blood through the body, they are also involved in patching up injuries in the blood vessels. Overzealous switching of these cells from the pumping to the repair mode can lead to atherosclerosis, resulting in the formation of plaques in the blood vessels that block the blood flow. Using state-of-the art genomics technologies, an interdisciplinary team of researchers has caught a tiny number of vascular muscle cells in mouse blood vessels in the act of switching and described their molecular properties. The researchers used an innovative methodology known as single-cell RNA-sequencing, which allows them to track the activity of most genes in the genome in hundreds of individual vascular muscle cells.

"We knew that although these cells in healthy tissues look similar to each other, they are actually quite a mixed bag at the molecular level. However, when we got the results, a very small number of cells in the vessel really stood out. These cells lost the activity of typical muscle cell genes to various degrees, and instead expressed a gene called that is best known to mark stem cells, the body's master cells." Knowing the molecular profile of these unusual cells has made it possible to study their behaviour in disease. Researchers have confirmed that these cells become much more numerous in damaged blood vessels and in atherosclerotic plaques, as would be expected from switching cells. "Theoretically, seeing an increase in the numbers of switching cells in otherwise healthy vessels should raise an alarm. Likewise, knowing the molecular features of these cells may help selectively target them with specific drugs."

Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels

Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion, and migration.

We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis, and prevention.

Lower protein intake is suspected of being a contributing cause of a number of age-related conditions, such as sarcopenia, the loss of muscle mass and strength. Researchers here find an association between lower protein intake and a faster pace of decline with age, but it is easy to argue over the direction of causation. After all, older people may eat less protein because of a metabolism that offers hunger prompts less frequently, or because of age-related conditions that make eating more of a challenge. The degeneration may be the cause rather than the result.

To live successfully and independently, older adults need to be able to manage two different levels of life skills: basic daily care and basic housekeeping activities. People 85-years-old and older form the fastest-growing age group in our society and are at higher risk for becoming less able to perform these life skills. For this reason, researchers are seeking ways to help older adults stay independent for longer. Recently, a research team focused their attention on learning whether eating more protein could contribute to helping people maintain independence.

Protein is known to slow the loss of muscle mass. Having enough muscle mass can help preserve the ability to perform daily activities and prevent disability. Older adults tend to have a lower protein intake than younger adults due to poorer health, reduced physical activity, and changes in the mouth and teeth. To learn more about protein intake and disability in older adults, the research team used data from the Newcastle 85+ Study. This study's researchers approached all people turning 85 in 2006 in two cities in the UK for participation. At the beginning of the study in 2006-2007, there were 722 participants, 60 percent of whom were women. The participants provided researchers with information about what they ate every day, their body weight and height measurements, their overall health assessment (including any level of disability), and their medical records.

The researchers learned that more than one-quarter (28 percent) of very old adults had protein intakes below the recommended dietary allowance. The researchers noted that older adults who have more chronic health conditions may also have different protein requirements. To learn more about the health benefits of adequate protein intake in older adults, the researchers examined the impact of protein intake on the increase of disability over five years. The researchers' theory was that eating more protein would be associated with slower disability development in very old adults, depending on their muscle mass and muscle strength. As it turned out, they were correct. Participants who ate more protein at the beginning of the study were less likely to become disabled when compared to people who ate less protein.

Link: http://www.healthinaging.org/blog/for-older-adults-does-eating-enough-protein-help-delay-disability/

The business community includes many supporting organizations that host conferences, cultivate professional networks, and analyze markets and businesses. The biotechnology industry is waking up to the potential of treating aging as a medical condition, particularly now that a sizable amount of venture funding is flowing to the development of the first rejuvenation therapies worthy of the name. The groups that run conferences and business networks are starting to play their part, such as LSX Leaders, a life science business network that is putting together the Longevity Leaders conference early next year. We should expect to see more conference series dedicated to this topic launching in the next few years if the present pace of growth keeps up.

The Longevity Leaders Conference is about both the science of longevity and the business of longevity. Its purpose is to connect the thought leaders, key opinion leaders, CEOs, innovators, and disruptors from the world of life sciences, technology, financial services, government and the investment community to discuss how the grand challenges of Longevity can be tackled, how the significant opportunities can be seized, and to forge the partnerships and relationships to succeed in this new age.

The themes in focus include: The future of the science of ageing, accelerating research and development to enable the eradication of age-related disease and cracking the code to treat ageing as a unitary disease. The future of care: what are the new business models and partnerships needed to support assisted living, the care homes of the future, domiciliary care, chronic care management and end of life care? Realising the potential of the longevity industry revolution: what are the business model innovations in research and development, care, consumer and financial services necessary to ensure success? Derisking longevity: how can companies and pension funds derisk from longevity? What are the best new ideas to manage longevity risk? The technology challenge: realising the potential of new connected and digital health possibilities and the power of artificial intelligence and blockchain to enhance and extend human health lifespans. The investment opportunity: how can investors reap the longevity dividend?

Revolutionary new developments in geroscience and biotechnology, the advent of personalised, precision, and preventative medicine and other disruptive technologies are all converging and conspiring to mean that extending lifespan and healthspan beyond 100 years will soon become the norm. There can be no doubt that the age of longevity is upon us, and it is up to us to tackle its grand challenges - from eradicating age-related disease, and perhaps ageing itself, to redefining the future of care, reimagining retirement living, derisking longevity in financial service industries and developing the commercial and business models that will lead to prosperity in this new age. Those who invest and develop the technology, products and solutions to meet these challenge stand to reap incredible dividends of the multi-trillion longevity industry that will disrupt traditional working norms, challenge virtually all businesses and transform society's structure.

Link: https://www.lsxleaders.com/longevity-leaders-congress

One of the approaches taken in efforts to understand a complex system such as metabolism is to break specific components, one by one, and observe the results: disable a gene, block the interactions of a protein, and so forth. This technique is widely used in investigations of calorie restriction, particularly regarding the way in which calorie restriction extends life span in short-lived species such as mice. It allows researchers to narrow the list of mechanisms and regulators that are most important in the way in which metabolism determines variations in the pace of aging. Calorie restriction is challenging as a topic for research, as near every aspect of cellular metabolism is changed by the adoption of a low calorie diet. While most of the important processes are known at a high level, decades of research have yet to result in a comprehensive understanding of the detailed interaction between metabolism and aging.

Today's open access paper reviews one of the mechanisms known to be vital to the operation of calorie restriction. If it is disabled, then calorie restriction no longer functions to extend life in mice. The mechanism involves alterations in the metabolism of white fat tissue via a master regulator that influences lipid storage and mitochondrial function in that tissue. Fat is metabolically active and via signals can influence the rest of the body in a variety of ways. It is evidently the case that eating fewer calories has a sizable impact on fat tissue, but it is interesting to see just how far researchers have progressed into understanding what that means at the detail level. The other vital mechanisms of calorie restriction are related to autophagy, the cellular processes of maintenance that recycle damaged proteins and cellular structures. Like many of the other ways to modestly slow aging in short-lived species, calorie restriction upregulates autophagy, and indeed requires the correct function of autophagy in order to extend life. When autophagy is disabled, calorie restriction fails to extend life.

SREBP-1c-Dependent Metabolic Remodeling of White Adipose Tissue by Caloric Restriction

Caloric restriction (CR), also known as dietary restriction, is a simple and reproducible manipulation that delays the onset of many age-related pathophysiological changes and extends both median and maximum lifespan. The life-extending effect of CR is observed in several species, including yeast, worms and mammals; hence, CR has been widely investigated in aging research. In general, CR animals exhibit low body temperature and plasma insulin, and high plasma dehydroepiandrosterone sulfate (DHEAS). Interestingly, it has been reported that humans with this phenotype live longer than their counterparts. Furthermore, a recent report has revealed the effectiveness of CR in non-human primates, implying that CR can be also beneficial for humans.

Previous studies have suggested that the beneficial effects of CR may involve various mechanisms; for example, the suppression of growth hormone/insulin-like growth factor (GH/IGF-1) signaling, reduction of mechanistic target of rapamycin complex 1 activity, activation of sirtuin, enhancement of mitochondrial biogenesis, attenuation of oxidative and other types of stress, suppression of inflammation, and alteration of the gut microbiome. Thus, the mechanisms underpinning the effects of CR are complex and diverse, and further research is required for them to be fully elucidated.

White adipose tissue (WAT) is a major site of energy storage in the form of triglyceride (TG), but WAT has also become established as an endocrine tissue that secretes adipokines. It is accepted that the characteristics of adipocytes and their secretory profile differ according to their size. Large adipocytes storing a large amount of TG. In contrast, small adipocytes secrete more adiponectin. Moreover, small adipocytes are more sensitive to insulin and play a buffering role for whole-body lipids by absorbing them after a meal and releasing them in the fasting state. Thus, differences in the characteristics of WAT can influence whole-body metabolism.

Recent studies have demonstrated that several models of genetic modification in WAT are associated with differences in lifespan. For example, fat-specific insulin receptor knockout (FIRKO) mice display lower adiposity, enhanced mitochondrial biogenesis, and extended lifespan, compared with a control group. In addition, genetic manipulation of master regulators of adipocyte differentiation in mice is known to alter lifespan. It has also been reported that differences in adipokine secretion profiles affect lifespan. For instance, liver-specific adiponectin transgenic mice are resistant to high-calorie diet-induced obesity and demonstrate an extended lifespan.

CR prevents age-induced adiposity by lowering plasma insulin and leptin concentration and raising adiponectin concentration, while also reducing the size of adipocytes in WAT. Therefore, we hypothesized that the beneficial effects of CR may be partially mediated by functional alterations in WAT. In the process of testing this hypothesis, we identified the sterol regulatory element-binding protein 1c (SREBP-1c), a master transcriptional regulator of lipogenic gene expression, as a mediator of CR. These findings were validated by showing that CR failed to upregulate factors involved in fatty acid biosynthesis and to extend longevity in SREBP-1c knockout mice. Furthermore, we revealed that SREBP-1c is implicated in CR-associated mitochondrial activation through the upregulation of PGC-1α, a master regulator of mitochondrial biogenesis. Notably, these CR-associated phenotypes were observed only in WAT.

The hallmarks of aging paper described a categorization of aging into discrete forms of damage and change, strongly influenced by more than a decade of work to popularize the SENS view of aging as a catalog of forms of molecular damage. The hallmarks are distinct from the SENS categorization, incorporating a number of items that are downstream from the molecular damage that causes aging, but the two overlap to some degree. We might also consider the seven pillars taxonomy of aging, and I'm sure that more similar overviews will arise in the future as various categories start to show promise in the development of therapies to treat aging as a medical condition. The challenge facing the effective use of any such taxonomy of facets of aging is that there are few to no animal models that exhibit just one of those facets, or in which a facet is easily manipulated in isolation of all of the others. Everything in cellular biochemistry connects to everything else.

In this open access paper, researchers review the current state of animal models from a hallmarks of aging perspective, finding it lacking. This is just as true for the SENS view of aging. In both cases, generating animal models that exhibit to at least some degree of physiological levels of only one of the forms of damage will be important. It is also important to understand that models that exhibit far greater than normal levels of damage observed in the usual course of aging may or may not be helpful. This is the situation for lineages with reduced DNA repair activity in the nucleus or mitochondria, where the animals exhibit far greater levels of mutational damage than normally occurs even in late old age. Despite existing for quite some time, these models have not to date resulted in a definitive outcome in the debate over nuclear DNA damage, and it is still the case that using them for studies of aging requires a very careful consideration of the details of the experiment to avoid misleading results.

The use of model organisms in aging research has been essential to achieve a key milestone in the field: the aging process can be modulated. Instead of just a passive, undefined decline of physiological functions, aging has turned out to be the result of a complex interconnection of genetic and biochemical mechanisms that have recently been categorized in 9 molecular hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Although we are still far from understanding how this intricate network of pathways inexorably coordinates organismal deterioration, in vivo studies in animal models have proven that single genetic manipulations can extend lifespan or ameliorate certain age-related phenotypes. Also, external interventions, that is, caloric restriction, which target specific pathways, have demonstrated that aging can be delayed in a variety of species.

For several years, the use of invertebrate animal models-such as the worm Caenorhabditis elegans or the fruit-fly Drosophila melanogaster-has led aging research by providing the first insights into those molecular pathways that are determinant in the aging process and for lifespan extension. Despite the great progress achieved by using simple model organisms carrying mutations in specific genes, increasing efforts have been made during recent years to address whether these fundamental mechanisms are also shared by mammalian systems. In this regard, mouse models have become an excellent tool in aging research because of their relative short lifespan (which allows the monitoring of the aging process in a reasonable window frame) and to the feasibility of performing genetic manipulations. Also, mice share many of the age-related phenotypes found in human subjects, including the increased risk to develop certain diseases with age, such as cancer. Nevertheless, those age-related pathologies frequently found in elderly humans and absent in aged mice, such as certain cardiovascular (ie, atherosclerosis) or neurodegenerative (ie, Alzheimer's) diseases, can be studied using the appropriate genetically modified mouse model already created to mimic these common human disorders. Accordingly, in this review, we revisit the hallmarks of aging through the prism of those biological insights provided exclusively by gain- and loss-of-function mouse models.

We have focused on those genetic interventions that have a direct impact on a specific hallmark and discuss how this manipulation affects the aging process. Of note, the pleiotropic function of certain genes together with the inherent interconnection of some hallmarks makes sometimes difficult to point at a single molecular pathway/hallmark once a gene has been deleted or overexpressed. Finally, we have primarily highlighted those genetically engineered mice that shorten or increase healthy lifespan, keeping in mind that certain features of mouse models showing accelerated aging are not present in normal aging and vice versa. We have found examples of existing animal models for the majority of hallmarks of aging. However, this analysis has also surfaced some weaknesses and many challenges ahead.

Link: https://doi.org/10.1161/CIRCRESAHA.118.312204

Modern hunter-gatherer societies are located in the poorer parts of the world, and thus still face challenges in the control of infectious disease. When it comes to age-related disease they can be notably better off than those of us in the typist-shopper societies of wealthier regions, however. This, I would say, has less to do with the components of diet and more to do with overall calorie intake and level of fitness throughout life. There are those who would debate that, and suggest that the specific dietary components shape gut microbe populations, and those populations have just as significant an effect as exercise over the span of a lifetime. Regardless, eating a calorie restricted diet tends to solve both of those problems, making the debate moot in a practical sense, and no-one is arguing against aerobic fitness as a good thing in life.

From the standpoint of heart health, the Tsimane are a model group. A population indigenous to the Bolivian Amazon, the Tsimane demonstrate next to no heart disease. They have minimal hypertension, low prevalence of obesity, and their cholesterol levels are relatively healthy. And those factors don't seem to change with age. Also minimal is the incidence of type 2 diabetes. Researchers have now conducted the first systematic study that examines what the Tsimane consume on a regular basis and compares it to that of the Moseten, a neighboring population with similar language and ancestry, but whose eating habits and lifeways are more impacted by outside forces.

Using the same measurement strategy employed by the U.S. Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey, the researchers interviewed 1,299 Tsimane and 229 Moseten multiple times about everything they had eaten or drunk in the previous 24 hours. Using published and their own nutritional estimates for all items, and a variety of methods to estimate portion size, they provided a detailed breakdown of daily food intake. The high-calorie (2,433-2,738 kcal/day) Tsimane diet was characterized by high carbohydrate and protein intake, and low fat intake (64, 21 and 15 percent of the diet, respectively). In addition, the Tsimane don't eat a wide variety of foods, relative to the average U.S. or Moseten diet. Almost two-thirds of their calories are derived from complex carbohydrates, particularly plantains and rice. Another 16 percent comes from over 40 species of fish, and 6 percent from wild game. Only 8 percent of the diet came from markets.

Despite the low dietary diversity, the researchers found little evidence of micronutrient deficiencies in the Tsimane's daily intake. Calcium and a few vitamins (D, E and K) were in short supply, but the intake of potassium, magnesium, and selenium - often linked to cardiovascular health - far exceeded U.S. levels. Dietary fiber intake was almost double U.S. and Moseten levels. The conclusion: A high-energy diet rich in complex carbohydrates is associated with low cardiovascular disease risk, at least when coupled with a physically active lifestyle (Tsimane adults average 17,000 or so steps per day, compared to Americans' 5,100). Moving away from a diet that is high in fiber and low in fat, salt, and processed sugar represents a serious health risk for transitioning populations.

Link: http://www.news.ucsb.edu/2018/019248/food-thought

The Longevity Forum, hosted by investor Jim Mellon and company yesterday in London, was a reminder that we still have a way to go when it comes to guiding the conversation on longevity and rejuvenation in a useful direction. On the one hand, most people give medicine and aging little serious thought until it is too late, and if we want large-scale funding for the goal of human rejuvenation through realization of the SENS research agenda, then the public at large really has to be on board in the same way that they are reflexively in favor of doing something about cancer and Alzheimer's disease. On the other hand, the first reaction of many people when presented with the concept of enhanced human longevity is to fixate on line items that really do not matter in the grand scheme of things: whether retirement will still exist; will life insurance companies have to change their ways; will some particular demographic gain slightly more or slightly less than another as a result of progress in medicine. None of these points matter anywhere near as much as does the act of building the therapies that will save lives and improve lives.

I should probably disclose that I am a technological determinist, in the sense that it is technology that determines society. People will adapt to new capabilities quite rapidly, as illustrated by any number of world-changing advances in communications, transport, and medicine introduced and enthusiastically embraced over the past few centuries. The shape of society will shift in response to those new capabilities. Building the technology is the first, foremost, and only goal: let the rejuvenation therapies be built and distributed, and let the world adapt to the wonders of a longer, healthier life. Insofar as we have to talk about it ahead of time, that talking should focus on whatever is needed in order to direct resources to the appropriate tasks of research and development.

But clearly others feel differently, in that broader discussions should take place, or that there is a process of awareness and coming to terms that must be undertaken. Expectations must be managed, and perhaps that is really all this comes down to at the end of the day. People don't want to be surprised, whether they are managing billions of dollars of life insurance liabilities, or managing their own career and little else. If the status quo today was that we all knew that rejuvenation was arriving soon, then that would be the status quo and everyone would be fine with it. Our job as advocates is, in some sense, to make this the status quo.

The Longevity Forum brought together scientists, insurance and medical industry functionaries, biotechnology investors, former politicians, people with interests in philosophy and self-empowerment, and a variety of less easily described types. There was a row of journalists in the back of the auditorium, heads down and taking notes. The scientific content was kept deliberately lightweight, and the focus was more on what this business of longer healthy lives means for people who live in the mundane world of pensions, life insurance, planning for retirement, and coping with the ugly realities of late life disability. I will say that these are all earnest folk in their own ways and their own bailiwicks, but their day to day concerns are about to be upended in the deluge. The technology has arrived, senolytic therapies to clear senescent cells exist, now, today, and there is no time to be concerned with what will be. By the time any bureaucracy has fully engaged with the question, we will be looking at the dawn of the age of rejuvenation in the rear view mirror.

Large financial institutions are not well positioned for any sort of upward leap in life expectancy in old age, of the sort that will take place the moment that widespread use of senolytic drugs occurs. They can cope with a slightly more aggressive upward trend, and indeed have been gearing up for that for quite some time. But a sudden leap? The result will make the bailouts of other industries in the past few decades look anemic. That is of course no reason to stop. Life for everyone is more important than the financial health of any given group of businesses earnestly engaged in making a severe strategic error. Those that serve poorly should become bankrupt and go under, though sadly the costs are all too often socialized these days. Nothing that was said by the representatives of these industries at the Longevity Forum gives me any hope that it will happen differently; those present either understood but were in no position to make changes, or did not give much weight to the possibility of large upward leaps in life expectancy.

I think one of the reasons that this decimation of the pensions and life insurance industries will happen is because many of the figureheads of the research community are very conservative in their view of timelines and potential. Eric Verdin is an interesting case in point; he was presenting at the Longevity Forum to give an overview of work at the Buck Institute. Verdin makes the case that we are not all that far in to the standard 50 year cycle for longevity-related technologies, and it takes at least 20 years to get anything moving in earnest, pointing to stem cell therapies as an example. On that basis he, like a number of others, sees only incremental advances ahead in human longevity. At the very same time, however, he is quite aware of senolytics, given that it arose in part at the Buck Institute, and touts that work as important. But I have to think that he doesn't see it as any being different than, say, calorie restriction mimetics, in terms of how one can talk about the prospects for human health and longevity. This seems like a deep and important error to me. These two classes of therapy are a world apart. One repairs a form of damage that causes aging, the other adjusts metabolism to slightly slow the onset of further damage. The size of effect and reliability of results are night and day.

In any case, to return to the original point, if one wants to swing society into line with the goal of building an industry whose products will enable people to live much longer in good health, then the established way of going about doing so involves efforts that look a lot like the Longevity Forum. Thus I expect to see more of this sort of thing in the years ahead, and not just in London. The goal of building an industry is far greater than just succeeding with a couple of startup biotechnology companies, and will, even initially, require billions in investment in new medical and research infrastructure. While the core technology demonstrations of the SENS rejuvenation research programs, to produce an old mouse that exhibits comprehensive rejuvenation and a doubling of remaining life span, could be achieved now for something less than a billion dollars spent over a decade, it is vastly more expensive to translate that work into human medicine and then provide it to the world. That requires very large, very conservative organizations to play their part, and they tend to follow public opinion, not lead it.

At one point near the end of the event I found myself advocating senolytics to one of the non-scientists present, a noted figure who runs a charity to help old people with their physical limitations - and is thus in a position to do a great deal of good as rejuvenation therapies emerge. I was forcefully reminded by the resulting polite rejection that people outside our community really cannot tell the difference between snake oil and real rejuvenation therapies. To them a suggestion to look into senolytics, because amazing things are happening in the laboratory and among self-experimenters, sounds no different from a pitch for supplements made by any random fraud in the anti-aging marketplace. Those on the outside are wary, or disinterested, and will be slow to come around. The need for patient advocacy doesn't end just because a treatment exists, and that includes the persuasion of existing patient advocates who work with old people. It seems a terrible thing to me that so many millions are suffering right now, and could make an educated choice on the risks and the rewards to seek benefit from any of the easily available senolytics, if they only knew what we know.

The Longevity Forum is a charitable concern, and part of its remit is not just to bring together the insiders and the outsiders in the matter of longevity science, but also to bring together public, private, and charitable concerns in order to advance their agendas. Charities for scleroderma and premature ovarian insufficiency presented at the event. Both conditions are more subtly age-related than the most common age-related conditions that we are all more familiar with. The latter of the two looks a lot like a very selective progeria in many ways, both superficially and in its biochemistry. There was some discussion of ways in which those present might help. Among those who could offer assistance on the technical front was Alex Zhavoronkov of In Silico Medicine. He presented on some of the capabilities of his company, using deep learning techniques with genetic and epigenetic data sets to find small molecule drug candidates and biomarkers that might accelerate research and development. This is particularly applicable to medical conditions wherein the research community has struggled to gain a good understanding of the underlying mechanisms and causes. It is true, however, that pharmaceutical development in general is one of the least efficient processes in medicine, regardless of the target condition. It is an area ripe for disruption, even if that disruption is limited to creating a very cheap, efficient source of candidate compounds for arbitrary medical conditions.

The formal event ended with a panel discussion on "life well lived." Do people really need to be told how to live? Will the applicability of the wisdom of the ancients really change in the slightest given another few decades of life? One day in the next few years doctors will start prescribing senolytics. Life spans will increase. A lot of ink will be spilled on viewpoints that are ultimately pointless and that will vanish from memory near immediately. Society will continue. But we still, it seems, need to be in the business of managing expectations as well as building new biotechnology.

The rationalist and effective altruism communities overlap to a considerable degree, and do engage with the goal of radical life extension through the development of rejuvenation therapies, but not to the degree that I think would be rational. The only rational use for excess capital in this day and age is purchasing an acceleration in the development of rejuvenation biotechnology, on the grounds being alive and healthy enables all other options. That acceleration can be achieved through philanthropy, via support of the SENS Research Foundation, Methuselah Foundation, and similar organizations, or via investment in startups focused on the development rejuvenation therapies. But it can be achieved, and that is perhaps the point that hasn't yet sunk in in a large enough fraction of people.

As our ability to affect the aging processes has been dramatically improved within the past decade, now is an excellent time for rationalists to consider new evidence regarding the necessity and feasibility of rejuvenation biotechnology. The amount of harm caused by aging is immense from a human standpoint. It is, by far, the greatest threat to living people today, even in the most violent of countries. (It has long since dethroned the previous all-time killer, infectious disease, which we did something about.) In a world with untreated aging, everyone who does not die of something else will suffer from decades of declining health. Death is the inevitable result.

Aging is a global tragedy from an economic standpoint as well. Aging is the largest driver of healthcare costs in the United States. As birthrates remain low and unhealthy lifespans remain relatively long, the proportion of the economy devoted to taking care of older people can only increase. This economic burden represents an enormous expenditure of human labor, as large amounts of money and time are spent on keeping people alive as their bodies slowly fail them.

Fifteen years ago, the idea of intervening against aging through rejuvenation biotechnology was widely considered unfeasible or outside of human ability; today, it is mainstream science. The Hallmarks of Aging is one of the most frequently cited papers in biology. A wide variety of researchers at prestigious universities are actively involved in pursuing rejuvenation biotechnology therapies. Multiple biotechnology companies are developing interventions against the Hallmarks of Aging, each one of which has at least one partial intervention currently in development. For any given person, it is possible that partial interventions may delay enough of the aging processes long enough for further interventions to allow for more healthy years of life, until, ultimately, a comprehensive suite of therapies is developed to control all of the aging processes. This concept is called longevity escape velocity.

Unfortunately, aging is an enormous problem, not just in terms of the harms it does but in the number of specific therapies that will need to be successfully developed in order to completely control it. The current amount of effort is significant but not enough to bring about the medical control of aging as soon as would otherwise be possible. As a rationalist, you know better than to suffer from the bystander effect, waiting for someone else to do what needs doing. If you have the aptitude and are entering college, consider becoming a researcher yourself. Alternatively, you can aid advocacy efforts, fund research efforts, or, if you are an investor, finance the development of rejuvenation biotechnology companies.

Link: https://www.leafscience.org/updating-your-priors-on-rejuvenation-biotechnology/

The personal cost of being overweight or obese is sizable, even when considering only financial matters, the greater expenditure on medical needs and the opportunity costs that accompany sickness and loss of capacity. Additional weight in the form of visceral fat tissue both shortens life expectancy and increases lifetime medical expense, this much is well established in the scientific literature. Summing those costs over the entire population produces some staggeringly large numbers. Those numbers can vary widely depending on the assumptions and what is included; those here are on the high end. Yet the cost of excess weight is just a tiny fraction of the cost of degenerative aging as a whole, and it largely arises because being overweight makes the process of aging incrementally worse and incrementally faster.

The impact of obesity and overweight on the U.S. economy has eclipsed $1.7 trillion, an amount equivalent to 9.3 percent of the nation's gross domestic product, according to a new report on the role excess weight plays in the prevalence and cost of chronic diseases. The estimate includes $480.7 billion in direct health-care costs and $1.24 trillion in lost productivity, as documented in America's Obesity Crisis: The Health and Economic Impact of Excess Weight. The study draws on research that shows how overweight and obesity elevate the risk of diseases such as breast cancer, heart disease, and osteoarthritis, and estimates the cost of medical treatment and lost productivity for each disease.

For example, the treatment cost for all type 2 diabetes cases - one of the most prevalent chronic diseases connected to excess weight - was $121 billion and indirect costs were $215 billion. On an individual basis, that comes to $7,109 in treatment costs per patient and $12,633 in productivity costs. America's Obesity Crisis assesses the role excess weight plays in the prevalence of 23 chronic diseases and the economic consequences that result. To mention a few, obesity and overweight are linked to 75 percent of osteoarthritis cases, 64 percent of type 2 diabetes cases, and 73 percent of kidney disease cases. "Despite the billions of dollars spent each year on public health programs and consumer weight-loss products, the situation isn't improving. A new approach is needed."

Link: http://www.milkeninstitute.org/newsroom/press-releases/view/348

By stretching the definition of European to include the United Kingdom, a topic about which everyone involved seems ambivalent, we can say that November opens with a set of three European longevity conferences, all within a few days of one another. The first is in London, running today, the second in Valencia, the third in Brussels. Conferences and concrete are metrics by which one can judge the health of a field: the more events, the more interest, and the more buildings under construction at various institutions, the more advanced the state of funding. First the conferences, and then the concrete, years later, if the field continues to grow and become successful.

It is still the case that most people remain to be informed that treating aging as a medical condition is a very real possibility for the near future. Most people remain to be persuaded that preventing death and disability by aging is of great importance, indeed the most important project that our species might undertake. Yet those very same people will be among the majority that will suffer and die from aging. Aging is by far the greatest cause of harm, loss, and cost in the world, its consequences many times larger than the next most severe affliction affecting humanity. We stand on the verge of doing something about this, but the silent majority doesn't know and doesn't care. The world still needs to be awoken.

Thus conferences, networking, advocacy, and spreading the word. This is an important juncture in the growth of the rejuvenation research community, as investment in the clinical development of senolytics, the first of the new classes of rejuvenation therapies outlined in the SENS vision for the treatment of aging, is pulling new groups into this sphere at an increasing pace. Rejuvenation through periodic repair of the molecular damage that causes aging will be the basis for a vast industry of medicine, larger than anything that has come before. Everyone adult is a customer at some price point. The first successful companies to deploy working rejuvenation therapies will become behemoths capable of funding the basic science to finalize all of the SENS rejuvenation biotechnologies. If the world can be awoken, if the resources for growth obtained, then the next few decades in the medical life sciences will prove to be a wild ride indeed.

The Longevity Forum, November 5th 2018

Our inaugural forum, which takes place on 5 November 2018 in London, is a true public and private partnership which will address a host of issues pertaining to the full human life cycle - both from a scientific and a social science perspective. It will bring together key opinion leaders from the worlds of government, business, science and education, to identify immediate and long-term priorities for The Longevity Forum.

Longevity World Forum, November 7th-8th, 2018

Life expectancy for humankind has increased considerably in the last 100 years. In fact, now we wonder about the limit of human longevity. Living better and longer is one of the main concerns of our society as well as one of the main objectives of contemporary medicine. Thus, the scientific community is working really hard to bring advances in this sense and to broaden knowledge about the genetic basis of human longevity and the biological mechanisms related to aging. Scientists want to find therapeutic strategies to prolong life and assure a quality standard. All in all, Longevity World Forum is conceived as a new space for experts to collaborate and develop knowledge about this field.

Fourth Eurosymposium on Healthy Ageing, November 8th-10th 2018

The defeat of aging lies within our collective grasp. It's time to seize this remarkable opportunity. The Eurosymposium on Healthy Ageing proclaims the possibility and the imperative of a moonshot project to overcome all age-related diseases within 25 years by tackling aging as their root cause. The result will be a world where healthcare is far less expensive; where human well-being can be radically extended; where people place greater value on the environment and on peace, in view of their expectation of much longer lives; where the right to life is more precious than ever, because life is longer.

Key steps in this initiative will include a paradigm shift stressing the need for research on aging itself, rather than only on individual diseases of old age; the removal of regulatory and other barriers which prevent or disincentivize companies from developing treatments for aging itself; an accelerated program to test anti-aging interventions on a much larger scale than anything that exists at the moment, leading to multiple human clinical trials of genuine rejuvenation biotechnologies by 2021. These programs will require a coordinated effort at national and international level, integrating diverse existing and novel research approaches. They need to be financed by both public and private organizations, and create inclusive, affordable solutions available on equal terms to everybody.

Researchers recently reported a most interesting finding: there is a good correlation between the number of neurons in the cortex and life span when comparing species. This holds up between classes of species, as well for a number of well known exceptions to other associations between physical characteristics and life span. For example, you might compare these results with the relationship between metabolic rate, mitochondrial composition, and life span that largely holds in mammals, save for bats, which are distinguished by their ability to fly. Flight imposes enormous demands on metabolism, and flying species are as a result biochemically quite different from even near cousin flightless species. Further afield in the taxonomic tree of life, birds tend to have far greater life spans than similarly sized mammals, and once again this is probably because of the demands of flight. Nonetheless, this association with cortical neuron count holds up well for birds and mammals alike. Why does this relationship exist? At this point researchers have nothing but educated guesses. I would imagine that we will hear more on this topic in the years ahead, however.

Whether you're looking at birds or primates or humans, the number of neurons that you find in the cortex of a species predicts around 75 percent of all of the variation in longevity across species. Body size and metabolism, in comparison, to usual standards for comparing animals, only predicted between 20-30 percent of longevity depending on species, and left many inconsistencies, like birds that live ten times longer than mammals of same size. Most importantly, humans were considered to be a "special" evolutionary oddity, with long childhood and postmenopausal periods. But this research finds that is not accurate. Humans take just as long to mature as expected of their number of cortical neurons - and live just as long as expected thereafter.

Researchers examined more than 700 warm-blooded animal species from the AnAge database which collects comprehensive longevity records. They then compared these records with data on the number of neurons in the brains of different species of animals. The researchers found that parrots and songbirds, including corvids, live systematically longer than primates of similar body mass, which in turn live longer than non-primate mammals of similar body mass. Previous studies determining what brains are made of showed that parrots and songbirds have more cortical neurons than similar-sized primates, which have more cortical neurons than any other mammal of comparable body size.

"The more cortical neurons a species has, the longer it lives - doesn't matter if it is a bird, a primate, or some other mammal, how large it is, and how fast it burns energy. It makes sense that the more neurons you have in the cortex, the longer it should take a species to reach that point where it's not only physiologically mature, but also mentally capable of being independent. The delay also gives those species with more cortical neurons more time to learn from experience, as they interact with the environment." What is the link between having more neurons in the cortex and living longer lives? That's the new big question researchers need to tackle.

Link: https://www.eurekalert.org/pub_releases/2018-10/vu-las103018.php

There has been some debate in the research community as to whether the observed relationship between cancer risk and height in our species is due to (a) taller people having more cells, and thus more chances to suffer a cancerous mutation, or (b) some more indirect factor, such as, for example, the role of growth hormone in cellular metabolism. The author of this study marshals data to argue convincingly for the former hypothesis, for most forms of cancer.

The multistage model of carcinogenesis predicts cancer risk will increase with tissue size, since more cells provide more targets for oncogenic somatic mutation. However, this increase is not seen among mammal species of different sizes (Peto's paradox), a paradox argued to be due to larger species evolving added cancer suppression. If this explanation is correct, the cell number effect is still expected within species.

Consistent with this, the hazard ratio for overall cancer risk per 10cm increase in human height (HR10) is about 1.1, indicating a 10% increase in cancer risk per 10cm; however, an alternative explanation invokes an indirect effect of height, with factors that increase cancer risk independently increasing adult height.

The data from four large-scale surveillance projects on 23 cancer categories were tested against quantitative predictions of the cell-number hypothesis, predictions that were accurately supported. For overall cancer risk the HR10 predicted versus observed was 1.13 versus 1.12 for women and 1.11 versus 1.09 for men, suggesting that cell number variation provides a null hypothesis for assessing height effects.

Melanoma showed an unexpectedly strong relationship to height, indicating an additional effect, perhaps due to an increasing cell division rate mediated through increasing IGF-I with height. Similarly, only about one-third of the higher incidence of non-reproductive cancers in men versus women can be explained by cell number. The cancer risks of obesity are not correlated with effects of height, consistent with different primary causation.

Link: https://doi.org/10.1098/rspb.2018.1743

Today's open access papers touch on aspects of the interaction between exercise and the pace of aging. People age at somewhat different rates, and for the vast majority of us lifestyle is a far greater determinant of that rate than our genes. Until such time as the clinical deployment of rejuvenation therapies is well underway, and in regions of the world sufficiently wealthy to have tamed the majority of infectious disease, it remains the case that our choices regarding our health, such as calorie restriction and exercise, are the most reliable means of improving life expectancy. The size of the effect is not enormous in the grand scheme of things: three quarters of slim, fit, well-considered people die before reaching 90 years of age, after all. You cannot add decades to your life by making incrementally better lifestyle choices.

So why bother? Well, firstly because being increasingly sick for a span of decades at the end of life is a real drag, and exercise and calorie restriction do make a sizable difference to the odds of avoiding much of that fate. But more importantly this is an era of radical, accelerating progress in the life sciences. With every passing year we move closer towards the deployment of real, working rejuvenation therapies. Some of the the first of those, senolytic treatments to clear senescent cells, can already be used by the adventurous. The times are changing rapidly when it comes to medical science. A few years of life gained through exercise, or achieving an extra decade of being fit enough to travel to try new therapies via medical tourism, may well make the difference between considerable benefits and a longer life, or missing out on that chance.

If exercise was incredibly expensive, or if exercise to improve health was only possible at the end of a multi-billion investment in medical research and development, then it wouldn't be worth it. That is the same story as for many lines of development that aim to modestly slow the aging process, those based on replicating calorie restriction, for example. Such treatments will be expensive to create, and the past twenty years tells us that this process has a high rate of failure. It just isn't worth it when other lines of rejuvenation research have far greater expected outcomes in terms of health gained and years added. But exercise is here now, free, and highly reliable. Modest gains achieved at little cost, and that near always work as intended, are not to be ignored. It helps.

The Inherent Human Aging Process and the Facilitating Role of Exercise

Arguably the best available depictions of the global physiological changes produced by age are the profiles of world record performance times in swimming, athletics, and cycling, depicting the trajectory of decline in maximal integrated physiological performance capability. The curves suggest that the aging process produces a synchronized, controlled decrease in physiological performance over the human lifespan. The shape of the performance profile by age is essentially independent of discipline, distance, or phenotype. Importantly, the specific times of performance are not the driving force in the production of the shape of the declining performance profile.

We suggest that in these highly trained individuals the shape of the curve is generated by the aging process operating on a physiology optimized for any given age. We hypothesize that with adequate training this same profile and trajectory, but with lower performance times, would be generated by all individuals who engage in sufficient physical activity/exercise. Unlike performance, data obtained from examining individual physiological systems or tissues do not give information on the unceasing and changing global integrating functions of the aging process. However, these data do give valuable information about the integrity of physiological systems at a particular age and allow a direct comparison to be made between the effects of inactivity and physical activity/exercise.

Being physically active has been shown to have global protective effects on physiological systems and thus facilitates the aging process by maintaining physiological integrity. There is emerging evidence which suggests that physiological regulation of aging may be multi-compartmentalized. We do not advocate exercise as a panacea, but all the evidence indicates that being physically active and exercising is far superior to any other alternative for achieving optimal aging.

Effects of Acute and Chronic Exercise on Immunological Parameters in the Elderly Aged: Can Physical Activity Counteract the Effects of Aging?

Immunosenescence is characterized by deterioration of the immune system caused by aging which induces changes to innate and adaptive immunity. Immunosenescence affects function and phenotype of immune cells, such as expression and function of receptors for immune cells which contributes to loss of immune function (chemotaxis, intracellular killing). Moreover, these alterations decrease the response to pathogens, which leads to several age-related diseases including cardiovascular disease, Alzheimer's disease, and diabetes in older individuals. Furthermore, increased risk of autoimmune disease and chronic infection is increased with an aging immune system, which is characterized by a pro-inflammatory environment, ultimately leading to accelerated biological aging.

During the last century, sedentarism rose dramatically, with a concomitant increase in certain type of cancers (such as breast cancer, colon, or prostate cancer), and autoimmune disease. Numerous studies on physical activity and immunity, with focus on special populations (i.e., people with diabetes, HIV patients) demonstrate that chronic exercise enhances immunity. However, the majority of previous work has focused on either a pathological population or healthy young adults whilst research in elderly populations is scarce. Research conducted to date has primarily focused on aerobic and resistance exercise training and its effect on immunity. This review focuses on the potential for exercise training to affect the aging immune system. The concept is that some lifestyle strategies such as high-intensity exercise training may prevent disease through the attenuation of immunosenescence.

The practice of calorie restriction slows aging across the board. Near every known measure of aging is diminished in calorie restricted mice, and it produces significant health gains in humans. While the short term benefits of calorie restriction are quite similar in all mammals, the long term gain in life span is only large in short-lived species. Understanding why this is the case will require a near complete understanding of cellular metabolism as a whole. Researchers can pinpoint key controlling mechanisms, but the interaction between cellular metabolism and the pace of aging is enormously complex, and far from fully mapped. This is one of the reasons why progress towards calorie restriction mimetic drugs has been so painfully slow and expensive.

The example here is one of many in which calorie restriction is shown to reduce the extent of an issue that accompanies aging. Chronic inflammation is a dysregulation of the immune system and associated signaling that has serious consequences over time, accelerating the progression of all of the common age-related conditions. It is particularly damaging in the context of blood vessel walls, where the immune cells known as macrophages gather in attempts to clean up the deposits of cholesterol associated with atherosclerosis. Inflammation is well known to speed up the growth of the atherosclerotic plaques that ultimately cause a stroke or heart attack. Less of it is a good thing.

Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction (CR) in rats improves arterial function and extends both health span and life span. How CR affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated.

Aortae were harvested from young (6-month-old) and old (24-month-old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40% CR beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that CR markedly reduced age-associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that CR effectively prevented an age-associated increase in the density of platelet-derived growth factor, matrix metalloproteinase type II activity, and transforming growth factor beta 1 and its downstream signaling molecules, phospho-mothers against decapentaplegic homolog-2/3 (p-SMAD-2/3) in the arterial wall. In early passage cultured vascular smooth muscle cells isolated from AL and CR rat aortae, CR alleviated the age-associated vascular smooth muscle cell phenotypic shifts, profibrogenic signaling, and migration/proliferation in response to platelet-derived growth factor.

In conclusion, CR reduces matrix and cellular proinflammation associated with aging that occurs within the aortic wall and that are attributable to platelet-derived growth factor signaling. Thus, CR reduces the platelet-derived growth factor-associated signaling cascade, contributing to the postponement of biological aging and preservation of a more youthful aortic wall phenotype.

Link: https://doi.org/10.1161/JAHA.118.009112

In a recent publication, researchers argue that there are flaws in past studies showing that, for the US population, wealth correlates with a sizeable increase in life expectancy. Those studies failed to consider the highly dynamic nature of wealth. Only a fraction of the population maintains a given level of wealth for decades: individual fortunes rise and fall quite rapidly. Taking this into account, the data actually shows that the size of the wealth effect for life expectancy is half of that previously estimated.

This is something of a distraction, however. The only real methodology by which wealth can be used to buy additional years of healthy life is to invest it into the right forms of medical research and development, meaning the establishment of rejuvenation therapies based on the SENS model of damage repair. Unfortunately all too few wealthy individuals have realized that this option is on the table. We can hope that this will change in the years ahead, as the first rejuvenation therapies worthy of the name make their way to the clinic.

New research results challenge previous findings of huge differences in life expectancy between the rich and those at the bottom of the income scale. In real life people don´t necessarily stay poor or stay rich, as assumed in previous research, and economists have now found a way to take this mobility between income-classes into account providing a more realistic way to calculate life expectancy for people from different walks of society. Their results show that in reality the difference between the lifespan of a rich and a poor person is really not that big.

In 2016 a research team showed that high-income people in the US can expect to live 6.5 years longer at age 40 than low-income individuals. The existing method assumes that the poor stay poor and the rich stay rich for the rest of their lives. In reality, however, over a ten-year period half of the poorest people actually move into groups with better incomes and likewise, half of the rich leak down into lower income classes. The mortality of those who move to a different income class is significantly different from those who stay in the same class.

When accounting for income mobility, life expectancy for a 40-year-old man in the upper income groups is 77.6 years compared with 75.2 for a man in poorer groups - a difference of 2.4 years. For women the difference between high and low-income groups is 2.2 years. However, without taking the income mobility into account the life expectancy difference was twice as big - around five years - for both men and women. Using the method, the authors suggest that the difference in the US is three years rather than 6.5.

Link: https://www.eurekalert.org/pub_releases/2018-10/uoc-irp102618.php

In the paper I'll point out today, the authors provide evidence in support of the concept that it is specifically oxidized cholesterol that is the primary cause of atherosclerosis rather than the condition resulting from too much cholesterol in general. In atherosclerosis, fatty deposits form in blood vessel walls, weakening them and narrowing the vessels. This ultimately leads to fatal structural failure as stressed blood vessels rupture or are blocked. Atherosclerosis is arguably a condition that arises because the macrophages responsible for removing cholesterol from blood vessel walls become overwhelmed, inflammatory, and incapable of keeping up the work of maintenance and repair. They become foam cells and die, adding their contents and their remnants to grow an atherosclerotic plaque, and attracting more of their fellows to the same location to repeat the cycle.

Here it is argued that this foam cell fate is largely the consequence of oxidized cholesterol. The macrophages are reacting to oxidized cholesterol in ways that sabotage their efforts to remove local deposits of cholesterol. The approach to this condition adopted by the SENS rejuvenation research programs is to find ways to break down the oxidized cholesterol that our cells struggle to deal with. Removing it from the picture should enable cells to continue as they were, and remove the fatty deposits. Researchers associated with the SENS Research Foundation have searched for bacteria capable of consuming these damaged forms of cholesterol, in order to adapt their enzymes into therapeutic molecules. This work has to date largely focused on 7-ketocholesterol, with some early success, but a broader and more heavily funded research program is very much called for.

Modified LDL particles activate inflammatory pathways in monocyte-derived macrophages

One of the main characteristics of atherosclerosis is the accumulation of lipids in the intimal layer of the arterial wall. In atherosclerotic plaques, phagocytic cells, such as macrophages, engulf atherogenic low-density lipoprotein (LDL) particles, but are unable to process them, and thus become foam cells, having cytoplasm packed with lipid droplets. Foam cells are characterized by several typical features: they have decreased ability to migrate, while displaying enhanced production of pro-inflammatory cytokines. Therefore foam cells participate in maintaining chronic inflammation in the lesion.

Previous studies have shown several clusters of genes up- or down-regulated in macrophages in response to oxidized LDL, which is known to be atherogenic. Regarding the inflammatory response, modified LDL appeared to trigger up-regulation of genes with anti-inflammatory activities. We performed a transcriptome analysis of macrophages treated with atherogenic LDL that causes intracellular cholesterol accumulation. We used the strategy of upstream analysis for causal interpretation of the expression changes.

In this study, we discovered 27 transcription factors that were potentially responsible for the changes in gene expression induced by modified atherogenic LDL. These transcription factors were used for identifying the master-regulators (genes and proteins) responsible for regulation of large cascades of differentially expressed genes. In general, the genes that were up-regulated in response to lipid accumulation in macrophages induced by atherogenic LDL were mostly involved in inflammation and immune response, and not in cholesterol metabolism. Our results suggest a possibility that it is not cholesterol accumulation that causes an innate immunity response, but rather the immune response is a consequence of a cellular reaction to modified LDL. These results highlight the importance of the inflammatory component in the pathogenesis of atherosclerosis.

Modified LDL Particles Activate Inflammatory Pathways in Monocyte-derived Macrophages: Transcriptome Analysis

A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation.

We attempted to identify the main master regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach. We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL-15, and CXCL8. Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling.

The latest Lifespan.io crowdfunding project launched last month and is already closing in on the final stretch goal of $75,000; congratulations to everyone involved. The funds will be used to run a mouse study of nicotinamide mononucleotide (NMN) supplementation, one of a number of similar approaches that can increase NAD+ levels in older animals. This in turn improves mitochondrial function, though without addressing any of the underlying causes of mitochondrial decline with aging - it is a way to narrowly compensate for some of the metabolic consequences of aging, or to selectively override some of the reactions to the biochemical damage of aging. It isn't repair, but it clearly produces some benefits. A study of increased NAD+ levels using the alternative approach of nicotinamide riboside supplementation in older humans showed a reduction in blood pressure, most likely by improving the performance of smooth muscle cells in blood vessel walls. The metrics taken over the course of this Lifespan.io funded mouse study will allow researchers to assess the degree to which the NMN intervention can slow aging in mice.

Yesterday, we announced the successful completion of the NAD+ Mouse Project after a great fundraiser, but it seems we are not done yet. The research team at Harvard has announced a new stretch goal for the last two days of the campaign. A new $75,000 goal is to be the final step, and to support that, Dr. David Sinclair is offering to fund match the next $5000 in donations to the project to help it reach this final goal. So, for the next two days, all donations are worth double.

In our project, we will test the hypothesis that by restoring bioavailable NAD+ we can reverse aspects of the aging process. Starting with mice that are 20 months old (roughly equivalent to a 50 year old human), longer-term NMN treatments will be applied in order to restore levels of cellular NAD+ to those found in youthful mice. Your donations will not only allow us to purchase the materials necessary to perform this experiment, but also pave the way for human clinical trials aimed at showing, for the first time, that we can actually slow down human aging.

The final stretch goal will be to add even more comprehensive testing, such as end-of-life pathology (frequency and specificity of neoplasms/tumors/cancer) and MRI diagnostics (body composition, lean-to-fat ratio). This would really allow the researchers to maximize the useful data they collect during the study and help assess any changes to cancer risk, why each animal died, and what age-related diseases were affected by the drug.

Link: https://www.leafscience.org/new-stretch-goal-announced/

Enough funding is now flowing into the clinical development of therapies to slow or reverse aging to ensure that the analysis and white paper industry has started to pay attention. Their efforts are one of the ways in which ideas move through the business community; market analyst organizations play a role somewhat analogous to that of media outlets. Their job is to inform, some are highly opinionated, and their efforts can cause some ideas to be taken more seriously than others.

That analysts are producing materials such as the example noted here is a sign that greater investment in this field is ahead. That said, it remains the case that, absent better guidance, new funding may largely support low-yield efforts that can only modestly slow aging, such as calorie restriction mimetic development, rather than high-yield efforts involving forms of rejuvenation therapy. Providing that guidance is an important function of our advocacy community, as outsiders typically find it challenging to tell the difference between better and worse approaches to the treatment of aging as a medical condition.

Senolytics. Blood transfusions. Placenta stem cells. These are just some of the innovative ways that startups are tackling mortality and increasing the human lifespan. How can we live longer? How do we become healthy enough so that we can extend our lifespans by 5, 10, or even 50 extra years? And it's not just about living longer, but also feeling younger. For example, what if you could feel 25 at the age of 75? These are the big questions that scientists have been trying to answer for decades, with few answers.

Understanding how we age on a physiological level is an incredibly complex topic. It shares many of the cellular and molecular processes that underlie age-related diseases like cancer or Alzheimer's, which continue to elude us in their pathology. While aging itself isn't a treatable disorder or condition, companies and researchers focused on longevity are looking at bodily processes at the cellular level to see how aging progresses and trying to find the right drugs, treatments, and vitamins that might slow these processes down. And as a result, we may discover the key to longevity, or living a longer life.

For instance, a new class of drugs known as "senolytics" are now being touted as the next big thing in anti-aging research for getting rid of decrepit (but harmful) cells that stop dividing as we age, known as senescent cells. And it's not just the biotech or pharma companies looking to combat mortality with novel drug therapies. Wellness companies are developing daily supplements that claim to prolong your lifespan. And some startups are even offering blood transfusions from younger individuals for a "rejuvenating" effect.

In this report, we explore the current landscape of initiatives that aim to slow down the aging process, and in turn, reduce the likelihood of several diseases. We look at how these initiatives could promote longevity and what this market looks like for both investors and consumers.

Link: https://www.cbinsights.com/research/report/future-aging-technology-startups/