Fight Aging!

Mitochondria are the power plants of the cell, turning out the chemical energy store molecule ATP that is needed to power cellular processes. Mitochondrial function declines with age, and this faltering of energy production is an important contribution to degenerative aging. A broad range of proximate causes have been identified, changes in gene expression that directly or indirectly disrupt the supply of rate-limiting molecules necessary for mitochondria to carry out their work. Researchers identified loss of NAD+ as one of those issues some years ago, and supplementation with precursor compounds derived from vitamin B3 (such as nicotinamide riboside) has been shown to increase NAD+ levels and improve mitochondrial function. Today's research materials report on an analogous effort to raise levels of the antioxidant glutathione, also lost with age, by supplementing with a combination of precursor compounds glycine and N-acetylcysteine.

Antioxidants are important to mitochondrial function and cell health. Creating ATP is an energetic process, producing reactive oxidizing molecules as a necessary side-effect. Too much oxidation harms the cell, though some oxidation is needed as a signaling mechanism. Cells employ antioxidants to soak up the excess. Researchers have in the past shown benefits in mice through genetic engineering to upregulate the natural mitochondrial antioxidant catalase, while mitochondrially targeted antioxidant compounds such as MitoQ and SKQ1 have also resulted in animal studies showing improvements in health and a modest extension of life span.

The results reported in this small pilot human study of glycine and N-acetylcysteine supplementation appear interesting, particularly given that the intervention doesn't just improve mitochondrial function, but also improves markers of age-related chronic inflammation. Exercise is more effective at increasing NAD+ levels than the present methods of NAD+ precursor supplementation, at least in published clinical trial data. Exercise is known to increase glutathione levels as well, but is it better for glutathione levels than this approach to precursor supplementation? Looking at blood samples or red blood cells, a 2007 study shows a ~25% increase in glutathione via exercise, which is considerably smaller than the ~100% increase via supplementation claimed in the present study. That suggests it to be worth the expense to replicate this outcome in a larger study.

For those who are minded to responsibly repeat this study as a self-experiment at home, hopefully also discussing with a physician beforehand and taking blood tests before and after to see how the metrics hold up, I should note that glycine and N-acetylcysteine are both easily obtained. They are existing supplements, widely used. Shop around, prices vary considerably. Per the papers, the daily intake of each supplement is large: ~100 mg/kg for glycine (~6 grams for a 60kg human) and ~130 mg/kg for N-acetylcysteine (~8 grams for a 60kg human), split into two doses.

GlyNAC improves strength and cognition in older humans

A pilot human clinical trial in eight older adults 70 to 80 years of age reveals that supplementation with GlyNAC - a combination of glycine and N-acetylcysteine as precursors of the natural antioxidant glutathione - could improve many age-associated defects in older humans to improve muscle strength and cognition, and promote healthy aging. The study participants taking GlyNAC for 24 weeks saw improvements in many characteristic defects of aging, including glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, body fat, genomic toxicity, muscle strength, gait speed, exercise capacity, and cognitive function. The benefits declined after stopping supplementation for 12 weeks. GlyNAC supplementation was well tolerated during the study period.

As mitochondria generate energy, they produce waste products such as free radicals. These highly reactive molecules can damage cells, membranes, lipids, proteins, and DNA. Cells depend on antioxidants, such as glutathione, the most abundant antioxidant in our cells, to neutralize these toxic free radicals. Failing to neutralize free radicals leads to harmful and damaging oxidative stress that can affect mitochondrial function. Interestingly, glutathione levels in older people are much lower than those in younger people, and the levels of oxidative stress are much higher. Animal studies have shown that restoring glutathione levels by providing GlyNAC reverses glutathione deficiency, reduces oxidative stress, and fully restores mitochondrial function in aged mice.

Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial

Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance.

This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition. A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks.

GlyNAC supplementation for 24 weeks in OA corrected red blood cell GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks.

It may turn out to be the case that many mechanisms of cellular regulation that slow aspects of aging function, at least in part, by slowing the pace at which senescent cells accumulate. Senescent cells induce tissue dysfunction via inflammatory signaling. Studies in which senescent cells are selectively destroyed in old tissues via senolytic drugs have resulted in rejuvenation, showing that the accumulation of these errant cells has a sizable role in the progression of degenerative aging. Atherosclerosis is a condition that is sensitive to chronic inflammation, as the behavior of macrophage cells is the primary determinant of the rate at which atherosclerotic lesions grow in blood vessel walls. More inflammation means that more macrophage cells abandon their task of repairing these lesions.

Atherosclerosis (AS) is a complex vascular disease that seriously harms the health of the elderly. It is closely related to endothelial cell aging, but the role of senescent cells in atherogenesis remains unclear. Studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) inhibits the development of AS by regulating lipid metabolism. Our previous research showed that PPARα was involved in regulating the repair of damaged vascular endothelial cells. Detecting senescent cells in atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice, we found that PPARα delayed atherosclerotic plaque formation by inhibiting vascular endothelial cell senescence, which was achieved by regulating the expression of growth differentiation factor 11 (GDF11).

We demonstrated a likely causal role for PPARα in vascular endothelial cell senescence and occurrence of AS, where PPARα inhibited cell aging and plaque formation by directly targeting GDF11. Pharmacologic stimulation of PPARα alleviated atherosclerotic plaque formation, vascular endothelial cell damage, and senescence, as well as increasing GDF11 expression in Apoe-/- model mice. At the same time, we proved that PPARα directly targeted the aging-related protein GDF11, thereby affecting the aging, proliferation, apoptosis, and angiogenesis of vascular endothelial cells in vitro. Our findings are consistent with the general hypothesis that inhibiting the aging of vascular endothelial cells helps prevent the formation of atherosclerotic plaques. Our work suggests that targeting PPARα or senescent vascular endothelial cells could be a promising avenue for delaying, preventing, alleviating, or treating AS.

Link: https://doi.org/10.1155/2021/2045259

Researchers have recently demonstrated a cell therapy approach that drives greater blood vessel formation in the brain. In mice this treatment restores most of the loss of motor function that occurs following a stroke, a surprisingly large restoration given that the brain is notoriously lacking in regenerative capacity. Therapies capable of inducing greater blood vessel growth are of interest more generally in aging, as the density of capillary networks diminishes with age, contributing to cell and tissue dysfunction due to a reduced supply of nutrients and oxygen. An approach that allows for the safe restoration of capillary density throughout the body, and also the creation of greater redundancy in the network of larger vessels, could prove to be a useful preventative measure, reducing the impact of vascular aging.

Researchers have developed technology that can "retrain" skin cells to help repair damaged brain tissue. The nonviral tissue nanotransfection (TNT) technique effectively reprograms the skin cells to become vascular cells, which generate new blood vessels to help get blood to the damaged tissue. In tests, stroke-affected mice that received intracranial injections of the cells recovered nearly all of their motor function, and exhibited repair to damaged brain areas.

The newly reported approach uses TNT to introduce a key set of genes into skin cells, which then drive direct reprogramming of the cells into vascular cells. For their mouse studies, the team pre-conditioned the cells by introducing a cocktail containing the developmental transcription factor genes Etv2, Foxc2, and Fli1 (collectively, EFF) and injected the cells back into the stroke-affected brains, where they triggered the formation of new blood vessels to deliver blood supply to the tissue and help to repair damage.

The team's experiments found that mice given this cell therapy regained 90% of their motor function, with MRI scans showing that damaged areas of the brain were repaired within a few weeks. "MRI and behavioral tests revealed ~70% infarct resolution and up to ~90% motor recovery for mice treated with EFF-nanotransfected fibroblasts. Our results indicate that intracranial delivery of fibroblasts nanotransfected with the EFF cocktail leads to dose-dependent increases in perfusion, reduced stroke volume, and significant recovery of locomotive abilities in stroke-affected mice. We found that the mice have a higher recovery because the cells that are being injected into the affected area also release healing signals in the form of vesicles that help in the recovery of damaged brain tissue."

Link: https://www.genengnews.com/news/cell-therapy-aids-stroke-damaged-brain-repair-restores-90-of-motor-function/

James Peyer was involved in the aging-focused fund Apollo Ventures before he moved on to the more recent venture industry initiative that evolved into Cambrian Biopharma. Cambrian is arguably even more focused on creating new biotech startups to treat aging, rather than investing in existing companies, than is the case for Apollo. Many venture capitalists are coming to the conclusion that the pace at which new biotech companies in this space are arising is too slow to provide sufficient opportunities for the capital that could be harnessed to produced progress. That pace must thus be accelerated.

Peyer is a regular on the conference circuit, and can be relied upon to give interesting, thoughtful presentations on the state of the science, the state of the funding, and what the venture community should do next in order to best support the growth of the longevity industry. You can find many of his talks on YouTube, and I recommend looking them over if you would like a sense of what the venture side of the longevity industry is thinking.

Q&A with Cambrian Biopharma's CEO - hallmarks of aging and classifying aging as a disease.

We wondered what Dr Peyer's views were on classifying aging itself as a disease? "I have a somewhat controversial view on this amongst folks in our field," says Dr Peyer. "I believe that the entire discussion about whether aging should be considered a disease is actually little more than a distraction from the real, more technical issues standing in the way of getting a medicine that enhances healthspan from being approved for that use. Many of my colleagues advocate in good faith that this would be a key inflection point for the field, and I used to believe the same. However, the more I have come to understand about the way that these drugs would be regulated in the future, the less concerned that I am with worrying about categorizing aging as a disease."

"I do absolutely think that it is appropriate and proper to classify the build-up of damage that accumulates during aging as a disease. There is already a gray area about when other conditions are labeled a pathology vs not a pathology. We have categorizations for pre-diabetes, mild cognitive impairment, benign tumors, and high cholesterol. Are these conditions diseases? I would argue that it's not important what we call it. What is important is the following: (A) Can we run a clinical trial to address the condition and (B) would health insurance companies provide such a medicine to its patients?"

"One of the most valuable learnings from the pioneering work of Nir Barzilai on the TAME trial and other conversations with the FDA has been that building a composite chronic disease endpoint is already acceptable to the FDA. Building a drug that reduces stroke and heart disease risk (what the statins were approved for) has been acceptable to the FDA for ~20 years. Building a drug that reduces heart disease, stroke, Alzheimer's, cancer, and diabetes risk is also acceptable. What would change in this context if the regulators labeled aging a disease? Nothing. We just have to do the trial to show that such a drug is actually working. The path is already there for us. The real challenge is how we design and power these trials and whether we can use biomarker-based endpoints to make the iteration time of testing these medicines shorter."

Tau is one of the few proteins in the body capable of becoming altered in ways that form harmful aggregates, capable of disrupting cell function or killing cells. Tau aggregation occurs in the aging brain, and particularly in the class of neurodegenerative conditions known as tauopathies. It is tau aggregation that is thought to cause widespread cell death in the late stages of Alzheimer's disease. Researchers here demonstrate a gene therapy approach to significantly reduce tau expression in the brain, a potential basis for long-lasting effects on Alzheimer's disease.

The microtubule-binding protein tau is a key player in Alzheimer's disease (AD) and frontotemporal dementia. The accumulation and aggregation of tau in the brain correlate with synaptic loss, neuronal loss, and cognitive decline. In patients with frontotemporal dementia, mutations in the tau gene, MAPT, lead to tau aggregation and cause widespread neurodegeneration. In addition to the neurotoxicity exerted by aggregated tau, soluble oligomeric forms of tau appear to be especially synaptotoxic.

Mice engineered to lack expression of MAPT have been shown to be protected against β-amyloid (Aβ)-induced synaptotoxicity, as well as against stress-induced and seizure-induced neuronal damage, and against learning and memory deficits resulting from traumatic brain injury. Moreover, reducing transgenic tau expression, even after tau has accumulated in mouse models of tauopathy, reverses the pathological effects of tau. These findings support the idea that the reduction of tau protein could be used as a therapeutic approach in AD or other tauopathies.

Translation of the neuroprotective effect of tau repression into a therapeutic approach for neurodegenerative diseases requires a treatment that reduces endogenous tau in the adult brain. We created a way to generate efficient, specific, and long-lasting down-regulation of the expression of endogenous tau by using a single viral administration: AAV encoding engineered zinc finger protein (ZFP) arrays that precisely target a short region of the genomic mouse MAPT sequence and down-regulate MAPT gene expression.

Using different AAV serotypes, we were able to reduce tau locally in the hippocampus - a brain region that is specifically affected by tau pathology in neurodegenerative diseases - through intracranial injections of AAV9 or brain-wide through intravenous delivery of blood-brain barrier-crossing AAV-PHP.B. In both cases, a single AAV administration was sufficient to repress tau mRNA and all isoforms of the protein by 50 to 80% in the brain and for as long as we carried out the study - nearly 1 year - following the treatment.

Furthermore, we performed proof-of-principle experiments for the use of tau-targeted ZFP-TFs to treat neurodegeneration in a mouse model in vivo: The repression of endogenous tau appeared to protect neurons from toxicity in mice with AD-like Aβ pathology (APP/PS1 mice). Tau repression by ZFP-TFs reduced amyloid plaque-associated neuritic dystrophies, which are a tau-dependent pathological hallmark in these mice.

Link: https://doi.org/10.1126/sciadv.abe1611

Some fraction of aging in the brain is due to a reduced blood flow to brain tissue, and thus a reduced delivery of nutrients and oxygen to brain cells. Vascular aging reduces the density of capillary networks in tissue, and increases stiffness of blood vessels. Equally, a sedentary lifestyle - and, later, heart failure - reduces the ability of the heart to pump blood uphill to the brain. Structured exercise programs consistent demonstrate health benefits in older individuals, likely because near everyone in later life fails to undertake sufficient exercise. Here, researchers show that one of those benefits is an increased flow of blood to the brain, an outcome that should slow the progression of neurodegeneration to some degree.

As many as one-fifth of people age 65 and older have some level of mild cognitive impairment (MCI) - slight changes to the brain that affect memory, decision-making, or reasoning skills. In many cases, MCI progresses to dementia, including Alzheimer's disease. Scientists have previously shown that lower-than-usual levels of blood flow to the brain, and stiffer blood vessels leading to the brain, are associated with MCI and dementia. Studies have also suggested that regular aerobic exercise may help improve cognition and memory in healthy older adults. However, scientists have not established whether there is a direct link between exercise, stiffer blood vessels, and brain blood flow.

Researchers followed 70 men and women aged 55 to 80 who had been diagnosed with MCI. Participants underwent cognitive exams, fitness tests, and brain magnetic resonance imaging (MRI) scans. Then they were randomly assigned to either follow a moderate aerobic exercise program or a stretching program for one year. The exercise program involved three to five exercise sessions a week, each with 30-40 minutes of moderate exercise such as a brisk walk. In both programs, exercise physiologists supervised participants for the first four to six weeks, then had the patients record their exercises and wear a heart rate monitor during exercise.

Forty-eight study participants - 29 in the stretching group and 19 in the aerobic exercise group - completed the full year of training and returned for follow-up tests. Among them, those who performed aerobic exercise showed decreased stiffness of blood vessels in their neck and increased overall blood flow to the brain. The more their oxygen consumption (one marker of aerobic fitness) increased, the greater the changes to the blood vessel stiffness and brain blood flow. Changes in these measurements were not found among people who followed the stretching program.

Link: https://www.utsouthwestern.edu/newsroom/articles/year-2021/exercise-boosts-blood-flow-to-the-brain.html

Alzheimer's disease is associated with a slow buildup of amyloid-β aggregates in the brain over the years of later life. The amyloid cascade hypothesis puts this process as the first step in the development of Alzheimer's disease, setting the stage for later neuroinflammation, tau aggregation, and cell death in the brain. This view of the condition has yet to lead to meaningful therapies, however. Several immunotherapy approaches have succeeded in clearing a meaningful degree of amyloid-β in human trials. Clinical improvement in those patients was very limited at best, even given a generous interpretation of the data.

Now a more recent anti-amyloid immunotherapy trial has resulted in a clear slowing of the progression of Alzheimer's disease following complete or near-complete clearance of amyloid-β aggregates. While the modest slowing of progression was not the result hoped for, in the sense that it is still too little benefit for the costs involved, it is nonetheless a much less ambiguous set of data than was the case for past trial outcomes in this class of therapy.

The data might be taken as a reinforcement of the view that amyloid-β is an important part of the early pre-clinical stages of Alzheimer's disease, but becomes increasingly irrelevant as the condition proceeds. Based on the research of recent years, the later stages of Alzheimer's are coming to look like a self-sustaining feedback loop between chronic inflammation, cellular senescence, immune dysfunction, and tau aggregation, culminating in widespread cell death in the brain.

The foundation of that later stage is perhaps created by amyloid-β aggregation, but it could in principle also arise from persistent infection. This data suggests that amyloid-β does indeed play a role, and that the genesis of later stages of Alzheimer's disease is not all a matter of other mechanisms. Yet the modest size of the outcome following complete amyloid-β aggregate clearance also suggests that amyloid-β simply isn't a viable target for patients exhibiting clinical symptoms.

Donanemab Confirms: Clearing Plaques Slows Decline-By a Bit

It has been clear for a while that anti-amyloid antibodies can sweep plaque from the brain, but until now the question of whether this slows cognitive decline has remained hotly contended. Despite some positive signals from four such antibodies, the data have been messy and hard to interpret. At the a recent conference, researchers presented the cleanest data yet on this question. In a Phase 2 trial, the company's anti-amyloid antibody donanemab met its primary endpoint. Participants did not get better. Even so, donanemab slowed their decline by an average of 32 percent on a combined cognitive and functional measure.

Donanemab banished plaque from the brain in a majority of participants, while nudging down the rate of neurofibrillary tangle accumulation in the frontal cortex and other regions. The trial included several innovative elements, such as screening participants by tangle burden, using tau PET as a secondary outcome measure, and stopping dosing once amyloid was gone. Most Alzheimer's researchers welcomed the findings. At the same time, researchers emphasized that, as with other anti-amyloid immunotherapies, the cognitive benefit was small. "The donanemab story is the most encouraging news on the amyloid front, ever, but whether the effect size is clinically meaningful is questionable."

Donanemab is unique among Alzheimer's disease (AD) immunotherapies in that it targets a modified version of amyloid-β (Aβ) that has a pyroglutamate attached to the N terminus. This pathological form of Aβ is highly prone to aggregate, depositing in the core of all amyloid plaques, but is found nowhere else in the brain. In Phase 1 trials, donanemab busted up plaques fast, in many cases clearing all deposits within six months. However, even dramatic amyloid clearance has not translated into a clear cognitive benefit in past Phase 2 and 3 immunotherapy trials.

Given that donanemab completely cleared plaque, the researchers acknowledged that a 32 percent slowing may represent the most it can achieve in people at this stage of AD. "This is probably the ceiling for an amyloid-lowering drug." To do more for patients, researchers likely will have to treat earlier in a prevention paradigm, or combine anti-amyloid treatment with an anti-tau drug, he suggested.

Senescent cells accumulate throughout the body with age, the result of an increased pace of creation and slowed pace of clearance. Senescent cells secrete a mix of inflammatory signals that disrupt tissue maintenance and function, and this contributes to the progression of degenerative aging. Clearing senescent cells with senolytic therapies has been shown to produce rejuvenation in mice, robust reversal of many different age-related conditions. That includes demonstrations of efficacy in animal models of neurodegenerative conditions such as Parkinson's disease and Alzheimer's disease. Senescent cells are not the whole of aging, but they are a large enough fraction of it to be most promising as a point of intervention.

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs.

Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression.

Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly it has emerged recently that non-proliferating neuronal cells present in the brain or cultivated in vitro can also exhibit some hallmarks, including SASP, typical for senescent cells that ceased to divide.

It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

Link: https://doi.org/10.3389/fnagi.2021.646924

The enormous variety of degenerative aging, the many forms of declining function and organ failure, derives from a simpler array of underlying cell and tissue damage. One might look at the SENS research proposals for an overview of that damage. Given this, it isn't surprising to see that many age-related conditions share metabolic signatures. One might suppose these signatures to be reactions to specific forms of damage or consequences of specific forms of damage.

Many elderly people suffer simultaneously from several, frequently very different diseases, a condition also known as multimorbidity. In a recent study, researchers have now identified a number of metabolic processes that are associated not only with one, but simultaneously with up to 14 diseases.

The scientists first examined the concentration of hundreds of different molecules in the blood samples of a total of 11,000 study participants. They then examined how the concentration of individual metabolites was related to the onset of a total of 27 serious diseases in the participants. The metabolites included not only known metabolic products such as sugars, fats, and vitamins, but also substances whose concentration depends on genetic or environmental factors. For example, the scientists were able to detect the degradation products of medications, coffee consumption or the presence of gut bacteria using a process known as molecular profiling.

The blood samples had already been taken from the participants more than 20 years ago and been stored at minus 196 degrees Celsius since then. At that time, the people were mostly healthy. The diseases they developed afterwards were systematically recorded in detail for more than 20 years through electronic hospital data.

For example, the team found that the concentration of many metabolites in the blood that were associated with disease onset were explained by impaired liver and kidney function, obesity, or chronic inflammation. But they also discovered that certain lifestyle factors or a reduced diversity of intestinal bacteria, also known as the gut microbiome, influence blood levels and can thus provide clues to the development of diseases over time. It turned out that half of all detected molecules were associated with an increased or decreased risk of at least one disease - the majority with multiple, sometimes very different, diseases, pointing to metabolic pathways that increase the risk of multimorbidity.

Link: https://www.bihealth.org/en/notices/different-diseases-common-metabolic-pathways

Cell reprogramming involves changing the expression of top-level regulatory genes, picking targets that will radically change cell form and function. Given a suitable recipe, many of which have been established, forms of cell reprogramming can be used to change somatic cells into stem cells, or change somatic cells of one type into somatic cells of another type. In the other direction, numerous approaches can be used to guide stem cells into differentiating into varieties of somatic cell.

A cancerous cell adopts some of the characteristics of a stem cell, primarily the unrestricted replication that is the hallmark of cancer, and sometimes some of the characteristics of other somatic cell types. Cancer stem cells are thought to exist for many forms of cancer, a class of cancerous cell in which stem cell characteristics are much more prevalent. Cancer stem cells support a cancer and its growth in much the same way that normal stem cells support a tissue.

Given all of this, it seems reasonable to suppose that it is possible to reprogram or otherwise guide a cancer cell into becoming a normal somatic cell. This could be an interesting basis for a cancer therapy, with all the usual caveats about whether or not the reprogramming therapy is inherently targeted to the cancer, or whether it would need to be delivered carefully to avoid side-effects in non-cancerous tissue. Today's open access paper offers an example of a form of reprogramming that turns one specific type of cancer cells into what appear to be normal somatic cells. It will be interesting to see whether this approach gains any traction or wider adoption, or whether killing cancerous cells will always tend to be the more efficient way forward.

Network Inference Analysis Identifies SETDB1 as a Key Regulator for Reverting Colorectal Cancer Cells into Differentiated Normal-Like Cells

Dysregulation of tissue-specific gene expression programs is a hallmark of cancer. Such dysregulation leads to cancer-promoting gene expression programs and, in various types of cancer, the consequent reprogramming of cells into those with stem or progenitor (stem/progenitor) properties. A study of cancer initiation revealed that normal differentiated cells with oncogenic mutations remain in a nonmalignant state until they undergo cellular reprogramming into a stem/progenitor state. This suggests that differentiated cells have an inherent resistance mechanism against malignant transformation and indicates that cellular reprogramming is indispensable for malignancy. Thus, we speculated that malignant properties might be eradicated if the tissue-specific gene expression program is reinstated.

In colorectal cancer, cellular differentiation is impeded through processes involving both oncogenic mutations and microenvironmental alterations. This cancer provides a model for exploring whether the malignant cells could be converted to normal-like cells through restoration of the tissue-specific gene expression program. To address this challenge in a systematic way, we employed a computational framework to identify the core factors to revert cancer cells back to their normal state. A recent computational framework for inferring gene regulatory networks (GRN) has effectively applied to the cell fate conversion study through identification of master regulators of tissue-specific gene expression programs.

Here, we reconstructed normal colon-specific GRNs and colorectal cancer-specific GRNs, and identified core transcription factors (TF) for differentiation of colorectal cancer cells. We further identified SET Domain Bifurcated 1 (SETDB1) as a key factor that hinders the function of core TFs. We demonstrated that SETDB1 depletion effectively reestablishes the normal colon-specific gene expression profile and induces a postmitotic differentiated state in three stem-like colorectal cancer cell lines and patient-derived colon cancer organoids by recapitulating the transcriptional activities of the core TFs.

Here, researchers advocate for a greater consideration of the role of random chance at the cellular level in the variations in life span exhibited by individuals of any given species. Why do people age at different rates and why does human life span exhibit a wide range? Exploration of human genetic data increasingly suggests that very little of this variation between individuals is due to our genes. That in turn might suggest that stochastic processes of damage and dysfunction are of greater importance to variations in aging than was previously thought to be the case by the research community.

Researchers introduced the "Tripartite Phenotype of Aging" as a new conceptual model that addresses why lifespan varies so much, even among human identical twins who share the same genes. Only about 10 to 35 percent of longevity can be traced to genes inherited from our parents. Researchers propose that the limited heritability of aging patterns and longevity in humans is an outcome of gene-environment interactions, together with stochastic, or chance, variations in the body's cells. These random changes can include cellular changes that happen during development, molecular damage that occurs later in life, and more.

The new model is a natural extension of the idea of the exposome, which was first proposed in 2005 to draw attention to the need for more data on lifetime exposure to environmental carcinogens. The exposome concept illustrates how external factors, ranging from air pollution and socioeconomic status to individual diet and exercise patterns, interact with endogenous, or internal, factors such as the body's microbiome and fat deposits.

The new model illustrates that cell-by-cell variations in gene expression, variations arising during development, random mutations, and epigenetic changes - turning genes "off" or "on" - should be explicitly considered apart from traditional genetic or environmental research regarding aging. More detailed study into these chance processes has been enabled by cutting-edge research techniques, including the study of gene transcription within single cells as well as ChIP-sequencing, which can illustrate how individual proteins interact with DNA.

The researchers offer several examples of how risks of age-related disease are poorly predicted by DNA alone but are heavily influenced by environmental exposures as well as the time and duration of the exposure, including during development or over the course of decades. One well-known example of a gene that is associated with increased Alzheimer's risk is ApoE-4; however, having the ApoE-4 gene doesn't definitively mean someone will get Alzheimer's. Studies in both mice and humans revealed that ApoE-4 and clusters of related genes interact with exposures such as air pollution or cigarette smoke to influence risk, and Alzheimer's patients also show differences in their epigenetics as compared to individuals without the disease.

Link: https://gero.usc.edu/2021/03/11/usc-finch-longevity-exposome-variation/

In this paper, the author argues for greater emphasis to be placed on identifying rate-limiting processes in aging, here termed "flux-controlling" processes. One can tinker with various aspects of cellular metabolism connected to any one given molecule or class of molecules, and do so in many different ways, but any given approach may or may not interact with a rate-limiting step. If it doesn't, then the outcome will not tell us all that much about whether or not this molecule, this process, is important in aging.

Let us imagine that Gustav Embden (1874-1933), one of the ingenious discoverers of glycolysis, would have had modern transgenic techniques at hand and intended to use them to investigate the role of phosphoglycerate kinase (PGK) in the biochemical degradation of glucose to pyruvate. He would have probably overexpressed the enzyme 10x first, and he would not have seen any relevant change in the rate of pyruvate formation in the perfused working heart, whereas the addition of insulin would have shown a clear effect. He then would have generated 90% knockdown animals and again would not have seen any decrease in the rate of glycolysis. Hence, he would have confidently concluded that PGK was not involved in glycolysis. Thus, he would have arrived at an overtly wrong conclusion (merely hypothetical; sorry, Gustav!).

In essence, this is what we do today when we conclude from unsuccessful overexpression or knockdown studies of antioxidant enzymes that free radicals were not involved in aging. We arrive at a wrong conclusion.

What is the mistake here, and what did Embden and his successors do better? First, they looked at the intrinsic chemical logic of the overall system. This should also be done in the study of aging. In particular, they recognized that steps can be involved and essential in a causal chain of (chemical) events even without ever being rate-limiting (or "flux-controlling") for the overall passage through the chain of events. This principle applies to linear chains, branched chains, branching-converging chains and even cyclic chains. Because aging certainly represents an arrangement of causally chained elementary steps (of whatever type and complexity), the decisive point will be to identify the flux-controlling steps of aging as narrowly as possible and then determine their control coefficients for the overall process.

Thus, the only thing we can learn from the fact that superoxide dismutase (SOD) modulation does not influence lifespan is that superoxide degradation is not flux-controlling for aging (in mice). This is still a valuable conclusion, even if it may not be particularly surprising: flux control is usually exerted by low-level, low-efficiency, or highly regulated enzymes, none of which applies to SOD. Moreover, if simple overexpression of SOD indeed would have had a measurable effect on lifespan, one might wonder why evolution has not yielded such a parsimonious solution before. Hence, it is quite unlikely that any isolated enzyme overexpression approach will ever substantially extend life in a species in which longevity is under positive selective pressure (like, arguably, in mammals). Extensive data support this generalization. We have to grab for higher-hanging fruit.

Link: https://doi.org/10.18632/aging.202821

D-galactose is often used by researchers in order to induce aging-like symptoms in mice. It is a damaging compound, provoking oxidative stress, inflammation, and cellular senescence. That in turn produces loss of tissue and organ function in ways that can appear similar to the outcomes of degenerative aging. In today's open access paper, researchers show that injection of fisetin can significantly reduce the harmful outcomes produced by D-galactose, including the loss of cognitive function.

This is of passing interest as fisetin has been shown to have senolytic effects in mice, when ingested at an appropriately high dose. (The injected dose here is much lower, 25 mg/kg versus 100 mg/kg, but one would expect injection to require lower doses than ingestion to be efficacious). Fisetin can selectively destroy significant numbers of senescent cells in aged tissues, leading to rejuvenation. Mice exhibit a reversal of measures of aging, a turning back of age-related conditions. This result occurs because senescent cells accumulate with age, and their secretions actively maintain an inflammatory state of disrupted cell and tissue function. The presence of lingering senescent cells is a major contributing cause of aging. One might hypothesize that benefits in the present study are emerging in large part via destruction of some of the excess senescent cells created by D-galactose.

Fisetin Rescues the Mice Brains Against D-Galactose-Induced Oxidative Stress, Neuroinflammation and Memory Impairment

Chronic administration of D-galactose induces brain aging and accelerates artificial senescence which is used for different anti-aging pharmacological research. D-galactose is a monosaccharide, which exists throughout the body. At higher concentrations, in the presence of galactose oxidase, it converts to hydrogen peroxide and aldose, causing disposition of a superoxide anion, oxygen-derived free radicals, and cellular damage. Chronic administration of d-galactose for 2 months induces cognitive and memory impairment through the accumulated reactive oxygen species (ROS), mitochondrial deficits, neuroinflammation, and neurodegeneration.

Recently, the use of phytonutrients and medicinal herbs have gained a special interest to treat neurological disorders such as Alzheimer's disease. Among the phytonutrients, Fisetin, a natural flavonoid is found in different fruits. Fisetin has shown strong anticarcinogenic, anti-inflammatory, antioxidant, neurotrophic, and neuroprotective effects against different neurodegenerative diseases.

Here, we explore the underlying neuroprotective mechanism of fisetin against d-galactose-induced aging in mice. Normal mice were injected with d-galactose (100 mg/kg/day for 60 days) and fisetin (20 mg/kg/day for 30 days). To elucidate the protective effects of fisetin against d-galactose induced oxidative stress-mediated neuroinflammation, we conducted western blotting, biochemical, behavioral, and immunofluorescence analyses.

According to our findings, d-galactose induced oxidative stress, neuroinflammation, synaptic dysfunctions, and cognitive impairment. Conversely, fisetin prevented the d-galactose-mediated ROS accumulation, by regulating the endogenous anti-oxidant mechanisms, such as Sirt1/Nrf2 signaling, suppressed the activated phosphorylated-JNK/NF-kB pathway, and its downstream targets, such as inflammatory cytokines. Hence, our results together with the previous reports suggest that fisetin may be beneficial in age-related neurological disorders.

Researchers here present epidemiological evidence for head injuries to leave permanent consequences that accelerate later cognitive decline. Speculatively, the mechanisms by which this might happen could include a increased lasting presence of senescent cells in injured tissue, raising local levels of inflammation. Certainly there is suggestive evidence for some forms of injury, including injuries to the brain, to leave a lasting mark in the form of raised inflammation in tissues. Senescent cells are frequently involved in inflammation-related mechanisms and conditions.

Head injuries did not appear to contribute to brain damage characteristic of Alzheimer's disease, but might make people more vulnerable to dementia symptoms, according to new findings. "Here we found compelling evidence that head injuries in early or mid-life can have a small but significant impact on brain health and thinking skills in the long term. It might be that a head injury makes the brain more vulnerable to, or accelerates, the normal brain ageing process."

The study involved 502 participants of the UK's longest-running cohort study, the MRC National Survey of Health and Development Cohort, which has been following participants since their birth in the same week in 1946. At age 53, they were asked 'Have you ever been knocked unconscious?' to assess whether they had ever suffered a substantial head injury; 21% of their sample had answered yes to this question. And then around age 70 (69-71), the study participants underwent brain scans (PET/MRI), and they took a suite of cognitive tests.

The participants had all completed standardised cognitive tests at age eight, so the researchers were able to compare their results at age 70 with expected results based on their childhood cognition and other factors such as educational attainment and socioeconomic status. The researchers found that 70-year-olds who had experienced a serious head injury more than 15 years earlier performed slightly worse than expected on cognitive tests for attention and quick thinking (a difference of two points, scoring 46 versus 48 on a 93-point scale). They also had smaller brain volumes (by 1%) and differences in brain microstructural integrity, in line with evidence from previous studies, which may explain the subtle cognitive differences.

The researchers did not find any differences in levels of the amyloid protein, implicated in Alzheimer's disease, or other signs of Alzheimer's-related damage. "It looks like head injuries can make our brains more vulnerable to the normal effects of ageing. We have not found evidence that a head injury would cause dementia, but it could exacerbate or accelerate some dementia symptoms."

Link: https://www.ucl.ac.uk/news/2021/mar/head-injuries-may-worsen-cognitive-decline-decades-later

Every cell contains hundreds of mitochondria, bacteria-like structures that carry their own small genome, the mitochondrial DNA. Mitochondria replicate like bacteria to maintain their population size, and are destroyed when worn and damaged by the quality control mechanism of mitophagy. The primary task undertaken by mitochondria is the generation of chemical energy store molecules (adenosine triphosphate, ATP) to power the cell, but they also play many other roles in fundamental cell processes. Mitochondrial DNA is poorly protected and repaired in comparison to nuclear DNA, and accumulates mutational damage over time. It is argued that this damage contributes to loss of mitochondrial function, and thus faltering tissue function, particularly in energy-hungry organs such as the heart.

The most common aging-associated diseases are cardiovascular diseases which affect 40% of elderly people. It is well accepted that the origin of aging-associated cardiovascular diseases is mitochondrial dysfunction. Mitochondria have their own genome (mtDNA) that is circular and double-stranded. There are between 500 to 6000 mtDNA copies per cell, depending on tissue type. As a by-product of ATP production, reactive oxygen species (ROS) are generated which damage proteins, lipids, and mtDNA.

ROS-mutated mtDNA co-existing with wild type mtDNA is called mtDNA heteroplasmy. The progressive increase in mtDNA heteroplasmy causes progressive mitochondrial dysfunction leading to a loss in their bioenergetic capacity, disruption in the balance of mitochondrial fusion and fission events (mitochondrial dynamics, MtDy) and decreased mitophagy. This failure in mitochondrial physiology leads to the accumulation of depolarized and ROS-generating mitochondria. Thus, besides attenuated ATP production, dysfunctional mitochondria interfere with proper cellular metabolism and signaling pathways in cardiac cells, contributing to the development of aging-associated cardiovascular diseases.

In this context, there is a growing interest to enhance mitochondrial function by decreasing mtDNA heteroplasmy. Reduction in mtDNA heteroplasmy is associated with increased mitophagy, proper MtDy balance and mitochondrial biogenesis; and those processes can delay the onset or progression of cardiovascular diseases. This has led to the development of mitochondrial therapies based on the application of nutritional, pharmacological, and genetic treatments, seeking to have a positive impact on mtDNA integrity, mitochondrial biogenesis, dynamics, and mitophagy in old and sick hearts.

Link: https://doi.org/10.3389/fcell.2021.625020

A growing faction within the research community has come to view chronic inflammation as one of the most important mechanisms that contribute to degenerative aging. It is certainly the case that in the Alzheimer's field the evidence of recent years points toward inflammation as the major mediating mechanism linking the diverse pathologies of this neurodegenerative condition.

In today's open access paper, researchers put forward their view of the connections between inflammatory disease outside the brain and inflammatory disease inside the brain. They contribute to one another, creating an accelerating downward spiral of damage and dysfunction. This isn't a novel concept, but rather the usual perception of the way in which interactions between systems in the body cause aging to accelerate over time.

There are plenty of examples when it comes to organ damage leading brain damage. Brain function depends on correct kidney function, the provision of metabolites and filtering of waste products, and thus chronic kidney disease contributes strongly to the progression of dementia. Similarly, the brain is injured by cardiovascular aging in a number of ways: hypertension resulting from stiffness of blood vessels causes rupture of capillaries and consequent cell death; heart failure reduces the supply of oxygen and nutrients; and so forth.

Inflammation Spreading: Negative Spiral Linking Systemic Inflammatory Disorders and Alzheimer's Disease

Chronic neuroinflammation is well accepted as the most relevant pathological features of AD, regulating other pathological hallmarks of Alzheimer's disease (AD), such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau, both of which are involved in the neuronal dysfunction in AD. However, there is a great deal of evidence suggesting the important role of systemic inflammation in the pathogenesis of AD, especially in neuroinflammation.

There is increasing evidence suggesting that chronic neuroinflammation, and indeed inflammation in general, is the most relevant pathological feature of Alzheimer's disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Therapies aimed at reducing systemic inflammation in individuals with mild cognitive impairment (MCI) and AD have proven beneficial by delaying the cognitive decline in these individuals, suggesting that recognition of the cross-talk between systemic inflammation and neuroinflammation has important implications for AD therapeutic strategies.

It is well accepted that the pro-inflammatory mediators, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, are co-related factors involved in both systemic inflammation and neuroinflammation and affecting their sustainment and convergence. In contrast, intracellular enzymes, such as lysosomal cathepsins, mediate the production of pro-inflammatory mediators from both the periphery and brain.

Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction. However, the neuroinflammation-accelerated neuronal dysfunction in AD also influences the functions of peripheral organs.

In the present review, we highlight the link between systemic inflammatory disorders and AD, with inflammation serving as the common explosion. We discuss the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation. In our view, inflammation spreading indicates a negative spiral between systemic diseases and AD. Therefore, "dampening inflammation" may be a novel therapeutic approach for delaying the onset of and enacting early intervention for AD.

The gut microbiome is known to change in harmful ways with advancing age. In old people there are too many inflammatory microbes, versus too few microbes generating beneficial metabolites. Researchers here note that the practice of calorie restriction, well established to slow aging and extend life in numerous species, prevents much of this age-related shift in microbial populations in mice. Calorie restriction changes near every measure of metabolism and outcome of aging, which makes it challenging to determine which aspects of the response to calorie restriction are more or less important than one another. Determining the specific contribution of the gut microbiome to degenerative aging remains a work in progress.

The first and the most studied manipulation shown to increase lifespan in mammals is caloric restriction (CR). Numerous laboratories have shown that reducing food consumption by 30% to 50% (without malnutrition) consistently increases both the mean and maximum lifespans of both laboratory rats and mice. The effect of CR on longevity is not limited to rodents as CR has been shown to increase the lifespan of a large number of diverse animal models ranging from invertebrates (yeast, C. elegans, and Drosophila) to dogs and non-human primates.

Because the gastrointestinal (GI) system is the first organ/tissue that encounters the impact of reduced food consumption, there have been several studies on the effect of CR on the GI-system. With the advent of metagenomics, it is now possible to interrogate the colon microbiome and study the effect of CR. Two groups have reported that long-term CR had a significant impact on the microbiome of old mice. These studies were conducted with aging colonies of mice specific to those particular laboratories and for which there were no lifespan data. Because the institutional animal husbandry environment and the health status of the host can have a major impact on the microbiome, we felt it was important to establish the effect of CR on the microbiome of well characterized mice from the aging colony maintained by National Institute on Aging (NIA).

Life-long CR increased microbial diversity and the Bacteroidetes/Firmicutes ratio and prevented the age-related changes in the microbiota, shifting it to a younger microbial and fecal metabolite profile in both C57BL/6JN and B6D2F1 mice. Old mice fed CR were enriched in the Rikenellaceae, S24-7, and Bacteroides families. The changes in the microbiome that occur with age and CR were initiated in the cecum and further modified in the colon. Short-term CR in adult mice had a minor effect on the microbiome but a major effect on the transcriptome of the colon mucosa. These data suggest that CR has a major impact on the physiological status of the gastrointestinal system, maintaining it in a more youthful state, which in turn could result in a more diverse and youthful microbiome.

Link: https://doi.org/10.18632/aging.202753

Much of cellular communication takes the form of secretion and uptake of extracellular vesicles, tiny membrane-wrapped packages of molecules. The use of these vesicles as a basis for therapy is spreading. Since first generation stem cell therapies appear to produce their benefits via the signals generated by transplanted stem cells, why not use vesicles harvested from stem cells instead the cells themselves? The logistics are far less challenging, the costs lower. Further, vesicles can be engineered to contain novel contents, or given different surface features.

Researchers here discuss the degree to which vesicles can be targeted to specific tissues via natural or artificial surface features. This is never an all or nothing proposition, but rather the case that one tissue may take up half as many or twice as vesicles of one type versus another. This is a big enough effect to be of great interest in the development of more effective therapies, however, enabling treatments with fewer side-effects.

Great strides have been made in advancing extracellular vesicles (EVs) to clinical testing. By late 2020, approximately 250 trials that utilize EVs in some way had been registered. Diagnostic, prognostic, and monitoring uses of EVs are evident in these registrations as well as applications of EVs in therapeutics. Interest in EVs stems in part from their biology. They are involved in natural processes of communication in the body and have a perceived safety profile that features low immunogenicity.

Additionally, EVs are 'targetable'. Display of specific proteins, and possibly other biomolecules, allows EVs to be sorted to certain cell types and tissues or away from undesired recipients. EV engineering, by manipulating the EV source or by altering EVs post-production, can be used to enhance such targeting. Modified EVs have been used for some time as delivery vehicles for small molecule drugs and natural products, short hairpin RNA (shRNA), short interfering RNA (siRNA), plasmid DNA, and microRNAs. However, a key factor in the success of this and other EV therapies is whether and how EVs can be targeted to, or away from, specific cells.

Targeting EVs to specific cell types could indeed be considered a holy grail of EV therapeutics, since cell specificity reduces the necessary dose and minimizes off-target effects. However, we should be clear that the word 'targeting' is used colloquially. The typical EV cannot move towards a destination as a result of interpreting signals, for example, by crawling along a chemical gradient, so the EV cannot truly 'home' to a specific cell. Instead, the word 'targeting' refers more accurately to 'selective retention' or 'capture' by the target cell.

To the extent possible, administering EVs at the site of intended action will enhance selective retention and help to avoid clearance. Many studies use intravenous delivery of EVs, but this results in delivery predominantly to just a few organs, especially lung and liver, as well as bone marrow, spleen, and kidney. Introducing EVs by different routes, or even directly to the target site by application (e.g. skin wound healing, eye) or tissue injection avoids rapid clearance and maximizes dosage.

Link: https://doi.org/10.1002/jev2.12032

Today's research materials report on an investigation of the age-related loss of myelin in the nervous system. The insulating sheath that surrounds nerves is made up of myelin. Its presence ensures the proper conduction of nerve impulses along the axons that connect neurons in the nervous system. The structure and maintenance of myelin sheathing has been most studied in the context of demyelinating conditions such as multiple sclerosis, in which the immune system causes a breakdown of myelin. This leads to increasingly severe symptoms as the nervous system loses its ability to function.

Loss of myelin sheathing integrity occurs not just in demyelinating conditions, however, but also in aging. There is compelling evidence for myelin degradation in old age to be a significant contribution to cognitive decline, for example. Here the problem appears to be a matter of diminished activity in the oligodendrocyte cell population responsible for maintaining myelin. There are numerous possible contributing causes: loss of stem cell function; cellular senescence; chronic inflammation; and many more. It remains unclear as to which of these mechanisms are more or less important. Regardless, therapies capable of restoring myelin, hopefully an outcome of ongoing work on demyelinating conditions, could be of great interest to older people as well.

Scientists discover the loss of a substance called 'myelin' can result in cognitive decline and diseases like Multiple Sclerosis and Alzheimer's

"Everyone is familiar with the brain's grey matter, but very few know about the white matter, which comprises of the insulated electrical wires that connect all the different parts of our brains. A key feature of the ageing brain is the progressive loss of white matter and myelin, but the reasons behind these processes are largely unknown. The brain cells that produce myelin - called oligodendrocytes - need to be replaced throughout life by stem cells called oligodendrocyte precursors. If this fails, then there is a loss of myelin and white matter, resulting in devastating effects on brain function and cognitive decline. An exciting new finding of our study is that we have uncovered one of the reasons that this process is slowed down in the ageing brain."

"By comparing the genome of a young mouse brain to that of a senile mouse, we identified which processes are affected by ageing. These very sophisticated analysis allowed us to unravel the reasons why the replenishment of oligodendrocytes and the myelin they produce is reduced in the ageing brain. We identified GPR17, the gene associated to these specific precursors, as the most affected gene in the ageing brain and that the loss of GPR17 is associated to a reduced ability of these precursors to actively work to replace the lost myelin."

Functional genomic analyses highlight a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

Brain ageing is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to ageing as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain ageing hinders the development of regenerative strategies.

Here, our combined systems biology and neurobiological approach demonstrate that oligodendroglial and myelin genes are amongst the most altered in the ageing mouse cerebrum. This was underscored by the identification of causal links between signalling pathways and their downstream transcriptional networks that define oligodendroglial disruption in ageing. The results highlighted that the G-protein coupled receptor Gpr17 is central to the disruption of OPCs in ageing and this was confirmed by genetic fate-mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPCs and restore myelination in age-related neuropathological contexts.

Researchers here note the results from a study in which a comparatively simple compound biomarker of aging exhibited correlations with the manifestations of aging and age-related disease. The past decade of work on measurement of aging has shown that it is comparatively straightforward to produce metrics that reflect the increasing burden of damage and dysfunction. Making use of the best of these metrics to assess potential approaches to the development of age-slowing and rejuvenating therapies has yet to be carried out in any widespread fashion, however.

As we age, the risk that we will experience chronic diseases (for example, heart disease, diabetes, and cancer) and declining capacities (for example, reduced strength, impaired hearing, and poorer memory) increases. All individuals age chronologically at the same rate, but there is marked variation in their rate of biological aging; this may help explain why some adults experience age-related decline faster than others.

Biological aging can be defined as decline that (1) simultaneously involves multiple organ systems and (2) is gradual and progressive5. Across the lifespan, the consequences of individual differences in genetic endowment, cellular biology, and life experiences accumulate, driving the divergence of biological age from chronological age for some people. Among older adults of the same chronological age, those with accelerated biological aging (as measured by blood and DNA methylation biomarkers) are more likely to develop heart disease, diabetes, and cancer and have a higher rate of cognitive decline, disability, and mortality.

Current disease-management strategies usually treat and manage each age-related chronic disease independently. In contrast, the geroscience hypothesis proposes that many age-related chronic diseases could be prevented by slowing biological aging itself. The geroscience hypothesis states that biological aging drives cellular-level deterioration across all organ systems, thereby causing the exponential rise in multimorbidity across the second half of the lifespan. The implication is that by slowing biological aging directly, instead of managing each disease separately, the risk for all chronic age-related diseases could be simultaneously ameliorated.

We measured biological aging in a population-representative 1972-1973 birth cohort of 1,037 individuals followed from birth to age 45 years in 2019 with 94% retention: the Dunedin Study. Over 20 years - at ages 26, 32, 38 and 45 - we repeatedly collected 19 biomarkers to assess changes in the function of cardiovascular, metabolic, renal, immune, dental, and pulmonary systems, and quantified age-related decline shared among these systems. We call this index of biological aging in the Dunedin Study the 'Pace of Aging'.

At age 45 in 2019, participants with faster Pace of Aging had more cognitive difficulties, signs of advanced brain aging, diminished sensory-motor functions, older appearances, and more pessimistic perceptions of aging. People who are aging more rapidly than same-age peers in midlife may prematurely need supports to sustain independence that are usually reserved for older adults. Chronological age does not adequately identify need for such supports.

Link: https://doi.org/10.1038/s43587-021-00044-4

For some years the ability to gather biological data has far outpaced the ability to analyze that data usefully. The genome, the epigenome, the proteome, the transcriptome, and more, all repeated over countless thousands of animals and humans. Enormous vaults of data now exist in all branches of the life sciences, enough to keep researchers occupied for decades. In order to speed up the process of analysis and understanding, scientists are increasingly applying modern tools of machine learning to life science data. This is still an incremental process, but a faster incremental process.

The blood transcriptome is expected to provide a detailed picture of an organism's physiological state with potential outcomes for applications in medical diagnostics and molecular and epidemiological research. We here present the analysis of blood specimens of 3,388 adult individuals, together with phenotype characteristics such as disease history, medication status, lifestyle factors, and body mass index (BMI). The size and heterogeneity of this data challenges analytics in terms of dimension reduction, knowledge mining, feature extraction, and data integration.

Self-organizing maps (SOM)-machine learning was applied to study transcriptional states on a population-wide scale. This method permits a detailed description and visualization of the molecular heterogeneity of transcriptomes and of their association with different phenotypic features.

The diversity of transcriptomes is described by personalized SOM-portraits, which specify the samples in terms of modules of co-expressed genes of different functional context. We identified two major blood transcriptome types where type 1 was found more in men, the elderly, and overweight people and it upregulated genes associated with inflammation and increased heme metabolism, while type 2 was predominantly found in women, younger, and normal weight participants and it was associated with activated immune responses, transcriptional, ribosomal, mitochondrial, and telomere-maintenance cell-functions. We find a striking overlap of signatures shared by multiple diseases, aging, and obesity driven by an underlying common pattern, which was associated with the immune response and the increase of inflammatory processes.

Link: https://doi.org/10.3389/fdata.2020.548873

When charting rising mortality against increasing chronological age, the result is a smooth exponential curve - the Gompertz-Makeham law of mortality. We might well ask how the exceptionally complicated process of degenerative aging, consisting of many distinct mechanisms butting heads and breaking things in a stochastic manner, can produce this outcome. This is one of the questions posed by epidemiologists in today's open access paper. It is a good example of the way in which a scientist can hypothesize about the operation of mechanisms given only data on the outcomes of those mechanisms.

For context, the authors of the paper here are the same researchers who applied reliability theory to aging some years ago. Reliability theory has historically been used to model the deterioration of complex machinery (such as electronics, and now biological organisms) by assuming the machinery to be a collection of various types of redundant parts. Loss of redundancy is the primary form of damage that takes place, and failure occurs when insufficient redundancy remains. Conceptually, this maps well to an organism consisting of cells, or an organ (a liver) consisting of repeated units (such as bile ducts), and so forth.

What Can We Learn about Aging and COVID-19 by Studying Mortality?

Discussing the age-related dynamics of mortality, we should consider the following relevant question in the study of aging: how is it possible for different diseases and causes of death to "negotiate" with each other in order to produce a simple exponential function for mortality from all causes of death combined (given that contribution of the different causes of death to total mortality varies greatly with age)? Linked to this question is the traditional approach to life extension, based on combating individual causes of death.

Indeed, it is well known which causes of death were reduced in order produce the mortality decrease that took place in the first half of the 20th century. These are primarily pneumonia, influenza, tuberculosis, enteritis and other infectious diseases. It is also known that mortality from each of these causes changes with age. Therefore, their elimination should inevitably change the age dynamics of total mortality and the size of its age-related component. However, mortality increases with age according to the fairly simple Gompertz formula (the Makeham term is close to zero in recent decades and has little effect on mortality dynamics). The only way to resolve this contradiction is to admit that the causes of death are not independent of each other, but are coordinated so that the age-related component of mortality increases exponentially with age, despite a dramatic change in the structure of causes of death. However, then the following question arises: how do the causes of death "agree" with each other so that the age-related component of mortality grows with age in accordance with a fairly simple Gompertz law?

The above facts can be explained by using the hypothesis of limited organism's reliability. According to this hypothesis, an organism is a multi-redundant system with high, but not infinitely high reliability. Therefore, there is always some probability that the interference in the work of individual elements of the organism will coincide randomly in time and the organism will move into a state of non-specific vulnerability. Such failure causes a whole cascade of dependent failures of other systems in the organism, so there are many observed causes of death.

In the simplest illustration of the idea of this hypothesis, an organism in a normal state can die only in extreme situations, certainly lethal for any organism (corresponding to the background component of mortality, which in the developed countries is already close to zero). In addition, as a result of the failure of one of the bodily systems, it may also pass into a state of non-specific vulnerability, which is called "non-survivor". It should be noted that this state has a quite clear biological meaning. For example, failures of immune system, the frequency of which sharply increases with age, create a nonspecific vulnerability to the widest range of diseases, both endogenous and exogenous.

Having fallen into a state of nonspecific vulnerability, an organism quickly dies from any of the first causes it has caught. This concept to a certain extent echoes the new concept of phenoptosis, when an organism is eliminated from the population as a result of multiple systems failure. The age-related component of mortality is determined by the rate of the first limiting stage of the organism's transition from a normal state to a state of non-specific vulnerability ("non-survivor"). This means that the age-related component of mortality is not summed-up of individual causes of death but, on the contrary, is being distributed between them.

In other words, the rate of the first limiting stage determines the value of "death quota", which is then distributed among its various particular manifestations, called "causes" of death. This explains why elimination of the separate age-dependent causes of death is not always capable of changing the size of the age component of mortality. In fact, any reduction of the death rate of organisms, being in a state of non-specific vulnerability, inevitably leads to the increase of share of the organisms being in this state, and to restoration of the former mortality rate due to increase of mortality from other causes.

The hypothesis of limited organism's reliability explains the phenomenon of historical stability of the age-related component of mortality before the early 1950s, as well as the facts of "independent" behavior of the total mortality in relation to its components. Moreover, this hypothesis makes it possible to justify the Gompertz-Makehan formula using such simple notions of the nature of aging as reduction of reserves of organism systems with age. Therefore, the idea of limited reliability of the organism is sufficiently well-founded and natural to be used as a working hypothesis in determining the ways and prospects for extension of human life.

This hypothesis argues that the problem of human lifespan extension is not reduced to fighting individual causes of death. Moreover, the hypothesis of limited reliability predicts that reduction of mortality from individual causes of death will only lead to a significant reduction of total mortality when the initial stage of organism's destruction (transition to a state of non-specific vulnerability) ceases to be a limiting stage of the whole process.

Apparently, the future belongs to another strategy based on explaining the mechanisms of organism's reliability providing nonspecific resistance to a wide range of damaging factors. If successful in this direction, we can expect simultaneous reduction in mortality from a wide variety of diseases. These ideas are conceptually close to the currently developing direction in gerontology, which is called geroscience. This direction is based on the well-known idea that in order to increase lifespan and healthy longevity in particular, it is necessary to move from combating specific diseases of old age to slowing down the pathological processes leading to aging (e.g., reduction of systemic sterile inflammation). Apparently, further success in gerontology should be expected in the development of this particular direction of research.

When building functional organ tissue from the starting point of pluripotent stem cells, a different recipe is required for each different tissue type. Good progress is being made in establishing these recipes, and over the past decade the research community has steadily expanded the number of organs for which tissue engineered organoids can be constructed. An organoid is a millimeter-scale segment of functional organ tissue, only lacking the blood vessel network needed to support larger structures. Organoids are very useful in research, but in many cases can also be used to restore lost organ function when transplanted in sufficient numbers. That has been achieved for the liver and the thymus, and here researchers demonstrate restored function of the thyroid in mice.

Hormones produced by the thyroid gland are essential regulators of organ function. The absence of these hormones either through thyroid dysfunction due to, for example, irradiation, thyroid cancer, autoimmune disease, or thyroidectomy leads to symptoms like fatigue, feeling cold, constipation, and weight gain. Although hypothyroidism can be treated by hormone replacement therapy, some patients have persistent symptoms and/or experience side effects. To investigate potential alternative treatment strategies for these patients, researchers have now for the first time succeeded in generating thyroid mini-organs in the lab.

In a new study researchers used healthy thyroid tissue from patients undergoing surgical removal of the thyroid to grow mini-thyroid organs in a lab which resembled thyroid glands in their structure and protein content. The thyroid mini-organs contained stem cells which re-grew and formed new mini-organs when the structures were dissociated, providing a potentially unlimited source of lab-grown thyroid tissue. Importantly, the thyroid mini-organs could be matured and produced thyroid hormones in the cultures.

Preliminary proof that these structures could potentially replace thyroid tissue came from experiments in mice with hypothyroidism, where transplantation of the mini-organs increased serum levels of thyroid hormones and extended the lifespan of the animals compared to un-transplanted mice. Further studies are required, however the study lays the foundation for generating thyroid mini-organs from surgically removed tissue and may potentially lead to a new therapy for hypothyroidism in the future.

Link: https://www.eurekalert.org/pub_releases/2021-03/isfs-flm030421.php

A part of the process of moving therapies to slow or reverse aging from the laboratory to the clinic is educating the physician population. While the scientific community is largely on board with the goal of controlling the processes of aging, the same is not true of the medical community. The first useful rejuvenation therapies already exist, in the form of senolytic treatments, particularly the combination of dasatinib and quercetin. There is thus more advocacy and persuasion yet to be accomplished in order for physician networks to emerge and enable widespread use of the first viable treatments for aging.

Longevity medicine is advanced personalised preventive medicine powered by deep biomarkers of aging and longevity, and is a fast-emerging field. The field encompasses the likewise rapidly evolving areas of biogerontology, geroscience, and precision, preventive, and functional medicine. With modern advances in artificial intelligence and machine learning, biomarker research and drug development have produced numerous tools for early diagnostics and prevention of communicable and non-communicable diseases, which remain largely unknown to the global medical community.

The notion of longevity and healthy aging as a major priority for healthcare will undoubtedly substantially impact primary, secondary, and tertiary prevention. Therefore, it is essential that practicing doctors have access to the appropriate education through a credible curriculum in longevity medicine.

The development of longevity-focused medical practices greatly depends on bridging the gap between health-care providers and interdisciplinary experts, such as academic biogerontologists, artificial intelligence experts, computer scientists, and informaticians. Health-care providers require customised courses on the most recent advances in longevity medicine and on how this knowledge can be implemented in the practice. Patients have insufficient access to the health-care providers who have been adequately trained in longevity medicine and can manage a patient from a longevity medicine standpoint. Viable longevity education with practical translation will thus ultimately improve health-care systems worldwide and decrease disease occurrence by training health-care providers to tackle the most common and strongest contributor of disease - unhealthy aging.

Aging is the greatest risk factor for most acute and chronic diseases. Previous decades have shown that we are now on the cusp of being able to intervene in the aging process, probably allowing us to decrease overall mortality and morbidity rates in elderly individuals. Although this progress has mostly occurred at the academic level, there is now a great need for expanding this knowledge into the realm of clinical practice. With this Comment, we hope to encourage this necessary step towards implementation of longevity education for health-care providers worldwide.

Link: https://doi.org/10.1016/S2666-7568(21)00024-6

One of the more curious aspects of aging is that risk of Alzheimer's disease and risk of cancer is inversely correlated. Why is this the case? Researchers here suggest that cellular senescence may be an important component of this relationship. If cells in a given individual are more than averagely prone to becoming senescent in response to stress and damage, then this may lower the risk of cancer, as precancerous cells will be blocked from replication and removed by the immune system more efficiently. On the other hand, increased cellular senescence in the aging brain will more rapidly drive chronic inflammation and neurological dysfunction, leading to an increased risk of dementia.

Given this, we are fortunately to live in an era in which senolytic drugs to selectively remove senescent cells now exist. Some of them, such as the combination of dasatinib and quercetin, can bypass the blood-brain barrier to destroy senescent cells in brain tissue. This therapy has been shown to reduce chronic inflammation and reverse Alzheimer's pathology in mouse models of the condition. Human trials in Alzheimer's patients are somewhere in the early stages of organization, and we can hope that this strategy will outperform past efforts.

Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells-Implications for Cancer and Neurodegeneration

The risk of both neurodegenerative disease and cancer increases with advanced age due to increased damage accumulation and decreased repair capabilities; yet the relative odds of developing one or the other are inversely correlated. Molecular profiling studies have identified disrupted genes, proteins, and signaling pathways shared by neurodegenerative diseases and cancer, but in opposing directions. For example, p53 is upregulated in Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, but downregulated in many cancers. Similarly, mutations of the Parkin gene (PARK2) have been shown to simultaneously contribute both to Parkinson's disease and tumor suppression. A recent study performed transcriptomic analyses of four different tissues from four different species at ages across their lifespan. Across samples, the largest number of shared risk single nucleotide polymorphisms (SNPs) were in the genomic locus containing the long non-coding RNA ANRIL which modulates many cell cycle regulators including CDKN2A/B, which codes for p16INK4A (hereon referred to as p16), one of the best characterized mediators of cellular senescence. Notably, SNPs in this locus were identified in the brain, as well as other tissues analyzed. These results point toward aberrant cell cycle, and in particular senescence, as a key age-associated molecular pathway worth further study.

Cellular senescence has emerged as a hallmark biological process that promotes aging. The pillars of aging, including cellular senescence, are highly interconnected and do not occur in isolation. For example, epigenetic changes, telomere attrition, DNA damage, and mitochondrial dysfunction all may induce cellular senescence, which then contributes to dysfunctional nutrient signaling and proteostasis. Consequences of cellular senescence include stem cell exhaustion and chronic inflammation. Thus, cellular senescence represents an intersection of aging hallmarks. While best studied as an anti-cancer stress response, recent studies highlight its pro-degenerative role in AD and tauopathies. As such, cellular senescence may contribute to the inverse correlation between the risk for developing neurodegeneration and that for cancer.

Bulk tissue analyses, while informative at a macroscopic level, may not capture important changes occurring in single cells. Senescent cell abundance increases with aging, but the relative contribution to a tissue is relatively low and may be missed in bulk analyses. Several laboratories are using single cell technologies to assign cell type specificity to tissue-level observations, but to date these analyses have not included senescent cells in the brain. To maximize generalization and interpretation across studies, in this review we only evaluate studies which investigated cellular senescence with cell type specificity, and not bulk analyses. The present compilation provides evidence on conditions in which cellular senescence may benefit (anti-cancer) or negatively impact (neurodegeneration) brain health. In doing so, this review explores how the cellular senescence stress response may simultaneously distinguish and connect AD and cancer risk.

Mitochondria are the power plants of the cell, generating the chemical energy store molecule ATP. The function of mitochondria declines throughout the body with age, and this is particularly impactful in energy-hungry tissues such as the heart. This decline appears to involve changes in mitochondrial shape and dynamics, as well as failing mitophagy, the quality control mechanism responsible for removing worn and damaged mitochondria. This is all clearly the end of a chain of cause and effect involving many other processes, starting with the root causes of aging, and passing through altered epigenetic regulation and expression of necessary proteins.

One possible approach to therapy is to bypass all of the unknowns and transplant functional mitochondria into the patient in large numbers. These are taken up by cells and put to work. This has been shown to produce benefits in animal models, and a few human clinical studies have taken place, but is nonetheless still a form of therapy in the comparatively early stages. There are plenty of unanswered questions, such as how large a fraction of the native mitochondria can be replaced safely at any one time, how long the benefits last before new mitochondria succumb to the aged cellular environment, and whether long-term complications can arise when a different mitochondrial genome is introduced. Still, it is quite an exciting area of development: we should start to see firm answers to these questions over the next decade or so.

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the "stem-less" approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of microRNAs or by modifying the cellular energy metabolism via targeting mitochondria.

Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations.

Despite previous promising usage of mitochondria for transplantations important considerations regarding significant aging effects of somatic cells, stem cells, and mitochondria as well as factors like safety issues, tissue sources, and possible disease effects deserve further investigations when mitochondrial transplantations are to be used for future applications. Factors influencing stem cell and mitochondria function include age of the cells, probably previous divisions of the cells, heterogeneity of stem cells as well as mitochondria, and likely tissue source and additional diseases. Furthermore after the first positive reports, the time of treatment for the most beneficial effect and repetitions of applications should be further investigated: positive effects have been shown pre ischemia, prior to and during reperfusion as well as after delayed application.

The quantity of mitochondria seems to be less critical as only a small number of mitochondria is needed for improving cardiac functions. The development of further safety and storage solutions for mitochondria could improve applications. Following the first promising reports of stem cell derived mitochondria further research especially considering the differences of autologous (maybe collection in early life stages and asservation for later use) vs. allogeneic vs. syngeneic sources deserve further investigations and will surely lead to exiting new developments during the upcoming years.

Link: https://doi.org/10.3390/ijms22041824

The present popularity of SPACs, special purpose acquisition companies, might be cynically thought of as being a sign that quantitative easing is catching up with us - there is too much money sloshing around in the system, all of it chasing too few opportunities for significant returns. A SPAC is a publicly traded shell company that accepts investment prior to any specific idea as to what exactly the funds will be used for, sets a few famous people as figureheads to drum up interest, and then buys established companies or sizable stakes in established companies. It is something of the reverse of the more traditional route to taking companies public. There will be SPACs for the longevity industry, because the longevity industry is a hot topic right now.

Will this help, in the sense of will it accelerate the path to widely available therapies that can meaningfully impact the course of aging? The argument for: there is still a dearth of funding for later stage longevity-focused companies, and it is harder than it should be to obtain the funds needed to make the transition from preclinical to clinical development in this space. The argument against: the clinical development funding gap isn't the real problem, which is instead that the right programs (i.e. an implementation of all of the component parts of the SENS agenda for human rejuvenation) are still not being funded at the research and seed stage in large enough numbers. Those programs will, on balance, achieve sizable enough results in animal studies to have no challenge in pulling in later funding.

Frontier Acquisition Corporation, a special purpose acquisition company formed for the purpose of entering into a combination with one or more biotech businesses, has announced the pricing of its initial public offering of $200 million. Interestingly, the line-up includes Co-Chairmen Peter Attia, a practising physician focusing on the applied science of longevity, and David Sinclair, Professor of Genetics at Harvard Medical School and co-founder of several biotechnology companies.

The new company is headed by German investor Christian Angermayer, founder of Apeiron Investment Group and Chairman and Co-Founder of Cambrian Biopharma. Angermayer laid out his views last year in a detailed post on LinkedIn, where he stated, "Put simply, I want to live forever! And in perfect health! And it is my sincere belief that we will achieve the means to do this within the next 20-30 years."

Angermayer is a serial entrepreneur, backing about 30 life sciences companies, including Atai Life Sciences, Sensei Biotherapeutics, Compass Pathways, and Abcellera. In a statement he said, "I deeply believe biotechnology will be one of the best asset classes to invest in over the next decade. We will see incredible progress that we so far didn't dare to dream about."

Link: https://longevity.technology/david-sinclair-to-co-chair-200-m-spac/

Growth hormone treatments (and other hormone therapies) have a legitimate use in patients suffering excessively low hormone levels due to one or another cause. They have also long been overhyped and aggressively marketed by the anti-aging medicine community, not a field noted for its adherence to standards of truth and scientific accuracy. At the same time, the scientific evidence has consistently shown that aging is accelerated by higher levels of growth hormone. Tall people exhibit a modestly greater degree of age-related disease and mortality, for example, while the longest-lived mice are those with genetically engineered disruption of growth hormone function.

So what to make of this? There are obviously differences in the manifestations of aging in mice and humans, going beyond the obvious divergence in life span, despite the fact that the root causes are the same forms of cell and tissue damage in both species. The damage can be of a similar class, but different in detail, such as the identity of cross-links that cause loss of tissue elasticity. The important cross-linking molecules in mice and humans are quite different, but both contribute to stiffening of arteries and hypertension. The systems that react to damage or are made dysfunctional by it are different enough to react in different ways: mice have a far more plastic life span, capable of larger relative increases in longevity in response to improved cell maintenance or environmental factors such as calorie intake. A calorie restricted mouse and a calorie restricted human exhibit broadly similar short-term metabolic changes, but only the mouse lives 40% longer.

Growth Hormone and Aging: New Findings

In an earlier article, we presented the evidence that growth hormone (GH) has an important role in the control of aging and longevity. Much of the evidence for this role of GH was derived from studies of mice with spontaneous or experimentally induced mutations affecting the somatotropic axis and transgenic mice with chronic increase in circulating GH levels. Results of these studies indicated that (i) major elevation of GH levels accelerates aging and shortens life; (ii) stimulatory actions of normal (physiological) GH levels on growth, maturation, and fecundity involve costs in terms of the rate of aging and average as well as maximal longevity; and (iii) suppression of GH signaling slows the process of aging, increases healthspan, and remarkably extends longevity at the expense of reduced growth, delayed puberty, diminutive adult body size, and reduced fecundity. Importantly, these effects of GH on aging as well as the associated trade-offs were shown to apply to normal mice (animals without genetic modifications) and to other mammalian species.

In humans, familial longevity is associated with reduced GH secretion, and height, a strongly GH-dependent trait, is negatively correlated with longevity in many (although not all) of the examined populations. Hereditary conditions of isolated GH deficiency (IGHD) or GH resistance do not extend human longevity, but appear to extend healthspan and provide strong, and in some cases complete, protection from age-associated diseases. Pathological elevation of GH levels in the syndrome of acromegaly reduces both healthspan and life expectancy, likely reflecting acceleration of the aging process.

Paradoxically, recombinant GH treatment of middle aged or elderly subjects, in whom secretion of GH is naturally reduced, can have beneficial effects on body composition along with subjective improvement in various aspects of the quality of life. Beneficial effects of insulin-like growth factor I (IGF-I), a key mediator of GH actions on various aging-associated traits, support the notion that GH can act as an anti-aging agent. However, age is not among the approved indications for GH therapy and side effects and risks of GH therapy are generally believed to outweigh known or hoped-for benefits.

Available evidence indicates that most of the aging-related effects of GH which were discovered in laboratory mice apply to other mammals, including humans, but important species differences also exist. We speculate that differences in the impact of GH on longevity in mice versus people stem from major differences in life history, energy partitioning, and reproductive strategy between species with a different pace-of-life. The slow pace-of-life of humans combined with the impacts of social organization, public health measures, and medical advances, favors longevity and makes it difficult to induce further increase in lifespan.

Upregulation of LAMP2A is capable of improving the operation of chaperone-mediated autophagy in later life. A while back researchers demonstrated meaningfully improved liver function in mice via this mechanism. Here, they start from the same point of LAMP2A and autophagy in order to try to address the age-related faltering of the hematopoietic system responsible for producing red blood cells and immune cells. With age hematopoietic stem cells become damaged and change their behavior in ways that degrade immune function, such as be producing too many myeloid cells and too few lymphoid cells. Can this be addressed to some degree by upregulation of chaperone-mediated autophagy? The evidence is suggestive.

Creating 200 billion-plus brand-new red blood cells a day can take a toll on a body. The capacity to replace components charged with the life-sustaining task of carrying oxygen eventually wears out with aging, resulting in health problems, from anemia to blood cancers. What if we could halt the aging process and maintain young blood cells for life? With blood cells making up a whopping 90% of the body's cells, it makes sense that keeping them abundant and fit could boost vitality into our golden years.

Blood cells are responsible for oxygen transport, infection control, and many other things scientists are just discovering. But they have a short lifespan - 120 days for red blood cells, and even shorter for other blood cells - and must regenerate continuously throughout life, he said. "This fascinating phenomenon is made possible by the capacity of hematopoietic stem cells (HSCs) to multiply and differentiate into all the blood cell types, a mechanism that unfortunately can become impaired as we get old. Results can include anemia, when we can't make enough red blood cells, or blood cancers, when some blood cell precursors go rogue and start multiplying without differentiating,"

The researchers targeted chaperone-mediated autophagy (CMA), one mechanism they found responsible for the degradation. Like a housekeeper gone awry, CMA with age can fail in its job of cleaning up damaged proteins and other wastes, sabotaging the HSCs' capacity to make new, healthy blood cells. Pinpointing one key protein (LAMP2A) that regulates CMA function whose expression and activity declines with age, the scientists used both genetic, dietary and pharmacological interventions that restored young hematopoiesis (formation of blood cellular components) in old laboratory mice.

The scientists also showed that a metabolic enzyme (FADS2) involved in fatty acid metabolism loses function with age, reducing healthy blood cell formation. By introducing gamma linolenic acid (GLA), a product of the failing enzyme, in the rodents' diets, the researchers again improved cell regeneration. After determining that the CMA dysfunctions in mice mirrored those in 70-plus-year-old humans, the researchers believe their findings could eventually translate into reversing the aging process of HSCs in humans, opening the door to numerous medical therapies.

Link: https://news.cuanschutz.edu/news-stories/scientists-discover-ways-of-making-old-blood-new-again

This article expresses sentiments regarding medical technology and human longevity that we'd all like to see more of in the mainstream media. At some point, it will come to be seen by the average person as basically sensible to work towards minimizing the tide of suffering and death caused aging and age-related disease. It has been, in hindsight, a strange thing to live in a world in which most people were reflexively opposed to that goal.

Death and aging constitute a mystery. Some of us die more quickly. We often ask about it as children, deny it in youth, and reluctantly come to accept it as adults. Aging is universal across all species. In the bare-fact of our aging and dying, we resemble all other animals; in the details, however, we've improved considerably over the course of our history. At some point, our bodies decide to grow senescent and then to die. It's intrinsic, initiated from within the organism. The repeated shuffling of sirtuins and other epigenetic factors away from genes to sites of broken DNA, then back again (while helpful in the short term) is ultimately what causes us to age. Over time the wrong genes come on at the wrong time and in the wrong place. When you disrupt the epigenome by dealing with DNA breaks, it results in an erosion of the epigenetic landscape of misguided and malfunctioning cells.

A malady that impacts less than half the population is a 'disease'. Aging impacts everyone and therefore is an inevitable, irreversible decline in organ function that occurs over time even in the absence of injury, illness, environmental risks, or poor lifestyle choices. Aging limits the quality of life and has a specific pathology. It does all this and in doing so it fulfills every category of what we call a 'disease', except one; it impacts more than half of the population. It's the mother of all diseases, the one we all suffer from. Aging, by all means, is a disease though not yet considered so by any country. Insurance companies don't cover pharmaceuticals to treat cases that aren't recognized by government regulators even if it benefits humanity and the nation's bottom line. Without such a designation, unless you're suffering from a specific disease, longevity drugs will have to be paid for out of pockets, for they'll be elective luxuries.

As nobody has been working on any cure, because what's wrong with oldies isn't viewed as an illness. It's thought to be an inevitable part of life. Cancer, heart diseases, Alzheimer's, and other conditions we commonly associate with getting old aren't necessarily diseases themselves but symptoms of something greater. Efforts to define aging as a 'disease' both in custom and on paper will change the course of the future. Besides public funding to augment the cure doctors will feel comfortable prescribing medicines, such as Metformin, to their patients before they become irreversibly frail. Jobs will be created and scientists and drug makers will flock, industries will flourish.

There's a difference between extending life and prolonging vitality. We're capable of both but simply keeping people alive is no virtue. Life-extension means the recovery of the physical/intellectual capital that's tied up in hospitals and clinics, treating sick oldies. Add to this the billions of additional women, if provided, much longer windows of opportunity for pregnancy and parenting and extended female fertility by up to a decade or so. Imagine the combined intellectual power of the men and women who're currently sidelined due to age-discrimination, socially enforced ideas about the right time to retire, and diseases that rob them of the physical and intellectual capacity to engage, as they once did.

Link: https://www.greaterkashmir.com/news/opinion/on-living-longer/

Telomeres are repeated DNA sequences that form the end caps of chromosomes. A little of their length is lost with each cell division, and cells self-destruct or become senescent and cease replication when telomeres become too short. This is a part of the Hayflick limit on cell replication: near all cells in the body can only divide a limited number of times. Stem cells are the first exception, using telomerase to extend telomeres. Cancer cells are the second exception, employing either telomerase or the alternative lengthening of telomeres (ALT) mechanisms that do not operate in normal cells. Telomere lengthening is a universal mechanism in cancer, and thus there is considerable interest in producing a single class of treatment, based on interference in telomere lengthening, that can potentially shut down all cancers.

The original vision for whole-body interdiction of telomere lengthening, a part of the SENS rejuvenation research agenda, was to turn off the processes that lengthen telomeres throughout the body. Perhaps temporarily, or, in a more futuristic option, perhaps permanently when deployed in conjunction with periodic replacement of stem cell populations. Since the original proposition was put forward, research into ALT hasn't made all that much progress, perhaps because only 10% of cancers exhibit this behavior. Research into interfering with telomerase-based telomere lengthening has progressed, however, and diversified into a number of interesting lines of work. All of these seem likely to be targeted to cancer cells, either as an inherent result of the mechanism, or by combining the therapy with a selective delivery system.

One recent example of many is the work of Maia Biotechnology, building on an approach that sabotages telomerase-based telomere lengthening in a subtle way that has the outcome of killing cells. Today's research materials are another example of a program at an earlier stage of exploration, more focused on an indirect approach to reducing telomerase activity, one that can involve signaling applied outside the cell. This makes it an attractive basis for the development of therapies.

Researchers discover how telomere involvement in tumour generation is regulated

Researchers have in the past provided evidence to suggest that shelterins, proteins that wrap around telomeres and act as a protective shield, might be therapeutic targets for cancer treatment. Subsequently, they found that eliminating one of these shelterins, TRF1, blocks the initiation and progression of lung cancer and glioblastoma in mouse models and prevents glioblastoma stem cells from forming secondary tumours. Now researchers go one step further and describe for the first time how telomeres can be regulated by signals outside the cell that induce cell proliferation and have been implicated in cancer. The finding opens the door to new therapeutic possibilities targeting telomeres to help treat cancer.

Researchers have outlined a link between TRF1 and the PI3K/AKT signalling pathway. This metabolic pathway, which also encompasses mTOR, is one of the pathways most frequently affected in numerous tumorigenic processes. However, it was not known whether preventing TRF1 regulation by this pathway can have an impact on telomere length and its ability to form tumours. AKT acts as a transmitter of extracellular signals triggered by, among others, nutrients, growth factors, and immune regulators, to the interior of cells.

Researchers modified the TRF1 protein in cells to make it unresponsive to AKT, using the gene-editing tool CRISPR/Cas9. This way, TRF1 and the telomeres became invisible to any extracellular signals transmitted by AKT. Telomeres in these cells shortened and accumulated more damage; most importantly, the cells were no longer able to form tumours, indicating that telomeres are important targets of AKT and its role in cancer development.

The paper shows that telomeres are among the most important intracellular targets of the AKT pathway to form tumours, since, although neither the function of AKT nor of any of the thousands of proteins that are regulated by it was altered, only blocking AKT's ability to modify telomeres was sufficient to slow tumour growth. The next step will be to generate genetically modified mice with telomeres that are invisible to AKT. The authors anticipate that these mice will be more resistant to cancer.

AKT-dependent signaling of extracellular cues through telomeres impact on tumorigenesis

The telomere-bound shelterin complex is essential for chromosome-end protection and genomic stability. Little is known on the regulation of shelterin components by extracellular signals including developmental and environmental cues. Here, we show that human TRF1 is subjected to AKT-dependent regulation. To study the importance of this modification in vivo, we generate knock-in human cell lines carrying non-phosphorylatable mutants of the AKT-dependent TRF1 phosphorylation sites by CRISPR-Cas9.

We find that TRF1 mutant cells show decreased TRF1 binding to telomeres and increased global and telomeric DNA damage. Human cells carrying non-phosphorylatable mutant TRF1 alleles show accelerated telomere shortening, demonstrating that AKT-dependent TRF1 phosphorylation regulates telomere maintenance in vivo. TRF1 mutant cells show an impaired response to proliferative extracellular signals as well as a decreased tumorigenesis potential. These findings indicate that telomere protection and telomere length can be regulated by extracellular signals upstream of PI3K/AKT activation, such as growth factors, nutrients, or immune regulators, and this has an impact on tumorigenesis potential.

Researchers here build an economic model of technological progress and its impact on human life span. The model suggests that advances in technology account for half of the gains in life span from the 1960s on. This is in much the same ballpark as other initiatives that have asked similar questions regarding the causes of the slow upward trend in human longevity over the past century or more.

Life expectancy at birth is presently increasing at something like two years per decade, while remaining life expectancy at 65 is increasing at one year per decade. We should expect this trend to leap upward as the first rejuvenation therapies to deliberately target the mechanisms of aging enter widespread use. Past gains were achieved almost accidentally, as no meaningful efforts were made at the time to directly address the causes of aging. That state of affairs has now changed, and we should expect better outcomes as a result.

We estimate a stochastic life-cycle model of endogenous health spending, asset accumulation, and retirement to investigate the causes behind the increase in health spending and longevity in the United States over the period 1965-2005. Accounting for changes over time in taxes, transfers, Social Security, income, health insurance, smoking and obesity, and technological progress, we estimate that technological progress is responsible for half of the increase in life expectancy over the period.

Substantial growth in health spending over the period is largely the result of growth in economic resources and the generosity of health insurance, with a modest role for medical technological progress. The growth in spending does not come from changes in a single source, but sources jointly interacted to increase spending: complementarity effects explain up to 26.3% of the increase in health spending. Overall, for those born in 1940, the combined changes in resources and health insurance that occurred over the period are valued at 35.7% of lifetime consumption.

Link: https://doi.org/10.1093/jeea/jvaa003

Lysosomes recycle unwanted and damaged molecules in the cell, and are thus vital to cell health. Unfortunately, lysosomal function is progressively impaired with age. This occurs as a result of the buildup of various persistent metabolic byproducts, particularly in long-lived cells such as those of the central nervous system. Much of the research on this topic is focused on the impact of lipofuscin, but, as noted in the materials here, other forms of metabolic waste can also negatively impact lysosomal function. This loss of function contributes to age-related conditions, such as the retinal degeneration discussed here.

Amyloid beta (Ab) proteins are the primary driver of Alzheimer's disease but also begin to collect in the retina as people get older. Donor eyes from patients who suffered from age-related macular degeneration (AMD), the most common cause of blindness amongst adults in the UK, have been shown to contain high levels of Ab in their retinas.

A new study builds on previous research which shows that Ab collects around a cell layer called the retinal pigment epithelium (RPE), to establish what damage these toxic proteins cause RPE cells. The research team exposed RPE cells of normal mouse eyes and in culture to Ab. The mouse model enabled the team to look at the effect the protein has in living eye tissue, using non-invasive imaging techniques that are used in ophthalmology clinics. Their findings showed that the mouse eyes developed retinal pathology that was strikingly similar to AMD in humans.

The investigators also used the cell models, which further reduced the use of mice in these experiments, to show that the toxic Ab proteins entered RPE cells and rapidly collected in lysosomes, the waste disposal system for the cells. Whilst the cells performed their usual function of increasing enzymes within lysosomes to break down this unwanted cargo, the study found that around 85% of Ab still remained within lysosomes, meaning that over time the toxic molecules would continue to accumulate inside RPE cells. Furthermore, the researchers discovered that once lysosomes had been invaded by Ab, around 20 percent fewer lysosomes were available to breakdown photoreceptor outer segments, a role they routinely perform as part of the daily visual cycle.

Link: https://www.southampton.ac.uk/news/2021/03/amd-amyloid-beta.page

Human life expectancy has increased through two distinct process; firstly a reduction in child mortality, and second a reduction in the burden of damage accumulated over an adult life span. Control of infectious disease has played a large role in both components of gains in life expectancy. The trend has been slow. In recent decades, something like 0.2 years of life expectancy at birth and 0.1 years of remaining life expectancy at age 60 have been added with each passing calendar year.

Life expectancy is an artificial measure, of course: it is the length of life remaining, on average, assuming that nothing changes in the state of medical science and public health practices. But there are always improvements. At present, the medical research community is shifting from a paradigm in which the mechanisms that cause aging were ignored, to a paradigm in which the mechanisms that cause aging are deliberately targeted. Meaningful slowing and reversal of degenerative aging are now on the table as options for the years ahead. This will cause considerable, and welcome, disruption to the slow historical increase in life expectancy. The future is bright.

Increasing life expectancy - the rise of longevity

A recent study analysed data from the Human Mortality Database (HMD), specifically looking at the probability of death at a given age. For various countries, including the US, Sweden, and Japan, individuals over 50 years had their mortality postponed, on average, by a decade for every age group (50s, 60s, 70s, etc.) from 1967 to 2017. In the example of Sweden, mortality remained constant more or less over the 19th and 20th centuries, until 1950 where an international life expectancy revolution took place.

This could be due to the colossal medical advancements that took place: the discovery of the structure of DNA, novel vaccines, the first successful kidney transplant, a novel antibiotic tetracycline, the first oral contraceptive and the invention of the internal pacemaker. Since then, life expectancy increased almost linearly at a rate of 2.5 years per decade all over the world. This same trend is observed in the longevity leader - Japan. Undoubtedly, the improvements in mortality stem from postponing it and thus prolonging both lifespan and healthspan. People are living longer due to being healthier and thus aging diseases are pushed back, developing later in life.

There are three predominant views on which longevity researchers speculate about the future of life expectancy: 1) life expectancy will rise, but more slowly that in the past due to reaching the 'limit'; 2) the same 2.5 year per decade increase in life expectancy will continue as in the past; 3) life expectancy will rise at a much faster rate due to biomedical advances, as previously seen in the 1950s. The future for longevity will differ from the past, as various mortality improvements play their part. A more effective public health strategy, along with devising treatments to cure aging diseases, such as dementia and cancer, would push out the current limits of healthspan and lifespan. Furthermore, developments in precision medicine, nanotechnology, regenerating tissues, and research on the biology of aging may all lead to slowing rates of aging.

It is of great importance to distinguish, where we can, between promising and poor approaches to the treatment of aging. If only poor approaches are developed, then we'll age, suffer, and die on much the same schedule as our grandparents. In the article here, metformin and senolytics are crammed together side by side, as though the same thing. They are very much not the same thing.

Metformin is almost certainly a poor approach to the treatment of aging. The animal data is terrible, while the human data shows only a modest effect size. Senolytics are most likely a promising approach. The animal data is amazing: robust, reliable rejuvenation and reversal of many currently untreatable age-related diseases via any approach that removes a third or more of the senescent cells that linger in old tissues. The degree to which this is going to do great things in people remains to be determined. But it is fair to wager that it will be a good deal better than the results to date from metformin. If we're going to spend extensive time and funding on something, why the obviously worse option? Why aim so low?

In recent years, many experts in the aging field have come to believe that certain medications acting at the cellular and metabolic level can slow aging by staving off its most striking effects - frailty and ­age-related diseases, for example - and extend healthy life in doing so. Now they are setting out to prove it. "We're not about the fountain of youth," says Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine. "That's taking an old person and making him young. What we are saying is that we can delay aging."

Drugs with the ability to postpone or prevent the onset of debilitating diseases could lead to additional healthier years, enhancing longevity and providing enormous societal benefits, experts say. Leading the list of candidates is metformin, a longtime treatment for type 2 diabetes, and rapamycin, a chemotherapy agent and immunosuppressant. Scientists also are studying a class of compounds known as senolytics, which attack "senescent" cells in the body that tend to proliferate with age. Senescent cells damage healthy cells around them, contributing to multiple age-related diseases.

But such drugs could face a daunting challenge, since aging is not considered a disease. This means the Food and Drug Administration is unlikely to approve a drug for its anti-aging effects, or as a new use for a licensed drug. Also, pharmaceutical companies probably wouldn't be inclined to develop drugs for that purpose only. Scientists hope to circumvent that hurdle by conducting a study - in this case, with metformin - to test whether it can prevent or delay three age-related diseases - dementia, heart disease and cancer - and, in doing so, extend life.

At least one study had heightened their interest in the drug as possibly life-extending after researchers noticed that diabetics who took the drug outlived non-diabetics who did not. Moreover, metformin had shown an effect in separate studies against each of the three diseases, prompting the researchers to try to put all the pieces together in one large randomized controlled clinical trial. The result is a proposed six-year clinical trial, known as Targeting Aging With Metformin (TAME), which will recruit 3,000 subjects ages 65 to 79 at 14 research sites. In testing whether metformin can prevent or delay the three diseases, researchers also hope to learn whether this results in those taking metformin outliving those not taking the drug, thus extending healthy life. (One reason for choosing metformin was because of its long track record, safety, and inexpensive cost.)

"The goal is not to help people live forever, but help them stay healthy longer," says Steven Austad, who chairs the biology department at the University of Alabama at Birmingham and is senior scientific director of the American Federation for Aging Research. "But the fringe benefit is that you live longer."

Link: https://www.washingtonpost.com/health/anti-aging-drugs-metformin-study/2021/03/05/d9de870a-7882-11eb-9537-496158cc5fd9_story.html

Researchers have in the past found that low levels of immunoglobulin-M antibodies correlate with an increased risk of thrombosis, the blockage of a blood vessel by, for example, fragments of a ruptured atherosclerotic plaque. Here, more details regarding this relationship are reported, suggesting that therapies designed to increase immunoglobulin-M antibody levels could be useful in reducing the incidence of heart attack and stroke resulting from thrombosis.

Antibodies are an important component of the immune system. On the one hand, these proteins serve in the body to defend against microbes, and on the other hand to remove the body's own "cell waste". Naturally occurring antibodies which are present from birth and mostly of the immunoglobulin-M (IgM) type, play an essential role in these processes. In the context of thrombosis, earlier studies demonstrated that people with a low number of IgM antibodies have an increased risk of thrombosis. Thrombotic occlusion of blood vessels, which leads to myocardial infarctions, strokes, and venous thromboembolisms, is the major cause of death in the western hemisphere. Therefore, it is of critical importance to understand mechanisms preventing thrombus formation.

Microvesicles, blebs shed from the membrane of cells, are critical mediators of blood coagulation and thrombus formation. Researchers have now demonstrated that natural IgM antibodies that bind oxidation-specific epitopes can prevent coagulation and thrombosis induced by microvesicles. This provides a mechanistic explanation for the previously published observation that low levels of these antibodies are associated with an increased risk of thrombosis. Both in experiments on a mouse model and directly on human blood samples, the scientists were able to show that the addition of IgM antibodies inhibited blood clotting caused by specific microvesicles and protected mice from lung thrombosis. Conversely, it was also shown that depletion of the IgM antibodies increased blood clotting.

"The results offer high potential for novel treatments to reduce the risk of thrombosis. Influencing IgM antibody levels in high-risk patients could be a viable addition to the previously established blood thinning treatment, as this is also known to be associated with side effects such as an increased tendency to bleed in the case of injuries."

Link: https://cemm.at/news/n/news/new-therapeutic-approach-discovered-for-reducing-the-risk-of-thrombosis/

Today's materials are a helpful overview of the brace of biotech companies working to slow or reverse aspects of mitochondrial aging. Mitochondria play a central role in core cellular processes and are important in degenerative aging. Every cell contains a herd of hundreds of mitochondria, the descendants of an ancient symbiosis between the first cells and bacteria that could help them survive. Each mitochondrion contains one or more copies of mitochondrial DNA, a small remnant of the original bacterial genome, just a few genes that evolution has yet to move to the cell nucleus. The mitochondrial population of a cell is dynamic: constant fission, fusion, swapping of protein machinery, and destruction by the quality control process of mitophagy when worn and damaged.

While mitochondria have many roles, their primary task is the packaging of the chemical energy store molecule ATP. This powers cellular operations, but its production is an energetic process by that produces a flux of oxidizing molecules as a byproduct. These molecules damage protein machinery in the cell via oxidative reactions, a form of damage that is constantly repaired, and which cells maintain antioxidant defenses to minimize. At low levels this is a beneficial signal for the cell to engage in greater repair efforts. At high levels it harms a cell.

There are several classes of mitochondrial problem that emerge with age. Firstly ATP production is reduced. Mitochondrial dynamics change: mitochondria become resistant to mitophagy, and falter in their tasks. Secondly, these changes also result in a greater production of oxidative molecules. Thirdly, mitochondrial DNA is less well protected and repaired than nuclear DNA, and some forms of mutational damage can produce malfunctioning mitochondria that outcompete their functional peers, taking over cells. This converts healthy cells into pathological exporters of oxidative molecules, damaging surrounding tissues through a range of related mechanisms. These include raised levels of oxidized cholesterol molecules in the bloodstream, contributing to the development of atherosclerosis by encouraging dysfunction in the macrophage cells responsible for keeping blood vessel walls clear of atherosclerotic lesions.

Something should be done about mitochondrial dysfunction in aging and age-related disease. It is very clearly implicated in the onset and progression of numerous age-related conditions. Numerous approaches are under consideration, with varying degrees of expected utility and progress towards availability. NAD+ upregulation, for example, attempts to correct one of the many observed changes in mitochondrial biochemistry. As presently practiced, using vitamin B3 derivative compounds, it is most likely less effective than structured exercise programs at achieving its goal. At the other end of the spectrum lie advanced biotechnologies in the early stages of development, such as copying mitochondrial genes into the cell nucleus via gene therapy in order to make mitochondrial DNA mutation irrelevant to aging. A great many other approaches lie between the two.

#022: A Map of Mitochondria Longevity Companies (PART 1)

In this newsletter, we're going to take a look at all the longevity biotech companies that are developing therapies that target mitochondrial dysfunction - one of the "Hallmarks of Aging". Mitochondria companies make up one of the biggest subcategories in longevity biotech. This makes sense as mitochondria are an extremely critical component of our cells. There are ~20+ longevity mitochondria companies currently, ranging from early stage-startups to Nasdaq-listed public companies. From small molecule drugs to gene therapies and mitochondrial transfusions. Seven of the companies are in clinical trials today.

Aging is not an accepted clinical indication (yet). So the current playbook for longevity biotech companies is to target a disease that shares the same underlying cause as one of the hallmarks/targets of aging for their first clinical trials and expand from there. Usually, this means an age-related disease or a rare genetic disease. Mitochondrial dysfunction is implicated in many diseases of aging. Longevity companies targeting mitochondrial dysfunction generally choose clinical indications such as: mitochondrial diseases caused by mitochondrial DNA mutation or nuclear DNA mutations (LHON, Pearson syndrome, etc), muscle dystrophy diseases or muscle loss (Duchenne muscular dystrophy, Becker muscular dystrophy, sarcopenia), metabolic disorders (NASH, Obesity, NAFLD, Type 2 Diabetes), neurodegenerative disease (Alzheimer's, Parkinson's, etc), or conditions linked to oxidative damage (ischemia-reperfusion injury).

#022: A Map of Mitochondria Longevity Companies (PART 2)

Mitochondria are complex. It's still an open question on how they drive aging. Hallmarks of Mitochondrial Aging? Mitochondria have their own DNA, membranes, ribosome, move around (sometimes outside of the cell!), undergo fission and fusion, and provide one of the most critical cellular functions. Since they are almost like their own organism they probably deserve their own "Hallmarks of (Mitochondria) Aging" paper. But just like the original Hallmarks paper, it will be filled with many correlations and questions while causation is not always clear.

Mitochondrial transfer is very promising. I'll admit I am biased towards replacement therapies for anti-aging when it makes sense. It's a clean philosophical approach that lends itself to engineering more than traditional drug development. And unlike stem cell therapies or cellular transplants mitochondria can be replaced easily without the need for extracellular scaffolding or any kind of extra in situ differentiation. There will likely be a number of challenges to work out, though (sourcing allogeneic mitochondria, systemic distribution, determining long-term side effects, etc). One caveat: It is possible that transplanting healthy mitochondria into an old and dysfunctional cellular environment will quickly impair the transplanted organelles. Also, we need to consider the microtubules mitochondria use to move around the cell.

Protect mitochondrial DNA or remove mutations? GenSight Biologics is definitely one of the most interesting biotech companies I have ever stumbled upon. And while their therapies aren't considered anti-aging at the moment (save for GS020 for dry AMD), the technology is a step towards possibly solving the problem of mitochondrial mutations. But even here it is not clear whether it is more important to protect mitochondrial DNA from new mutations or stop already mutated mitochondrial DNA from accumulating via clonal expansion (like Shift Bioscience). Some researchers have also proposed using various DNA editing techniques (TALENS, Zinc Finger Nuclease, CRISPR) to destroy mutant mitochondrial DNA.

Researchers here note that the visible signs of vascular degeneration in the retina correlate with the risk of cardiovascular disease. The worse the state of the retina, the more likely it is that a patient will develop cardiovascular disease. Similar degenerative processes are at work throughout the vasculature, but the location of the retina allows for a cost-effective visual inspection of blood vessels using established tools.

Researchers have identified a potential new marker that shows cardiovascular disease may be present in a patient using an optical coherence tomography (OCT) scan - a non-invasive diagnostic tool commonly used in ophthalmology and optometry clinics to create images of the retina. The finding suggests it may be possible to detect heart disease during an eye examination. The research team examined lesions of the retina, the inner-most, light-sensitive layer of the eye, to determine if a cardiovascular disorder may be present.

"The eyes are a window into our health, and many diseases can manifest in the eye; cardiovascular disease is no exception. Ischemia, which is decreased blood flow caused by heart disease, can lead to inadequate blood flow to the eye and may cause cells in the retina to die, leaving behind a permanent mark. We termed this mark 'retinal ischemic perivascular lesions,' or RIPLs, and sought to determine if this finding could serve as a biomarker for cardiovascular disease."

As part of the study, the team reviewed the records of individuals who received a retinal OCT scan. From that cohort, two groups were identified after medical chart review: one consisted of 84 individuals with heart disease and the other included 76 healthy individuals as the study's control group. An increased number of RIPLs was observed in the eyes of individuals with heart disease. According to the researchers, the higher number of RIPLs in the eye, the higher the risk for cardiovascular disease. Detection of RIPLs could result in identification of cardiovascular disease that would enable early therapy and preventative measures, and potentially reduce numbers of heart attacks or strokes.

Link: https://ucsdnews.ucsd.edu/pressrelease/heart-disease-is-in-the-eye-of-the-beholder

This interesting study shows that when given the choice to consume sugar or protein, flies consume a lot of sugar and exhibit reduced life span as a result. Feeding the same proportional mix of sugar and protein to flies without giving them the choice of what to consume does not reduce life span to the same degree, however. The researchers identify specific signaling responsible for this outcome, involved in the neuronal regulation of metabolism, a part of the only partially explored feedback loop between diet and appetite. This is all fascinating, but it is hard to say whether it has any near term relevance to health in humans.

What constitutes a good diet remains a matter of continuous debate. The typical way of addressing such questions in a laboratory setting would be to compare groups given diets with different macronutrient compositions and measure their lifespans. But in real life, food is neither presented nor consumed that way. First, foods vary in their composition of macronutrients. Second, all creatures tend to have innate preferences towards certain foods. Taking these discrepancies into account, would we see a connection between macronutrients and longevity in a more naturalistic, choice-based food environment?

Researchers set out to address this topic in a widely used model system, the fruit fly Drosophila melanogaster. In the first set of experiments, one group of wild-type fruit flies spent their lives on a diet consisting of equal amounts of sugar and protein (fixed diet). The second group received the same amount and ratio of sugar and protein, but they could choose between the two foods (choice diet). Then, the amount of food consumed and lifespans were measured and compared across both groups. Alas - and perhaps unsurprisingly - flies given the choice between sugar and protein consumed far more sugar and lived less long than those given no choice in the matter.

However, the reduced longevity of the 'sweet-toothed' flies could not be attributed solely to sugar-induced toxicity. Even flies given up to three times as much sugar as protein in the fixed-diet group had an intermediate lifespan. Additionally, other measures, such as intestinal permeability and locomotion, were unaltered by the choice diet, at least in young flies. Not even a major messenger molecule in the insulin signaling pathway (dFOXO), a key culprit in diet-induced longevity, was greatly affected by a choice-driven diet. Instead, it appeared that being presented with the choice itself led to increased sugar consumption and reduced longevity.

Researchers were able to show that a serotonin receptor called 5HT2A was responsible for the choice-induced reduction in lifespan. However, when 5HT2A was removed, flies on a choice diet no longer had shortened lifespans, even though they consumed just as much sugar as the wild-type flies. Researchers suspected that variations in internal nutrients could be behind the observed changes in lifespan. They compared a large number of metabolites relevant for converting food to energy in flies raised on both diets, and with or without 5HT2A. Over 80% of these metabolites did not change. However, in flies raised on a choice-diet, four amino acids (lysine, glutamine, asparagine, and aspartate) increased in a 5HT2A-dependent manner.

Link: https://doi.org/10.7554/eLife.66755

Piperlongumine, an extract of long peppers, was shown to be senolytic a few years ago. The compound is capable of selectively destroying senescent cells by sensitizing them to oxidative damage, provoking apoptosis. The accumulation of senescent cells is one of the causes of aging, and means of clearance are thus potentially valuable. For those considering introducing more long peppers into their diet, note that a senolytic dose of piperlongumine would require ingesting an impossibly large weight of pepper. Just a few peppers will do absolutely nothing, as they contain far too little piperlongumine individually to make any difference.

Interestingly, this discovery doesn't appear to have made its way all that far into that part of the research community that works with piperlongumine on a regular basis. I keep seeing papers in which scientists report on the evaluation of piperlongumine as a treatment for an age-related condition that is known to be caused in part by cellular senescence, in which there is no mention of senescent cells. It is odd.

Today's open access paper is an example of the type, in which piperlongumine is deployed to treat aortic calcification, a cause of vascular stiffness, hypertension, and consequent cardiovascular disease. There is good evidence for senescent cells to contribute to this process via their secretions, inflammatory signaling that causes cells in blood vessel walls to begin to behave as though they are in bone tissue, depositing calcium into the extracellular matrix. Not that you would learn that from this paper, which focuses instead on the downstream changes that take place in these misbehaving blood vessel cells.

Piperlongumine Attenuates High Calcium/Phosphate-Induced Arterial Calcification by Preserving P53/PTEN Signaling

Vascular calcification is a complex disease that can occur in large and small blood vessels throughout the body. The main feature of vascular calcification is the deposition of calcium-containing complexes along the blood vessel wall. These deposits are mainly composed of calcium and phosphate minerals in the form of hydroxyapatite crystals, which are similar to those in bone tissue. Vascular calcification is now recognized as an active biological process that shares many features with physiological bone formation. There are many causes of vascular calcification, including diabetic angiopathy, chronic kidney disease, lipid metabolism disorders, and genetic factors. Currently, no theory completely explains the pathogenesis of vascular calcification, and no specific treatment methods for vascular calcification are preferred. Therefore, the search for effective treatment methods for vascular calcification is of great significance for the future protection of human cardiovascular health.

Vascular smooth muscle cells (VSMCs) are thought to constitute the main cell type in vascular calcification. In calcified blood vessels, VSMCs show osteogenic differentiation, that is, transformation from a contractile phenotype to a bone/cartilage mineralized phenotype, which is characterized by the development of calcified vesicles, downregulation of mineralization-inhibiting molecules, and increased calcified matrix. This transformation is accompanied by loss of the smooth muscle cell marker smooth muscle 22 alpha (SM22α) and increase in osteochondrocyte markers, including runt-related transcription factor 2 (Runx2), bone morphogenetic protein 2 (Bmp2), osteopontin (OPN), osteocalcin, and alkaline phosphatase (ALP). Overexpression of Bmp2 in vascular smooth muscle cells increases the level of calcification, and Bmp2 expression is increased in the calcified atherosclerotic plaques of blood vessels.

Piperlongumine is a cell-permeable, orally bioavailable natural product isolated from the Piper longum L. plant species. The reported pharmacological activities of PLG include anti-inflammatory, antibacterial, anti-atherosclerotic, antioxidant, antitumour, antiangiogenic and anti-diabetic activities. In this study, we determined the effect of PLG on high calcium- and phosphate-induced vascular calcification, and we further explored its potential molecular mechanisms.

In vitro, PLG inhibited calcium deposition of VSMCs treated with high calcium/phosphate medium. PLG also decreased the expression of osteogenic genes and proteins, including Runx2, Bmp2, and OPN. In a vitamin D-induced aortic calcification mouse model, a 5 mg/kg dose of PLG decreased calcium deposition in the aortic wall as well as Runx2 expression. With regard to the mechanism, we found that the levels of P53 mRNA and protein in both VSMCs and mouse aortic tissues were decreased in the calcification models, and we observed that PLG preserved the levels of P53 and its downstream gene PTEN. Concurrent treatment of VSMCs with P53 ShRNA and PLG blunted the anti-calcific effect of PLG. In conclusion, PLG attenuates high calcium/phosphate-induced vascular calcification by upregulating P53/PTEN signaling in VSMCs.

Now that some groups, such as Volumetric, are working on ways to print tissue with blood vessel networks, ways to more efficiently bioprint larger volumes of tissue will be necessary. Costs must come down in order for the technologies to spread and evolve more rapidly. The road to bioprinting of entire replacement organs lies ahead, given (a) a robust solution for the production of tissues containing small-scale blood vessels, and (b) bioprinters that can turn out tissues reliably and rapidly.

It looks like science fiction: A machine dips into a shallow vat of translucent yellow goo and pulls out what becomes a life-sized hand. But the seven-second video, which is sped-up from 19 minutes, is real. The hand, which would take six hours to create using conventional 3D printing methods, demonstrates what engineers say is progress toward 3D-printed human tissue and organs - biotechnology that could eventually save countless lives lost due to the shortage of donor organs. "The technology we've developed is 10-50 times faster than the industry standard, and it works with large sample sizes that have been very difficult to achieve previously."

It centers on a 3D printing method called stereolithography and jelly-like materials known as hydrogels, which are used to create scaffolds in tissue engineering. The latter application is particularly useful in 3D printing, and it's something the research team spent a major part of its effort optimizing to achieve its incredibly fast and accurate 3D printing technique. "Our method allows for the rapid printing of centimeter-sized hydrogel models. It significantly reduces part deformation and cellular injuries caused by the prolonged exposure to the environmental stresses you commonly see in conventional 3D printing methods." Researchers say the method is particularly suitable for printing cells with embedded blood vessel networks, a nascent technology expected to be a central part of the production of 3D-printed human tissue and organs.

Link: https://www.buffalo.edu/news/releases/2021/03/007.html

Researchers here note an association between vision impairment and mortality in later life. This has the look of a correlation that exists because aging is a global process at work throughout the body. It stems from the accumulation of a few classes of cell and tissue damage. That damage causes downstream consequences that spread out into a complex, diverse array of degeneration and diseases. If vision is failing more rapidly in any given individual, then the odds are very good that this is also the case for other, more critical systems in the body.

For this systematic review and meta-analysis, we searched for prospective and retrospective cohort studies that measured the association between vision impairment and all-cause mortality in people aged 40 years or older who were followed up for 1 year or more. In a protocol amendment, we also included randomised controlled trials that met the same criteria as for cohort studies, in which the association between visual impairment and mortality was independent of the study intervention. Our searches identified 3845 articles, of which 28 studies, representing 30 cohorts (446,088 participants) from 12 countries, were included in the systematic review.

There was variability in the methods used to assess and report vision impairment. Pooled hazard ratios for all-cause mortality were 1.29 for visual acuity <6/12 versus ≥6/12; 1.43 for visual acuity <6/18 versus ≥6/18; 1.89 for visual acuity <6/60 versus ≥6/18; and 1.02 for visual acuity <6/60 versus ≥6/60. Effect sizes were greater for studies that used best-corrected visual acuity compared with those that used presenting visual acuity as the vision assessment method, but the effect sizes did not vary in terms of risk of bias, study design, or participant-level factors (ie, age). We judged the evidence to be of moderate certainty.

The hazard for all-cause mortality was higher in people with vision impairment compared with those that had normal vision or mild vision impairment, and the magnitude of this effect increased with more severe vision impairment. These findings have implications for promoting healthy longevity.

Link: https://doi.org/10.1016/S2214-109X(20)30549-0

A major challenge in the study of aging and age-related disease is establishing the direction of causation. A great many mechanisms of aging are known, but it is difficult to firmly establish the relationships between them. The body is made up of many interacting systems, and changes in any one system tend affect the others, directly or indirectly. Equally, any two specific aspects of aging can be quite disconnected from one another but nonetheless proceed in parallel because they are both influenced by a third underlying mechanism. For example, the chronic inflammation of aging is a systemic problem, driving dysfunction in tissues throughout the body and accelerating the onset and progression of a wide range of age-related conditions.

Today's research materials are an example of this point. Here, researchers debate the direction of causation between atherosclerosis and clonal hematopoiesis. In atherosclerosis, macrophage cells in blood vessel walls become overwhelmed by oxidized and excessive amounts of cholesterol, resulting in fatty lesions that weaken and narrow the blood vessels. Because immune cells are involved, inflammation tends to make things worse by further impacting the ability of macrophages to repair tissues. In clonal hematopoiesis, mutational damage to the hematopoietic cells in the bone marrow leads to growing populations of (possibly mildly dysfunctional) immune cells. It is a specific instance of the more general age-related issue of somatic mosiacism, in which mutations in stem cells spread throughout tissues via their daughter somatic cells. It remains unclear as to just how big of a problem this is, in terms of the degree to which it contributes to aging.

Is the relationship between these two aspects of aging bidirectional, or are the observed correlations driven by an underlying process such as chronic inflammation? Questions of this nature are hard to answer definitively. The best approach is to find a way to reverse and repair one of the processes, and observe the result on the other. In general this is what the research and medical communities should be working towards in any case. It is far better to forge ahead to produce therapies of rejuvenation rather than first establishing how all of the mechanisms of aging interact, as success in rejuvenation will answer most of those questions about the inner workings of aging along the way.

Atherosclerosis can accelerate the development of clonal hematopoiesis, study finds

Billions of peripheral white blood cells are produced every day by the regular divisions of hematopoietic stem cells and their descendants in the bone marrow. Clonal hematopoiesis is a common age-related condition in which the descendants of one of these hematopoietic stem cells begin to dominate substantial portions of the blood. Genome-wide analyses have determined that clonal hematopoiesis is frequently driven by recurrent genetic alterations that confer a competitive advantage to specific hematopoietic stem cells, thus giving them the ability to expand disproportionately. Multiple independent studies have shown that clonal hematopoiesis often goes hand in hand with atherosclerosis and cardiovascular disease. Since its discovery, this surprising association has been the subject of intense interest from clinicians and researchers alike.

In a new study, researchers now suggest a different, additional possibility: Atherosclerosis causes clonal hematopoiesis. Patients with atherosclerosis suffer from hyperlipidemia and inflammation, two conditions that are known to chronically boost hematopoietic stem cell division rates. In the new study, the researchers now demonstrate that this increased division accelerates the development of clonal hematopoiesis. "Patients with atherosclerosis essentially experience 'accelerated time.' This is because the speed with which genetic alterations arise and spread through the hematopoietic system is determined by the underlying rate of stem cell division. From a genetic point of view, you could say that atherosclerosis accelerates aging of the blood. Since clonal hematopoiesis is an age-related condition, atherosclerosis patients are prone to developing it earlier than healthy individuals."

Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis

Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2-/- cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.

The proteasome is a complex structure in the cell that is responsible for breaking down unwanted proteins. Like other recycling processes, proteasomal function is connected to life span in short-lived species. Better cell maintenance in response to stress and damage improves cell function, organ function, and longevity. The proteasome is made up of many different proteins, produced in the cell at difference rates. The least produced proteins are rate-limiting for proteasomal activity, and researchers have shown that boosting production of some of the proteasome subunit proteins can improve proteasomal function and increase life span in flies and nematodes. In the work here, researchers suggest that the transcription factor FOXO1, known to influence life span, works at least in part through this mechanism: it may either influence proteasomal function by determining the number of subunit protein molecules that are available for use in the cell.

Proteostasis collapses during aging resulting, among other things, in the accumulation of damaged and aggregated proteins. The proteasome is the main cellular proteolytic system and plays a fundamental role in the maintenance of protein homeostasis. Our previous work has demonstrated that senescence and aging are related to a decline in proteasome content and activities, while its activation extends lifespan in vitro and in vivo in various species. In addition, pharmacological or genetic induction of the proteasome alleviates the pathological phenotype of protein aggregation-related diseases, such as Alzheimer's disease. Here, we demonstrate that the Forkhead box-O1 (FoxO1) transcription factor directly regulates the expression of the 20S proteasome catalytic subunit β5 and, hence, proteasome activity.

The 20S core proteasome has barrel-like configuration and is comprised by seven different α subunits and seven distinct β subunits. Three β subunits, namely β1, β2, and β5, possess proteolytic activities with different substrate specificities. We have shown that human mesenchymal stem cells (hMSCs) exhibit a senescence-related decline of proteasome content and aberrations in physiological assembly of proteasome complexes during prolonged in vitro expansion, while proteasome activation via overexpression of the catalytic β5 subunit can enhance their stemness and lifespan.

We demonstrate that knockout of FoxO1, but not of FoxO3, in mice severely impairs proteasome activity in several tissues, while depletion of IRS1 enhances proteasome function. Importantly, we show that FoxO1 directly binds on the promoter region of the rate-limiting catalytic β5 proteasome subunit to regulate its expression. In summary, this study reveals the direct role of FoxO factors in the regulation of proteasome function and provides new insight into how FoxOs affect proteostasis and, in turn, longevity.

Link: https://doi.org/10.3389/fcell.2021.625715

The immune system becomes disordered and dysfunctional with age in numerous different ways. The B cell component accumulates inflammatory and problematic cells that are known as age-associated B cells. Here, researchers show that these errant B cells produce antibodies that provoke autoimmunity. B cell aging is a problem with a solution demonstrated in animal models: just destroy all B cells. Mammals can get by without B cells for at least a short period of time, and the B cell population regenerates quite rapidly following clearance even in later life. The newly replaced B cells do not exhibit the problems of their destroyed predecessors, improving immune function as a result. There is still too little movement when it comes to adapting this approach for human medicine, alas.

Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. In this paper we evaluated the metabolic profile of B cells isolated from the spleens of young and old mice, with the aim to identify metabolic pathways associated with intrinsic B cell inflammation and with the secretion of autoimmune antibodies.

We focused on the secretion of autoimmune antibodies because our recent human B cell results have shown that higher intrinsic inflammation in unstimulated B cells from elderly individuals induces a "pre-activation" status associated with the secretion of IgG antibodies with autoimmune specificities, similar to what has been observed in autoimmune diseases. In order to identify the B cell subsets driving the phenotype and function of B cells in the splenic B cell pool of old mice, we sorted the major splenic B cell subsets, Follicular (FO) B cells and Age-associated B cells (ABCs).

Results have shown that ABCs are the cells driving the phenotype and function of B cells in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic and supported by a specific metabolic profile needed not only to support intrinsic inflammation but also autoimmune antibody secretion. Our results allow the identification of a relationship between intrinsic inflammation, metabolism and autoimmune B cells, advancing our understanding of critical mechanisms leading to the generation of pathogenic B cells.

Pathogenic B cells that are hyper-inflammatory and secrete autoimmune antibodies can also induce pro-inflammatory T cells in both mice and humans, and it has been shown that immunotherapy of autoimmune (rheumatoid arthritis) patients with anti-CD20 antibody not only specifically depletes B cells, but also blocks glucose uptake and usage in T cells and impairs the differentiation of pathogenic T cells, leading to an improved health condition.

Link: https://doi.org/10.1186/s12979-021-00222-3

Patterns of epigenetic regulation of gene expression (and thus RNA and protein levels) change constantly in response to cell state and environment. Some of those changes are characteristic responses to the damage and dysfunction of aging. Since the demonstration of the first epigenetic clocks, those that predict age based on an algorithmic combination of the status of DNA methylation at CpG sites on the genome, researchers have produced any number of new clocks based on mining epigenomic, transcriptomic, proteomic, and other databases for correlations with age. Today's open access paper is yet another example of a new transcriptomic clock.

It remains the case that in none of these clocks is there is a good, well understood connection between specific mechanisms of aging and specific components of the clock algorithm. This makes it hard to make good use of aging clocks: it isn't at all clear that any given result is meaningful. If one applies a potentially rejuvenating or age-slowing intervention, and it produces a change in the clock measurements taken before and afterward treatment, what does that change mean? Is a drop in measured age a sign that the therapy is great, or a sign that the clock is overly weighted towards the subset of mechanisms of aging that are targeted by the intervention? If the clock shows little to no change, does that mean the therapy is useless, or the clock is unhelpful for this class of intervention? And so forth.

Thus clocks and therapies will have to be calibrated against one another in order to make the clocks useful. This process is only in the earliest stages, where it is occurring at all. As matters progress, this calibration will most likely mean running the slow, costly life span studies that we'd all like to avoid by using the clocks instead. There is no free lunch here.

BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy

Aging biomarkers that predict the biological age of an organism are important for identifying genetic and environmental factors that influence the aging process and for accelerating studies examining potential rejuvenating treatments. Diverse studies tried to identify biomarkers and predict the age of individuals, ranging from proteomics, transcriptomics, the microbiome, frailty index assessments to neuroimaging, and DNA methylation. Currently, the most common predictors are based on DNA methylation. The DNA methylation marks themselves might influence the transcriptional response, but aging also affects the transcriptional network by altering the histone abundance, histone modifications, and the 3D organization of chromatin. The difference in RNA molecule abundance, thereby, integrates a variety of regulation and influences resulting in a notable gene expression change during the lifespan of an organism. These changes sparked interest in the identification of transcriptomic aging biomarkers, an RNA expression signature for age classification, and the development of transcriptomic aging clocks.

While a large variety of data, techniques, and analyses have been used to identify aging biomarkers and aging clocks in humans, issues remain with regard to pronounced variability and difficulties in replicability. Indeed, a recent analysis of gene expression, plasma protein, blood metabolite, blood cytokine, microbiome, and clinical marker data showed that individual age slopes diverged among the participants over the longitudinal measurement time and subsequently that individuals have different molecular aging pattern, called ageotypes. These interindividual differences show that it is still difficult to pinpoint biomarkers for aging in humans.

Model organisms, instead, can give a more controllable view on the aging process and biomarker discovery. Caenorhabditis elegans has revolutionized the aging field and has vast advantages as a model organism. To date, no aging clock for C. elegans has been built solely on RNA-seq data and been shown to predict the biological age of diverse strains, treatments, and conditions to a high accuracy. In this study, we build such a transcriptomic aging clock that predicts the biological age of C. elegans based on high-throughput gene expression data to an unprecedented accuracy. We combine a temporal rescaling approach, to make samples of diverse lifespans comparable, with a novel binarization approach, which overcomes current limitations in the prediction of the biological age. Moreover, we show that the model accurately predicts the effects of several lifespan-affecting factors such as insulin-like signaling, a dysregulated miRNA regulation, the effect of an epigenetic mark, translational efficiency, dietary restriction, heat stress, pathogen exposure, the diet-, and dosage-dependent effects of drugs.

This combination of rescaling and binarization of gene expression data therefore allows for the first time to build an accurate aging clock that predicts the biological age regardless of the genotype or treatment. Lastly, we show how our binarized transcriptomic aging (BiT age) clock model has the potential to improve the prediction of the transcriptomic age of humans and might therefore be universally applicable to assess biological age.

Mitochondrial uncoupling diverts the output of the electron transport chain into heat rather than the production of ATP. Induction of higher than usual levels of uncoupling is a calorie restriction mimetic strategy: it produces some of the same gains in health and longevity as the practice of calorie restriction, with some overlap in the processes affected and metabolic changes produced. Historically, the only available pharmacological approach to increased uncoupling, 2,4-dinitrophenol (DNP), has been regarded, correctly, as dangerous. Take a little too much and you will die, because your mitochondria generate enough heat to raise your body temperature to a lethal level. In recent years some progress has been made in finding safe ways to achieve the goal of mild, self-limiting mitochondrial uncoupling, but it is a little early to say how well these will fare as therapies.

In the past few years, there's been something of a renaissance in the mitochondrial uncoupling space. In 2019, the FDA gave Mitochon Pharmaceuticals permission to test DNP as a treatment for Huntington's disease. Mitochondrial energy production generates various toxic byproducts which make neurological diseases worse, and making the mitochondria less efficient might produce fewer of them. They suggest they might have some way of giving it as a prodrug with fewer side effects, but pharma companies are always saying this sort of thing.

Last year, an Australian team published a paper about a new mitochondrial uncoupler, BAM-15. They claim it's non-toxic, doesn't explode, and doesn't increase body temperature (all uncouplers produce heat, but the body has a certain capacity to adjust for that, and if the heat produced is below the body's adjustment capacity there's no fever). Everyone involved works for Continuum Biosciences, an ambitious-looking biotech startup including anti-aging expert David Sinclair, so I'm sure they're not missing the implications. But I haven't seen any clear signs of where they're going with this.

Closer to home, a team from UCSF recently figured out the specifics of natural mitochondrial uncoupling. All mitochondria contain certain uncoupling proteins - think of them as doors, in contrast to 2,4-DNP punching holes in the wall - for generating heat. These are well-understood in brown fat, a special kind of fat used to maintain body temperature, but most of the rest of the body is a mystery. The new paper suggests that uncoupling in other cells is orchestrated by the mitochondrial ADP/ATP carrier, a protein which helps shuffle the "depleted cellular battery" ADP into the mitochondria and the "recharged cellular battery" ATP out of it. At the same time, it lets a few protons escape the positively-charged side, uncoupling the mitochondrion a little bit. Depending on the relative level of ADP on either side, it might let more or fewer protons through. This forms a feedback loop that raises or lowers the level of uncoupling depending on the level of ATP in the cell.

This is a natural biological process - it's part of how your body generates heat. It seems pretty safe - if there's too little ATP, the feedback loop kicks in and closes the doors. A drug that modified this process could potentially replicate the fat-burning properties of DNP without its side effects. And if they targeted it to be a little less intense than DNP, it wouldn't be able to reach the point where it caused deadly fevers either. This group also hasn't missed the implications - they've started Equator Therapeutics, a biotech company focused on developing drugs to hit this target.

Link: https://astralcodexten.substack.com/p/shilling-for-big-mitochondria

CAR-T immunotherapy involves equipping T cells extracted from a patient with a chimeric antigen receptor (CAR), expanding them in culture, and then reintroducing these genetically engineered T cells into the patient. The artificial receptor allows the T cells to aggressively respond to the patient's cancer, as it is targeted to a cell surface feature that is characteristic of cancer cells. Different cancers have different features, and thus different CARs are used. CAR-T therapies were first trialed for blood cancers, and continue to do well on this front, as noted here.

A CAR T-cell therapy has generated deep, sustained remissions in patients who had relapsed from several previous therapies, an international clinical trial has found. The trial leaders report that almost 75% of the participants responded to the therapy, known as idecabtagene vicleucel (ide-cel), and one-third of them had a complete response, or disappearance of all signs of their cancer. These rates, and the duration of the responses, are significantly better than those produced by currently available therapies for patients with multiple relapses.

Multiple myeloma is a cancer of plasma cells, which are white blood cells responsible for making antibodies against invasive germs. Standard treatment for myeloma includes three main classes of therapy: immunomodulatory drugs, proteasome inhibitors (which block the action of protein-degrading structures in cells), and anti-CD38 antibodies. Patients who exhaust these approaches are in urgent need of better treatments. Like all CAR T-cell therapies, ide-cel is made by collecting a patient's T cells and genetically modifying them to express a receptor for a protein on cancer cells. Infused back into the patient, the CAR T cells lock onto tumor cells and destroy them.

The target of ide-cel is a protein on myeloma cells called B-cell maturation antigen, or BCMA. BCMA has several advantages as a therapeutic target in myeloma: It is expressed exclusively on plasma cells and in particularly large quantities on plasma-turned-myeloma cells; BCMA conducts signals important for myeloma growth and survival; and it is expressed in virtually all patients with the disease.

In the trial, 128 patients with active myeloma after receiving at least three previous therapies were treated with a single dose of ide-cel (different doses were tested in different patients). At a median follow-up of 13.3 months, 73% of the patients had a response - a measurable reduction in their cancer - and 33% had a complete response or better. Within this latter group, 79% had no detectable myeloma. The median progression-free survival - the length of time after treatment that the disease didn't worsen - was 8-9 months. Some of the patients have not relapsed more than two years after treatment.

Link: https://www.dana-farber.org/newsroom/news-releases/2021/car-t-cell-therapy-generates-lasting-remissions-in-patients-with-multiple-myeloma/

There is much debate these days over the contribution of persistent infection (such as by herpesviruses) to the development of Alzheimer's disease. Not everyone with the evident risk factors, such as obesity, frailty, chronic inflammation, and so forth, progresses from mild cognitive impairment to full blown Alzheimer's disease. Why is this? The state of viral infection and the ability of any given aged immune system to contain that infection could be the variables needed to explain why Alzheimer's disease is only prevalent rather than universal. Despite the results presented in today's open access study, the epidemiological evidence to date is mixed and contradictory regarding a significant role for herpesviruses in Alzheimer's risk.

The infection-senescence hypothesis suggests that a burden of infection results in a raised pace of creation of senescent cells, particularly in the immune system, including the immune cell populations of the brain. Over time, this overwhelms the systems responsible for clearing senescent cells. When too many senescent cells accumulate, all actively secreting pro-inflammatory signals, they collectively produce a self-sustaining state of chronic inflammation. That unresolved inflammation disrupts normal tissue function in many ways - and Alzheimer's disease is known to have a strong inflammatory component.

An alternative view is that persistent infection ramps up the generation of amyloid-β, in its role as an antimicrobial peptide, a component of the innate immune system. The early, preclinical stages of Alzheimer's disease are characterized by a slow accumulation of misfolded amyloid-β in the brain, and the amyloid cascade hypothesis is the dominant explanation for why the disease occurs: in essence, amyloid-β aggregates cause enough dysfunction and inflammation to trigger the later pathologies of the condition. Why do some people accumulate more amyloid-β than others? Perhaps because they have a greater burden of persistent infection. But again, a conclusive weight of evidence for this viewpoint has yet to emerge.

Herpesvirus infections, antiviral treatment, and the risk of dementia - a registry-based cohort study in Sweden

There is growing evidence to support the link between herpes infections and Alzheimer's disease (AD). Targeting herpesviruses with specific antiviral agents could provide new AD treatment possibilities if a preventive effect is confirmed. Herpes simplex virus type 1 (HSV1) is the herpesvirus most strongly associated with AD. Several population-based cohort studies have demonstrated an increased risk of AD development for carriers of HSV1. Both in vivo and in vitro, inoculation with HSV1 among other pathogens causes AD-related changes with amyloid deposition.

Another neurotropic member of the Herpesviridae family implicated in dementia development is varicella zoster virus (VZV). Herpes zoster ophthalmicus is a subtype of the herpes zoster infection that affects the ophthalmic division of the trigeminal nerve. VZV infection of the central nervous system (CNS) has previously been linked to long-term cognitive decline. Recent data suggest that herpes zoster ophthalmicus and herpes zoster infection are associated with a 3.0- and 1.1-fold increased risk of dementia development. It has been hypothesized that in the event of herpes zoster ophthalmicus, the virus more frequently spreads to the brain, thereby explaining a stronger association with dementia development.

Previous findings have indicated a potential protective role of antiviral treatment against dementia development, and these results need to be corroborated in other large-scale cohorts. The aim of this study was to investigate whether specific antiviral treatment targeting herpesviruses and herpes infection with VZV and HSV, in absence of treatment, affects the risk of subsequent dementia in a large registry-based cohort in Sweden. The matched cohort study followed 265,172 subjects with herpes diagnoses and antiviral treatment, and the same number of controls.

Individuals with herpes diagnoses who did not receive antiviral treatment had higher incidence rates of dementia compared to their controls (12.9 and 10.2 per 1000 person-years, respectively). In contrast, herpes-diagnosed subjects who received antiviral treatment had lower incidence rates of dementia than their controls (8.5 and 9.4 per 1000 person-years, respectively). Last, the dementia incidence rates of antiviral users irrespective of diagnosis and their controls were 6.6 and 7.4 per 1000 person-years, respectively). Specific antiviral treatment targeting herpesviruses was associated with an 11% risk reduction of dementia. In contrast, having received a herpes diagnosis without antiviral treatment was associated with a 50% increased risk of dementia compared to controls. These results are in line with previous register-based studies indicating the potential protective role of antiviral treatment in dementia.

The control group in this study comprised both seropositive and seronegative individuals as the seropositivity status of the subjects is unknown, especially considering that approximately 70% of the population could be expected to carry HSV1 and more than 95% VZV. It is reasonable to assume that the controls probably have better immunological resilience to herpes infections with fewer episodes of symptomatic reactivations because they have not received a herpes diagnosis or been subjected to specialist medical care for this. Importantly, the herpes diagnoses primarily reflect symptomatic reactivation or primary infection with overt signs. Thus, the individuals with herpes diagnoses constitute a subgroup of those carrying the pathogen.

It is comparatively easy to build companies that sell customized mixes of various supplements shown to modestly slow aging in mice, and the same goes for companies that offer personalized advice on health matters relating to aging. Neither of these options are going to do much to meaningfully extend the healthy human life span. As participation in the longevity industry grows, it will inevitably be the case that a great many participants will gravitate towards safer businesses and returns on investment, while doing very little to change the healthy human life span. I feel that we shouldn't encourage this sort of behavior. We all have only so much time left, and we have been given the opportunity to produce actual, working rejuvenation therapies by implementing the SENS programs to repair the cell and tissue damage that causes aging. We can collectively reach for that goal, or we can collectively waste our time working on yet another round of overhyped supplements that cannot move the needle on human life span. It is a very real choice, with very real consequences.

Switzerland is now home to what claims to be the country's first longevity company builder. Maximon will start several companies each year, providing what it calls "a comprehensive set of resources that empowers founders to focus on and create superior services and products and execute at speed on a global scale." Maximon says it plans to allocate more than $50 million over the next four years and to raise a larger longevity focused fund thereafter. The company is already in the process of building its first two companies, one focused on the development of precision longevity supplements and the other on the development of a digital platform for the provision of personalised longevity advice.

"The real difference is that we really build the companies from scratch, not just incubation or early seed money. We start with ideas, form the teams, bring the people together, give them money, and everything. Founders don't have to think about fundraising, we do that here, they don't have think about finding offices, we provide workspace and equipment, the HR is done, the insurance is done, and so on. I think that we're the first ones to do this in longevity." The Maximon principals believe that this approach will benefit the start-ups to emerge from Maximon, both in terms of speed of execution, but also in terms of equity.

While the idea for getting into the longevity area had been in their minds for several years, the Maximon principals say that the coronavirus pandemic provided the time needed for the co-founders to start making things happen - starting with last October's Longevity Investors Conference. "After the success of the conference, we thought about what else we could do. We knew that we were good at building companies and identifying what you can do with certain technologies in the market, and so out of this conference, the idea was born to start a company builder." Things have moved quickly since then, and the founders have assembled an initial $6 million to get things started with the first two companies in the Maximon family. After raising the rest of the $50 million or more, Maximon will be in a position to support the creation of eight to 10 new companies over the next few years.

Link: https://www.longevity.technology/swiss-longevity-company-builder-launches/

Epigenetic age acceleration is the degree to which epigenetic age is higher than chronological age. Epigenetic age is assessed via one of the epigenetic clocks, measuring the status of DNA methylation at numerous CpG sites on the genome. Some changes in DNA methylation patterns are characteristic of aging, a reaction to the accumulation of damage and dysfunction in aged tissues. People with lower epigenetic ages are, on balance, less burdened by the damage and dysfunction of aging than their peers. The caveat is that it is not yet understood what exactly causes any specific change in the patterns of DNA methylation, and thus while correlations with health and mortality risk show up quite reliably in study populations, one cannot yet draw much of a conclusion from the data for any given individual. A measurement of epigenetic age isn't yet actionable, and does little other than reinforce the general sentiment of "work to improve your health".

In 2010, the American Heart Association defined the construct of ideal cardiovascular health (CVH) as the simultaneous presence of 7 ideal health factors: healthy diet, absence of smoking, healthy body mass index (BMI), and optimal levels of physical activity, blood pressure, fasting glucose, and total cholesterol. Higher levels of CVH have been prospectively associated with greater longevity and healthy longevity, as well as markedly lower incidence of chronic diseases related to aging. Higher CVH is also associated with lower incidence of cardiovascular disease.

DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age. Thus we performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score.

We examined the association between CVH score and EAA adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (6 months younger age per 1 point higher CVH score), and lower intrinsic EAA (3 months younger age per 1 point higher CVH score). This work provides initial evidence for epigenetic age acceleration to be considered as a potential early detection biomarker for CVH. Future studies are needed to evaluate if measures to promote optimal CVH through lifestyle and behavioral interventions could substantially alter an individual's epigenetic signature and the clinical utility of such a signature

Link: https://doi.org/10.1186/s13148-021-01028-2

Cell therapies for Parkinson's disease have been under development for a very long time indeed, decades at this point. The condition is characterized by aggregation of α-synuclein and loss of the small but critical population of dopamine-generating neurons in the brain. The latter is the proximate of cause of the loss of motor control and depression observed in patients. These cells are particularly sensitive to the combination of toxic α-synuclein biochemistry, mitochondrial dysfunction, chronic inflammation, and other contributing factors that manifest in this condition - and in aging in general. The motivation for a cell therapy approach to Parkinson's disease is the replacement of these lost cells, and thus restoration of the supply of dopamine in the brain.

Cell therapy has proven challenging to implement sufficiently well for widespread use in the case of Parkinson's disease. Early attempts used fetal cells, while later attempts produced neurons from embryonic stem cells and then induced pluripotent stem cells. A recent small trial used cell reprogramming to generate neurons for transplantation from a patient's own cells. This is the end goal, a therapy with patient-matched cells that are generated to order and have minimal risk of rejection. Things move very slowly in this part of the field, however, as demonstrated by the animal study discussed in today's research materials. This project has been ongoing for a decade in order to produce results in non-human primates, wile it has been more than thirty years since the first fetal cell transplants were carried out in human trials for Parkinson's disease.

Individualized brain cell grafts reverse Parkinson's symptoms in monkeys

Parkinson's disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate muscles for even simple movements and cause rigidity, slowness, and tremors that are the disease's hallmark symptoms. Patients - especially those in earlier stages of Parkinson's - are typically treated with drugs like L-DOPA to increase dopamine production.

Scientists have tried with some success to treat later-stage Parkinson's in patients by implanting cells from fetal tissue, but research and outcomes were limited by the availability of useful cells and interference from patients' immune systems. Researchers have instead spent years learning how to dial donor cells from a patient back into a stem cell state, in which they have the power to grow into nearly any kind of cell in the body, and then redirect that development to create neurons. "The idea is very simple. When you have stem cells, you can generate the right type of target cells in a consistent manner. And when they come from the individual you want to graft them into, the body recognizes and welcomes them as their own."

The application was less simple. More than a decade in the works, the new study began in earnest with a dozen rhesus monkeys several years ago. A neurotoxin was administered - a common practice for inducing Parkinson's-like damage for research - and researchers evaluated the monkeys monthly to assess the progression of symptoms. During the course of the Parkinson's study, the researchers injected millions of dopamine-producing neurons and supporting cells into each monkey's brain in an area called the striatum, which is depleted of dopamine as a consequence of the ravaging effects of Parkinson's in neurons. Half the monkeys received a graft made from their own induced pluripotent stem cells (called an autologous transplant). Half received cells from other monkeys (an allogenic transplant). And that made all the difference.

Within six months, the monkeys that got grafts of their own cells were making significant improvements. Within a year, their dopamine levels had doubled and tripled. The monkeys who received allogenic cells showed no such lasting boost in dopamine or improvement in muscle strength or control, and the physical differences in the brains were stark. The axons - the extensions of nerve cells that reach out to carry electrical impulses to other cells - of the autologous grafts were long and intermingled with the surrounding tissue.

Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys

Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues.

Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.

Researchers here discuss, in some detail, what is known of age-related changes in the levels of various lipid molecules in cell membranes. There is evidence for these changes to be disruptive to cell function, and thus a meaningful contribution to age-related degeneration. Like many of the areas of interest in the study of aging, this has the look of a form of disarray that is downstream of the molecular damage that lies at the root of aging. Nonetheless, it is suggested that supplementing the levels of specific lipids, where they decline with age, may be beneficial enough to be worth the effort.

Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid), and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA, and DHA, and their metabolites.

LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements, and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA, and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA, and DHA noted in these conditions are due to the decreased activity of desaturases and elongases.

PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA, and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs, PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity, and PGC1-α. This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-LOX, 12-LOX, and 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.

Link: https://doi.org/10.3390/biom11020241

Epidemiological data for the Tsimane and Moseten populations in Bolivia shows that they suffer very little cardiovascular disease in later life, despite a presumably greater lifetime burden of infectious disease (and consequent inflammation) than is the case for people in wealthier regions. The differences in lifestyle are fairly straightforward: a much greater level of physical activity throughout life, and a diet that is high in fiber and low in all of the terrible things, like processed sugars, that people in the wealthier regions of the world tend to consume these days.

Atrial fibrillation is the most common arrhythmia in post-industrialized populations. Older age, hypertension, obesity, chronic inflammation, and diabetes are significant atrial fibrillation risk factors, suggesting that modern urban environments may promote atrial fibrillation. Here we assess atrial fibrillation prevalence and incidence among tropical horticulturalists of the Bolivian Amazon with high levels of physical activity, a lean diet, and minimal coronary atherosclerosis, but also high infectious disease burden and associated inflammation.

Between 2005-2019, 1314 Tsimane aged 40-94 years (52% female) and 534 Moseten Amerindians aged 40-89 years (50% female) underwent resting 12-lead electrocardiograms to assess atrial fibrillation prevalence. For atrial fibrillation incidence assessment, 1059 (81% of original sample) Tsimane and 310 Moseten (58%) underwent additional electrocardiograms. Only one (male) of 1314 Tsimane (0.076%) and one (male) of 534 Moseten (0.187%) demonstrated atrial fibrillation at baseline. There was one new (female) Tsimane case in 7395 risk years for the 1059 participants with greater than 1 electrocardiogram (incidence rate = 0.14 per 1,000 risk years). No new cases were detected among Moseten, based on 542 risk years.

Tsimane and Moseten show the lowest levels of atrial fibrillation ever reported, 1/20 to ~1/6 of rates in high-income countries. These findings provide additional evidence that a subsistence lifestyle with high levels of physical activity, and a diet low in processed carbohydrates and fat is cardioprotective, despite frequent infection-induced inflammation. Findings suggest that atrial fibrillation is a modifiable lifestyle disease rather than an inevitable feature of cardiovascular aging.

Link: https://doi.org/10.5334/aogh.3252

Cell reprogramming can be achieved by gene therapies that express pluripotency genes - some or all of the Yamanaka factors. It is akin to the process that takes place in the early stages of embryonic development, and which removes the mitochondrial dysfunction and epigenetic alterations found in old tissues. Although germline cells are already very well protected, this extra step is necessary in order for children to be born physiologically young.

Cell reprogramming has largely been used to produce induced pluripotent stem cells, an important tool in the field of regenerative medicine and tissue engineering. In recent years, however, researchers have started to deploy cell reprogramming gene therapies in animal studies, finding the potential to achieve reversal of at least some markers of aging. Mitochondrial function and epigenetic regulation of gene expression are the targets of greatest interest, and this is giving new energy to the minority faction in the research community who think of aging as an evolved epigenetic program.

To my eyes, epigenetic change looks like a downstream outcome of deeper processes of aging, such as repeated cycles of DNA damage and repair, perhaps. Raised blood pressure is also a downstream consequence, but reduced mortality in older people can be achieved via forced control of blood pressure, implemented without addressing the underlying causes. Will reversal of epigenetic change prove to be a better version of blood pressure control, so to speak? A greater possible gain for health, while still leaving the underlying causes of aging to produce other harms? That remains to be seen.

There are clearly issues that cannot be solved by success in the application of reprogramming to reverse age-related epigenetic alterations. Many forms of harmful metabolic waste (persistent cross-links, lipofuscin components, and the like) cannot be broken down effectively even in youthful cells and tissues. Nuclear DNA damage and somatic mosaicism cannot be erased by rejuvenating cells. Cancerous and senescent cells should be destroyed, not rejuvenated. And so forth.

Aging and rejuvenation - a modular epigenome model

Gerontology is perhaps the biological discipline that has given rise to the largest number and variety of theories even before the development of modern science. Most theories aimed not only at elucidating the mechanism of aging but also at providing effective interventions to slow aging down. In the late 1950s the focus of research attention moved to DNA as the likely driver of aging either by expressing a program of aging or by being the target of endogenous and external insults that accumulated damage on the molecule during the lifetime of an organism. Up to this stage, aging was considered as an essentially irreversible process. However, with the discovery of cell reprogramming, early in this century, a view began to emerge that considers aging as a reversible epigenetic process.

The hypothesis proposing the epigenome as the driver of aging was significantly strengthened by the converging discovery that DNA methylation at specific CpG sites could be used as a highly accurate biomarker of age defined by the Horvath clock. The strong correlation between the dynamics of DNA methylation profiles and the rate of biological aging leads to the idea that the epigenetic clock may in fact be the pacemaker of aging or at least a component of it. And it is at this point where epigenetic rejuvenation comes into play as a strategy to reveal to what extent biological age can be set back by making the clock tick backwards.

The few initial results already documented seem to suggest that when the clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. Nevertheless, it would be premature to draw firm conclusions from the scanty experimental results so far documented. What seems to be clear is that epigenetic rejuvenation by cyclic partial reprogramming or alternative non-reprogramming strategies holds the key to both understanding the mechanism by which the epigenome drives the aging process and arresting or even reversing organismal aging.

A well established field of research is focused on the development of implantable scaffold materials to encourage regeneration of lost tissue, such as in the case of severe muscle injuries. A wide variety of scaffold approaches incorporate signaling molecules and increasingly sophisticated small-scale structure, all intended to mimic aspects of the natural extracellular matrix, as well as other features. Use of a natural extracellular matrix is also an option, via decellularization of donor tissue. A great deal of innovation is taking place. As an example, researchers here combine a scaffolding approach with cell reprogramming to demonstrate muscle regrowth in an animal model.

In serious injuries such as those sustained in car accidents or tumor resection which results in a volumetric muscle loss (VML), the muscle's ability to recover is greatly diminished. A promising strategy to improve the functional capacity of the damaged muscle is to induce de novo regeneration of skeletal muscle via the integration of transplanted cells. Diverse types of cells, including satellite cells (muscle stem cells), myoblasts, and mesenchymal stem cells, have been used to treat muscle loss.

An important issue is controlling the three-dimensional microenvironment at the injury site to ensure that the transplanted cells properly differentiate into muscle tissues with desirable structures. A variety of natural and synthetic biomaterials have been used to enhance the survival and maturation of transplanted cells while recruiting host cells for muscle regeneration. However, there are unsolved, long-lasting dilemmas in tissue scaffold development. Natural scaffolds exhibit high cell recognition and cell binding affinity, but often fail to provide mechanical robustness in large lesions or load-bearing tissues that require long-term mechanical support. In contrast, synthetic scaffolds provide a precisely engineered alternative with tunable mechanical and physical properties, as well as tailored structures and biochemical compositions, but are often hampered by lack of cell recruitment and poor integration with host tissue.

To overcome these challenges, a research team has devised a novel protocol for artificial muscle regeneration. The team achieved effective treatment of VML in a mouse model by employing direct cell reprogramming technology in combination with a natural-synthetic hybrid scaffold. Direct cell reprogramming, also called direct conversion, is an efficient strategy that provides effective cell therapy because it allows the rapid generation of patient-specific target cells using autologous cells from the tissue biopsy. Fibroblasts are the cells that are commonly found within the connective tissues, and they are extensively involved in wound healing. As the fibroblasts are not terminally differentiated cells, it is possible to turn them into induced myogenic progenitor cells (iMPCs) using several different transcription factors. Herein, this strategy was applied to provide iMPC for muscle tissue engineering.

In order to provide structural support for the proliferating muscle cells, polycaprolactone (PCL), was chosen as a material for the fabrication of a porous scaffold due to its high biocompatibility. However, the synthetic PCL fiber scaffolds alone do not provide optimal biochemical and local mechanical cues that mimic muscle-specific microenvironment. Hence the construction of a hybrid scaffold was completed through the incorporation of decellularized muscle extracellular matrix (MEM) hydrogel into the PCL structure.

The resultant bioengineered muscle fiber constructs showed mechanical stiffness similar to that of muscle tissues and exhibited enhanced muscle differentiation and elongated muscle alignment in vitro. Furthermore, implantation of bioengineered muscle constructs in the VML mouse model not only promoted muscle regeneration with increased innervation and angiogenesis but also facilitated the functional recovery of damaged muscles.

Link: https://www.ibs.re.kr/cop/bbs/BBSMSTR_000000000738/selectBoardArticle.do?nttId=19669

Calcification of tissues is one of the mechanisms by which stiffening occurs in the cardiovascular system, leading to a range of increasingly serious downstream consequences. The evidence of recent years suggests that chronic inflammation and the harmful signaling of senescent cells are a major cause of cells in blood vessel walls inappropriately taking on osteoblast-like behavior, depositing calcium into the extracellular matrix as though they are building bone. Among the many other consequences, this process damages the elastin molecules in areas in which it occurs, and the approach taken by biotech startup Elastrin Therapeutics is to use that damage as a target in order to deliver nanoparticles that will remove the calcification. It is an interesting approach.

Elastrin, a biotechnology start-up leveraging a platform technology to develop therapeutics that render calcified tissue and organs supple again, will receive seed funding from Kizoo Technology Capital. It is the latest addition to the growing portfolio of Kizoo, a rejuvenation biotech investor focused on reversing age-related damage on a cellular and molecular level. Elastrin's lead asset is a nanoparticle conjugated with a novel monoclonal antibody to treat heart valve and vascular calcification. The platform targets and restores degraded elastin by removing the harmful calcification that stiffens arteries, improving the efficacy of drugs and eliminating side-effects by combining particle design with elastin targeting.

"Elastin fibers are critical for the homeostasis of tissues around the body, including the skin, vasculature, and pulmonary tissues. As elastin fibers become damaged over time, arterial walls weaken, and the body's physiological response results in aortic wall stiffening, aneurysms, and hypertension." The Elastrin team has developed a platform that can restore vascular health by removing pathological calcification, specifically from sites where elastin has been degraded. This is achieved via targeting albumin nanoparticles loaded with therapeutic agents directly to the tissue site of interest with the company's anti-elastin monoclonal antibody.

"Cardiovascular diseases are the number one cause of death globally, taking an estimated 18 million lives each year. On top of that, everyone above 30 years old is suffering from damage to the cardiovascular system, resulting in severe symptoms one day. Our technology can reverse damage to the arteries and heart and bring the body back to a state before the damage even occurred. This is a true game-changer in the industry and one of the puzzle pieces towards healthy aging. Nobody wants to live forever in an old and sick body, but we do want to live long in a healthy one."

Link: https://www.longevity.technology/elastrin-limbers-up-for-success-with-kizoo-funding-boost/

Every compound and aspect of biology has a dose-response relationship of some sort. Wildly different outcomes should be expected at different levels of a drug, different degrees of expression of a protein, differing activity of a signaling pathway. What is a beneficial therapy at one dose is a toxin at another. A great many toxic substances and ostensibly harmful processes that damage the mechanisms of a cell are in fact beneficial at low doses, thanks to the hormetic response. A cell senses damage and engages a greater activity of its repair and maintenance processes, such as autophagy. The result is a net gain in cell maintenance. A mild stress, repeated infrequently, can improve cell function, tissue function, and, as a consequence, overall health and life span.

This underlies much of the observed complexity of the interaction between oxidative molecules and aging. In old age, there is an excess of oxidative molecules, reactive oxygen species, as a result of mitochondrial dysfunction, chronic inflammation, and other issues that provoke a greater generation of oxidative stress. This is harmful, it is past the point at which any benefit occurs. Interventions that greatly increase oxidative stress in animal models shorten life span. But there are many examples of genetic alterations in short-lived species in which a mild increase in the output of reactive oxygen species by mitochondria results in a gain in life span. Similarly, many of the metabolic improvements of exercise are provoked by raised mitochondrial generation of reactive oxygen species, as they work harder to provide energy to muscles.

For cells, an increase in reactive oxygen species is both a signal to undertake beneficial activities, and a harm that must be defended against by antioxidants and repair of damaged molecules. The two are tied together. The outcome depends on the dose, a dose that rises steadily with age as damage and dysfunction overtakes the biological systems of the body.

Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies

Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration, and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging.

To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation.

Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan.

Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.

There is an increased interest in the mitochondrial permeability transition pore as a target for interventions that might improve mitochondrial function in aging. Mitochondria are the power plants of the cell, bacteria-like factories that package the chemical energy store molecule ATP via an energetic process of reactions. Mitochondria become dysfunction in aged tissues for reasons that include changes in their ability to divide and fuse together, and a faltering in the quality control mechanism of mitophagy. This loss of function is particularly important in the aging of energy-hungry tissues such as the muscles and brain.

The research community is at present largely focused on trying to reverse specific symptoms of mitochondrial dysfunction, such as lower NAD+ levels, or changes in gene expression related to mitochondrial dynamics, or changes in mitochondrial permeability transition pore behavior. It isn't clear as to how effective these options will turn out to be, whether they are targeted close enough to the root of the problem to make a meaningful difference. There are also efforts to replace mitochondria, or eliminate those that are dysfunctional, and copy mitochondrial genes to the cell nucleus as a backup source of necessary proteins for mitochondrial function. These will probably be better approaches, but these are still comparatively early days in which there is all too little data for efficacy.

A better understanding of the cellular and molecular mechanisms underlying aging is central to the successful development and clinical translation of novel therapies and prevention strategies. Recent work has demonstrated that changes in mitochondrial permeability transition pore (mPTP) function may contribute directly to cellular dysfunction with aging. These changes include increases in reactive oxygen species (ROS) production, induction of cellular senescence (particularly in aging stem cells), and activation of the inflammasome, the latter contributing directly to the chronic state of inflammation often referred to as "inflammaging". mPTP dysfunction has been cited as a key factor in neurodegenerative pathologies through its role in collapsing mitochondrial membrane potential, repressing mitochondrial respiratory function, releasing mitochondrial Ca2+ and cytochrome c, and enhancing ROS generation. Thus, the mPTP has received increased attention as a potential therapeutic target.

The relationship between the mPTP and the generation of mitochondrial reactive oxygen species (mROS) has attracted significant interest within the context of aging and age-related tissue degeneration. Recently, it was found that mROS can stimulate the opening of the mPTP, which can lead to further mROS production and release. This positive feedback mechanism ultimately leads to an excessive amount of ROS accumulation. ROS accumulation in turn damages nuclear DNA, activates pro-apoptotic signaling pathways, and drives cellular aging. On the other hand, ROS can in some cases activate protective pathways, decrease stress on the mitochondria, and increase lifespan. It is currently thought that the mPTP plays an important role in integrating the effects of mROS and hence may play a vital role in the aging process. In this review, we discuss the various mechanisms inducing activation of the mPTP and the age-associated cell damage seen as a byproduct of mPTP activation. Furthermore, we discuss potential therapies that target the mPTP and may therefore inhibit the effects of aging and injury.

Link: https://doi.org/10.1155/2021/6626484

The measurement of biological rather than chronological age is a goal for many research groups. Numerous approaches are under development, and the levels of a wide variety of compounds in the blood have been found to vary with advancing age. The example here, neurofilament light chain, is just one of many. A robust biomarker of biological age, measuring the burden of many different forms of cell and tissue damage, as well as their downstream consequences, will likely be a combination of numerous different measures.

Neurofilament light chain (NfL) is a structural protein found in nerve cells. The nervous system has been implicated in aging and longevity, so the fact that NfL can be detected in human bodily fluids makes it potentially useful as a biomarker for aging. NfL levels are known to increase with age and in response to neurodegenerative diseases, strengthening the case for its use as a biomarker.

To test the idea, an international team of scientists measured NfL levels in blood plasma from a cohort of people aged 21 to 107. They found a non-linear increase and greater variability with age. Plasma proteome data had already been generated from the same cohort, and NfL levels correlated with 53 of the proteins (out of roughly 1300). The proteins correlated with NfL levels are involved in apoptosis as well as synapse formation and plasticity, supporting the notion that plasma NfL levels reflect the activity of pathways associated with neuronal function.

The researchers then evaluated NfL as a predictor of mortality. They collected blood from separate cohorts of centenarians and nonagenarians, measured NfL levels, and tracked the cohorts over the next few years (or until death). They used activities of daily living (ADL) and Mini-Mental State Examination (MMSE) measures to assess the health of the participants. Overall, individuals with lower NfL levels lived longer than those with higher levels and did better on MMSE and ADL measures, though the difference was smaller for ADL. Finally, the team also showed that NfL levels increase with age in mice and that dietary restriction, which is known to extend the lifespan of mice, brings down NfL levels.

Link: https://www.lifespan.io/news/measuring-age-with-a-bloodborne-neural-protein/

This post is a report on a self-experiment with flagellin immunization, tested as an approach to adjust the gut microbiome in a favorable direction. Flagellin is the protein that makes up bacterial flagellae, and it is hypothesized that there is a sizable overlap between populations of gut microbes that possess flagellae and populations of gut microbes that are harmful rather than helpful. The harmful microbes are largely a problem because they contribute to chronic inflammation, while helpful microbes are largely beneficial due to the metabolites that they produce. The gut microbiome changes with age, shifting towards more harmful and fewer helpful microbes.

If the immune system can be roused to do a better job of eliminating the problem microbes, then perhaps this could lead to improved health. Flagellin immunization has been trialed in humans as a vaccine adjuvant, and shown to be safe in the small studies conducted to date. Recently, researchers tested its ability to adjust the gut microbiome in mice, with favorable results. Last year I posted a study outline for a self-experiment in flagellin immunization, and this year I have a report from one adventurous self-experimenter.

Setting Expectations

The motivation for this self-experiment was curiosity: would human data be similar to the mouse data? The results here were on balance positive. This is a self-experiment in which there is an unusually clear readout for the outcome of interest, in the form of the Viome gut microbiome assay. This is nonetheless a study population of one. The results should be taken as interesting, but not supportive of any particular conclusion beyond the desire to run a larger and more formal study.

Schedule for the Self-Experiment

The self-experiment ran for ten weeks. Weekly intramuscular injections of 10 μg flagellin in 0.5ml phosphate-buffered saline were used, with Viome gut microbiome assays performed beforehand, at 10 weeks, and six months later.

• Day 0: Perform a Viome gut microbiome assessment.
• Day 1: Intramuscular injection of 10 μg of flagellin.
• Day 8: Intramuscular injection of 10 μg of flagellin.
• Day 15: Intramuscular injection of 10 μg of flagellin.
• Day 22: Intramuscular injection of 10 μg of flagellin.
• Day 29: Intramuscular injection of 10 μg of flagellin.
• Day 36: Intramuscular injection of 10 μg of flagellin.
• Day 43: Intramuscular injection of 10 μg of flagellin.
• Day 50: Intramuscular injection of 10 μg of flagellin.
• Day 57: Intramuscular injection of 10 μg of flagellin.
• Day 64: Intramuscular injection of 10 μg of flagellin.
• Day 65: Perform a Viome gut microbiome assessment.
• Day 225: Perform a Viome gut microbiome assessment.

Subject Details

The subject for the self-experiment was in the 45-50 age range, healthy and without chronic conditions, with a BMI of ~22 throughout the duration of the experiment. Diet and exercise were described as "relatively consistent" across this time, including the six month follow up assessment. I feel that one should always be relatively skeptical of that sort of claim, however, no matter how formal or informal the study.

Summary of Results

Viome does not provide raw data on species and prevalence of gut microbes and their biochemistry, but rather a set of scores derived from that raw data. The algorithm used isn't public, meaning that one can't really dispute any of their choices or the studies used to support those choices, unfortunately. The algorithm is, nonetheless, consistent between assays at different times, and so can be used as a point of comparison for the purposes of a self-experiment, at least.

Over the course of the self-experiment, Viome summary scores improved for Inflammatory Activity, Digestive Efficiency, Gut Lining Health, Protein Fermentation, and Gas Production. The summary scores declined for Metabolic Fitness and Active Microbial Diversity. The gains (largely bad scores transforming into good scores) were larger than the declines (bad scores becoming worse scores).

Viome Data

Gut Microbiome Health (overall score):
   Before: 27
   After: 43
   +6 months: 49

Inflammatory Activity (lower is better):
   Before: 50
   After: 45
   +6 months: 28
Metabolic Fitness (higher is better):
   Before: 25
   After: 29
   +6 months: 21
Digestive Efficency (higher is better):
   Before: 0
   After: 57
   +6 months: 68
Gut Lining Health (higher is better):
   Before: 12
   After: 64
   +6 months: 69
Protein Fermentation (lower is better):
   Before: 87
   After: 49
   +6 months: 33
Gas Production (lower is better):
   Before: 83
   After: 48
   +6 months: 35
Active Microbial Diversity (higher is better):
   Before: 34
   After: 15
   +6 months: 15

Ammonia Production Pathways
   Before: Not Optimal
   After: Average
   +6 months: Good
Bile Acid Metabolism Pathways
   Before: Average
   After: Good
   +6 months: Good
Biofilm, Chemotaxis, and Virulence Pathways
   Before: Not Optimal
   After: Not Optimal
   +6 months: Good
Butyrate Production Pathways
   Before: Average
   After: Average
   +6 months: Not Optimal
Flagellar Assembly Pathways
   Before: Not Optimal
   After: Not Optimal
   +6 months: Average
LPS Biosynthesis Pathways
   Before: Average
   After: Average
   +6 months: Average
Methane Gas Production Pathways
   Before: Good
   After: Not Optimal
   +6 months: Good
Oxylate Metabolism Pathways
   Before: Average
   After: Not Optimal
   +6 months: Not Optimal
Putrescine Production Pathways
   Before: Not Optimal
   After: Not Optimal
   +6 months: Average
Salt Stress Pathways
   Before: Average
   After: Average
   +6 months: Average
Sulfide Gas Production Pathways
   Before: Not Optimal
   After: Average
   +6 months: Average
TMA Production Pathways
   Before: Good
   After: Good
   +6 months: Good
Uric Acid Production Pathways
   Before: Not Optimal
   After: Not Optimal
   +6 months: Not Optimal

Anecdotal Notes

The first few injections of flagellin produced a minor injection site reaction that lasted a few days: red and tender. That was reduced with each injection, and later injections produced no reaction. Beyond that, no perceptible change in health or digestion, positive or negative, was observed as a result of the self-experiment.

Conclusion

Coupled with the animal data, and the existing human trial data for safety, the results here suggests that someone should run a formal, controlled trial of flagellin immunization in older people, 65 and over. The goal would be to see whether (a) this sort of outcome holds up in a larger group of people, and (b) there is a meaningful impact on chronic inflammation and other parameters of health that are known to be affected by the aging of the gut microbiome.

Regular exercise is very beneficial for long-term health, generating sweeping changes in metabolism and improving tissue and organ function across the board. Research suggests that present recommendations for the optimal amount of exercise are probably half or less of what they should be. Given that most people do not reach those recommendations, and all too many are entirely sedentary, there is certainly room for improvement. Studies show that structured exercise programs reverse a surprisingly large degree of age-related loss of function and mortality, a fraction of the declines of old age that is entirely self-inflicted. An era of low-cost comfort, telecommunication, and omnipresent engines of transport has allowed us to self-sabotage ourselves into losing years of health and life span.

Researchers have discovered that forces created from walking or running are transmitted from bone surfaces along arteriolar blood vessels into the marrow inside bones. Bone-forming cells that line the outside of the arterioles sense these forces and are induced to proliferate. This not only allows the formation of new bone cells, which helps to thicken bones, but the bone-forming cells also secrete a growth factor that increases the frequency of cells that form lymphocytes around the arterioles. Lymphocytes are the B cells and T cells that allow the immune system to fight infections. When the ability of the bone-forming cells to sense pressure caused by movement was blocked, it reduced the formation of new bone cells and lymphocytes, causing bones to become thinner and reducing the ability of mice to clear a bacterial infection.

The skeletal stem cells that give rise to most of the new bone cells that form during adulthood in the bone marrow. They are Leptin Receptor+ (LepR+) cells. They line the outside of blood vessels in the bone marrow and form critical growth factors for the maintenance of blood-forming cells. Researchers also found that a subset of LepR+ cells synthesize a previously undiscovered bone-forming growth factor called Osteolectin. Osteolectin promotes the maintenance of the adult skeleton by causing LepR+ to form new bone cells.

In the current study, researchers looked more carefully at the subset of LepR+ cells that make Osteolectin. They discovered that these cells reside exclusively around arteriolar blood vessels in the bone marrow and that they maintain nearby lymphoid progenitors by synthesizing stem cell factor (SCF) - a growth factor on which those cells depend. Deleting SCF from Osteolectin-positive cells depleted lymphoid progenitors and undermined the ability of mice to mount an immune response to bacterial infection. "The findings in this study show Osteolectin-positive cells create a specialized niche for bone-forming and lymphoid progenitors around the arterioles. Therapeutic interventions that expand the number of Osteolectin-positive cells could increase bone formation and immune responses, particularly in the elderly."

Link: https://www.utsouthwestern.edu/newsroom/articles/year-2021/researchers-identify-mechanism-by-which-exercise-strengthens-bones-and-immunity.html

Cancers subvert the immune system in a variety of ways, such as in order to aid growth, or suppress the immune response normally triggered by the presence of cancerous cells. Regulatory T cells are involved in halting the immune response after it is has done its job, and in preventing autoimmunity, in which the immune system attacks the body. This role is abused in cancerous tissue in order to protect the cancer from the immune system. Researchers here identify some of the controlling biochemistry that makes regulatory T cells behave differently in this scenario. The mechanism appears distinct enough, operating only in cancerous tissue, to be a good basis for the development of therapies that could in principle strip much of this protection from a cancer.

Immunologists have discovered that tumors use a unique mechanism to switch on regulatory T cells to protect themselves from attack by the immune system. Surprisingly, the mechanism does not affect regulatory T cell function outside the tumor and may therefore limit the immune-associated toxicities of targeting regulatory T cells. The finding offers the promise of drug treatment to selectively shut down regulatory T cells in a tumor, rendering the tumor vulnerable to cancer immunotherapies that activate the immune system to kill the tumor. The researchers showed that blocking tumor-associated regulatory T cell activity eliminated tumors cells in mice and sensitized the cells to cancer immunotherapy called anti-PD-1 therapy.

Researchers discovered the pathway by challenging mice with melanoma cells and then analyzing which genes were switched on in regulatory T cells. Investigators compared tumor-infiltrating regulatory T cells with regulatory T cells in other tissues to compare gene activation. The experiment revealed a master genetic switch that was activated only in regulatory T cells in the tumor microenvironment. The switch was a transcription factor family called SREBP.

The researchers determined that the tumor-specific regulatory T cell pathway was switched on in a range of cancers - melanoma, breast cancer, and head and neck cancer. The tumor-specific pathway was not switched on in animal models of inflammation or autoimmune disease. Genetically blocking the SREBP pathway selectively in regulatory T cells led to rapid clearance of tumor cells in mice with melanoma and colon adenocarcinoma. Targeting the pathway also reduced tumor growth in mice with established tumors. Blocking the pathway had no effect on the proliferation of regulatory T cells or their overall function in the body.

Link: https://www.stjude.org/media-resources/news-releases/2021-medicine-science-news/discovery-offers-potential-for-stripping-tumors-of-t-cell-protection.html

Neurogenesis is the creation and integration of new neurons into neural circuits, necessary for learning, and for the maintenance of functional brain tissue. Neural stem cells are responsible for providing a supply of new neurons, but, as is the case for stem cells throughout the body, their activity declines with age. Loss of neurogenesis is one important contributing factor in the aging of the brain. Considered at the high level, a progressive loss of stem cell activity may be an evolved response to rising levels of cell and tissue damage and dysfunction, reducing the risk of death by cancer at the cost of a slow decline into death by loss of tissue function. At the low level, scientists are digging in to the specific mechanisms involved in age-related stem cell dysfunction. Today's research materials are an example of this sort of research program, focused on neural stem cells in this case.

All stem cells produce daughter somatic cells via replication in order to maintain the tissues that they support. Stem cells practice asymmetric cell division as one of several necessary strategies needed to maintain the pace of replication over a lifetime. They unload accumulated metabolic waste and damaged components onto each new daughter somatic cell in order to keep the level of damage in the stem cell low. Researchers here identified that lamin B1 is important in ensuring this asymmetry in neural stem cells, but levels decline with age. They used a gene therapy approach to increase lamin B1 expression, thereby improving neural stem cell function and the supply of new neurons in mice.

Reactivating Aging Stem Cells in the Brain

A new study shows how the formation of new neurons is impaired with advancing age. Protein structures in the nuclei of neural stem cells make sure that harmful proteins accumulating over time are unevenly distributed onto the two daughter cells during cell division. This seems to be an important part of the cells' ability to proliferate over a long time in order to maintain the supply of neurons. With advancing age, however, the amounts of nucleic proteins change, resulting in defective distribution of harmful proteins between the two daughter cells. This results in a decrease in the numbers of newly generated neurons in the brains of older mice.

The central element in this process is a nuclear protein called lamin B1, the levels of which decrease as people age. When the researchers increased lamin B1 levels in experiments in aging mice, stem cell division improved and the number of new neurons grew. The research is part of several ongoing projects aiming to reactivate aging stem cells. The ability to regenerate damaged tissue generally declines with age, thus affecting almost all types of stem cells in the body. These latest findings are an important step towards exploring age-dependent changes in the behavior of stem cells. "We now know that we can reactivate aging stem cells in the brain. Our hope is that these findings will one day help increase levels of neurogenesis, for example in older people or those suffering from degenerative diseases such as Alzheimer's. Even if this may still be many years in the future."

Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity

Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus. With advancing age, levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Here, we show that the nuclear lamina protein lamin B1 (LB1) is downregulated with age in mouse hippocampal NSCs, whereas protein levels of SUN-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), increase. Balancing the levels of LB1 and SUN1 in aged NSCs restores the strength of the endoplasmic reticulum diffusion barrier that is associated with segregation of aging factors in proliferating NSCs. Virus-based restoration of LB1 expression in aged NSCs enhances stem cell activity in vitro and increases progenitor cell proliferation and neurogenesis in vivo. Thus, we here identify a mechanism that mediates age-related decline of neurogenesis in the mammalian hippocampus.

Cancers subvert the immune system in order to survive, but also to accelerate their growth. Macrophages are a part of the innate immune system, and have roles in wound healing. They become engaged by a tumor; tumor-associated macrophages assist in the rampant growth of tumor cells by supporting them in an analogous way to the support of regrowth in injured tissues. A cancer is, in many ways, the twisted reflection of regeneration. In place of the intricate dance between macrophages, stem cells, and somatic cells, there is instead an equally complex interaction between tumor-associated macrophages, cancer stem cells, and cancer cells. Better understanding of these interactions might lead to ways to sabotage a cancer by picking apart the signaling, or finding ways in which tumor-associated macrophages or cancer stem cells could be selectively targeted for destruction.

Cancer stem cells (CSCs) constitute a cancer cell subpopulation similar to the other stem cell types in terms of self-renewal and multilineage differentiation potential but drive tumor development besides heterogeneity and dissemination of cancer cells. Targeting CSCs for therapeutic purposes is a goal of the scientific community. Currently, cancer treatments target the bulk population of the tumor cells without identifying and targeting CSCs. The significant problem in this regard is the lack of identification marker/s specific for CSCs.

Macrophages are large specialized phagocytic cells that exist in tissues or at infection sites. They arise from monocytes in the bone marrow and perform different functions and roles in the microenvironments of normal and tumor tissue. Macrophages differentiate into classically activated subtypes: CD68 expressing M1 mainly involved in pro-inflammatory activities, and CD163 expressing M2, that promote anti-inflammatory processes. In tumors, tumor-associated macrophages (TAM) comprise up to 50% of the tumor mass, with M2 phenotype being most abundant in the TME. The primary signals provided by TAMs include interleukin 4 (IL-4) and transforming growth factor-beta (TGF-β). TAMs play a key role in tumor initiation, development, and cancer cell propagation.

TAMs promote tumor growth by inducing neoangiogenesis, supporting CSCs, and downregulating tumour-targeting immune cells' number and function. Due to the significance of the tasks in which TAMs are involved, TAMs are increasingly becoming principal targets of novel therapeutic approaches, especially in the field of nanomedicine. The roles, connections, and functions of the crosstalk between TAMs and CSCs have been studied in-depth during the recent past. The interactions may be direct or indirect, and the effects on CSCs include chemoresistance, preservation, and the capacity to differentiate. TAMs produce cytokines including milk fat globule epidermal growth factor 8 (MFG-E8); interleukin 6 (IL-6), which can activate STAT3; and the Hedgehog signaling pathway, which seems to be one of the causes of drug resistance. For example, in hepatocarcinoma, IL-6 promotes the expression of CD44, inducing tumor development.

In-depth understanding of interaction between TAMs and CSCs is needed to develop novel treatment strategies in future. In this direction, researchers have already reported the presence of CSCs in many solid tumors as the leading cause of cancer relapse and chemotherapeutic drug resistance. In addition to this subpopulation of cells, macrophages and other immune cells also participate in interactions that may aid or impede the fight against cancer. For this reason, the targeting TAMs offer a novel treatment option against cancer. We believe that targeting TAMs may trigger various stromal reactions in the tumor milieu that are difficult to predict, even if the variability from patient to patient is kept as a consideration. Targeting TAMs could not only inhibit the tumor microenvironment, but also renovate the tumor "soil" to build a tumor-suppressive microenvironment, thereby suppressing tumor development. This strategy may become an effective therapeutic intervention that may be used either alone or in combination with other therapeutic strategies to treat cancer.

Link: https://doi.org/10.18632/oncotarget.27870

Structured exercise programs cause sweeping beneficial changes in metabolism and the transcriptional landscape of cells in older individuals. Health improves, mortality is reduced, numerous measures of the aging of muscle tissue slowed. Researchers here look at one small slice of this bigger picture, the activity of non-coding RNAs in muscle tissue. These molecules are produced via transcription from genetic blueprints, but are not translated into functional proteins. Instead they largely appear to influence the process of translation of other RNA molecules into proteins. This class of RNA molecule is far from fully catalogued or understood, and there are likely functions yet to be discovered and catalogued.

In a previous study, the whole transcriptome of the vastus lateralis muscle from sedentary elderly and from age-matched athletes with an exceptional record of high-intensity, life-long exercise training was compared - the two groups representing the two extremes on a physical activity scale. Exercise training enabled the skeletal muscle to counteract age-related sarcopenia by inducing a wide range of adaptations, sustained by the expression of protein-coding genes involved in energy handling, proteostasis, cytoskeletal organization, inflammation control, and cellular senescence. Building on the previous study, we examined here the network of non-coding RNAs participating in the orchestration of gene expression and identified differentially expressed microRNAs and long-non-coding RNAs and some of their possible targets and roles.

Unsupervised hierarchical clustering analyses of all non-coding RNAs were able to discriminate between sedentary and trained individuals, regardless of the exercise typology. Validated targets of differentially expressed microRNA were grouped by KEGG analysis, which pointed to functional areas involved in cell cycle, cytoskeletal control, longevity, and many signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), which had been shown to be pivotal in the modulation of the effects of high-intensity, life-long exercise training. The analysis of differentially expressed long-non-coding RNAs identified transcriptional networks, involving long-non-coding RNAs, microRNAs and messenger RNAs, affecting processes in line with the beneficial role of exercise training.

Link: https://doi.org/10.3390/ijms22041539

Aging is caused primarily by our biology, not by our choices. You can certainly cause yourself to age more rapidly by neglecting your health, but the only reason that we see any great level of concern regarding social and behavioral factors in aging is that rejuvenation therapies that have far larger beneficial results than exercise and diet are not yet in widespread use. So people can today look at effect sizes of a year gained here and a year lost there via lifestyle choices and think that this merits further investigation and funding, as it is on a par with what has been achieved via the poor past approaches to treating age-related disease.

In reality we should care very little about such small effects, and focus instead on medical research programs that can in principle add decades to healthy life spans by repairing the cell and tissue damage that causes aging. Bluntly, people who declare that breakthroughs in aging research must incorporate the study of social and behavioral factors are talking nonsense. It is the usual process of the social sciences fishing for funding in the wake of actually important work, combined with low expectations as to how much aging can be slowed or reversed in the decades ahead.

For breakthroughs in slowing aging, scientists must look beyond biolog

A trio of recent studies highlight the need to incorporate behavioral and social science alongside the study of biological mechanisms in order to slow aging. Exciting biological discoveries about rate of aging in non-human species are sometimes not applicable or lost when we apply them to humans. Including behavioral and social research can support translation of geroscience findings from animal models to benefit human. "The move from slowing fundamental processes of aging in laboratory animals to slowing aging in humans will not be as simple as prescribing a pill and watching it work. Compared to aging in laboratory animals, human aging has many behavioral/social in addition to cellular origins and influences. These influences include potential intervention targets that are uniquely human, and therefore are not easily investigated in animal research."

Several of these human factors have big impacts on health and mortality: stress and early life adversity, psychiatric history, personality traits, intelligence, loneliness and social connection, and purpose in life are connected to a variety of late-life health outcomes. These important factors need to be taken into account to get a meaningful prediction of human biological aging. "Geroscience can be augmented through collaboration with behavioral and social science to accomplish translation from animal models to humans, and improve the design of clinical trials of anti-aging therapies. It's vital that geroscience advances be delivered to everyone, not just the well-to-do, because individuals who experience low education, low incomes, adverse early-life experiences, and prejudice are the people who age fastest and die youngest."

"Social hallmarks of aging" can be strongly predictive of age-related health outcomes - in many cases, even more so than biological factors. While the aging field commonly discusses the biological hallmarks of aging, we don't tend to include the social and behavioral factors that lead to premature aging. Researchers have called the main five factors "the Social Hallmarks of aging" and poses that these should not be ignored in any sample of humans and the concepts should be incorporated where possible into non-human studies.

Researchers examined data that was collected in 2016 from the Health and Retirement Study, a large, nationally representative study of Americans over the age of 56 that incorporates both surveys regarding social factors and biological measurements, including a blood sample for genetic analysis. For the study, she focused the five social hallmarks for poor health outcomes: 1) low lifetime socioeconomic status, including lower levels of education, 2) adversity in childhood and adulthood, including trauma and other hardships, 3) being a member of a minority group, 4) adverse health behaviors, including smoking, obesity, and problem drinking, 5) adverse psychological states, such as depression, negative psychological outlook and chronic stress. The presence of these five factors were strongly associated with older adults having difficulty with activities of daily living, experiencing problems with cognition, and multimorbidity (having five or more diseases).

Traditional pharmacological drug development involves (a) identifying a protein or protein interaction of interest in the body, (b) screening the small molecule libraries for a compound that affects that target, and then (c) making a better version of that small molecule: more effective, less harmful. That remains the bulk of the medical research and development industry, despite the proliferation of other approaches, including cell therapies, gene therapies, recombinant proteins, monoclonal antibodies, and so forth. There are goals that cannot be achieved by small molecules, and, as techniques improve and costs fall, gene therapies of various sorts will ultimately replace a great many small molecule therapies.

That is yet to come, however, and thus much of the first wave of the longevity industry is focused on turning out small molecule drugs that can in some way influence mechanisms of aging. This can be very promising, as in the case of senolytic drugs that cause senescent cells to self-destruct, or it can be likely of only modest benefit, as in the case of mTOR inhibitors that provoke cells into greater stress response activity. All too much of the work taking place today is of the latter category, and will probably provide, at best, similar gains in long term health and life span to those that can be achieved by exercise or the practice of calorie restriction. If we want to truly change the shape of a human life, more than this is needed.

The number of compounds that have been shown to increase longevity in preclinical models is growing exponentially: it was approximately 300 in 2005, 1300 in 2015, and most recently to 2000 in 2020. Meanwhile, the discovery of longevity-associated genes has plateaued, following an exponential growth until approximately 2010 before transitioning to a slower growth over the last decade. There are probably many more longevity genes left, but the incentives for their discovery are reduced since most newly discovered genes now tend to eventually lead towards already known pathways.

The number of longevity companies has also doubtlessly increased dramatically, although this is harder to subjectively measure, as it is difficult to define what makes a company longevity-focused. Most of these companies deal with the hallmarks of aging, most notably oxidative stress and mitochondrial dysfunction, cellular senescence, and pathways implicated in caloric restriction, such as mTOR. The acquisition of longevity companies by big pharma, for example the purchase of Alkahest by Grifols, is also just beginning to occur. One concern is the lack of strategic diversity. It is possible that too much weight is being put on these areas despite the much broader range of potential strategies.

Recently, the field has also seen its first clinical failures, a notable rite of passage for all new fields of medicine. In 2019, ResTORbio's mTOR inhibitor RTB101 failed its Phase 3 trial for a lung disease, and Unity Biotechnology's senolytic UBX0101 failed to meet its endpoints in osteoarthritis just last year. A myriad of challenges can complicate translation, such as a lack of genetic diversity in preclinical models, pathways that are not conserved between species, and the selection of proper primary endpoints. However, the list of ongoing clinical trials is constantly growing, with active studies including COVID-19, macular degeneration, frailty, and neurodegenerative diseases. The TAME trial of metformin represents a pivotal proof-of-concept study, which may pave the way for future therapies aiming to broadly target longevity in their applications to the FDA rather than any specific disease. Interest has also been growing in off-label prescriptions and nutritional supplements.

There has also been a ramping up of computer-based methods being applied to the field of longevity. Bioinformatics, machine learning, and artificial intelligence, -omics approaches, and large public databases are just beginning to be fully utilized. These techniques may someday improve our abilities to predict the outcomes of clinical trials. They also aim to identify candidate drugs and biomarker and may eventually play a role in the application of personalized, precision medicine. When taken as a whole, these trends characterize a vibrant, growing longevity industry in its early maturation stage. There are many parallels to the early days of some fields of pharmacology that are now well established, such as cancer and heart disease.

Link: https://www.lifespan.io/news/longevity-pharmacology-comes-of-age/

Being active and fit slows the impact of aging on the brain. A diverse set of mechanisms are involved, and, as is often the case in these matters, it is far from clear as to which of these mechanisms are the most important. Fitness helps to maintain the vascular system in a better shape, keep levels of chronic inflammation lower, causes mild stress that makes cells throughout the body undertake greater maintenance activities, ensures that the gut microbiome ages more slowly, better maintaining the production of metabolites that affect neurogenesis. And so forth - the list goes on.

Nowadays, we are constantly bombarded by media, physicians, and other health professionals to engage in physical/sports activities to reduce physical/psychological stress, improve our health, and reduce the risk of chronic disease. The literature has clearly demonstrated aerobic fitness as one of the best indicators of resilience. This is supported by evidence from a number of studies showing that physical fitness confers physiological and psychological benefits and protects against the development of stress-related disorders, as well as improves cognition and motor function that are a consequence of aging and of neurological disorders.

Although we have learned about neurobiological mechanisms of physical fitness from the neuroplasticity and neuroprotection that confer resilience, these effects and mechanisms are diverse and complex and need to be further explored. However, we can summarize that exercise modulates several mechanisms that may increase brain health and counteract brain disorders. Exercise positively influences neuronal reserve by increasing BDNF expression which promotes neurogenesis and synaptic plasticity, reduces oxidative stress and inflammation, and enhances cerebral and peripheral blood flow, which stimulates angiogenic factors that lead to positive changes in the structure and morphology of brain vasculature. All these changes shape brain activity and serve as a buffer against stress-related disorders.

While several models of physical activity or exercise may impact positively on brain resilience such yoga, dance, martial arts, etc., in this review we aimed to focus mainly on the effects of aerobic exercise of low and moderate intensity or resistance exercise. Thus, physiological markers including heart rate variability, blood pressure, and cortisol might be regularly used as indicator of stress to determine the impact of exercise on brain resilience. Some examples of stress systems are the immune-inflammatory system, the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. Disturbance of these systems could lead to hyperactivity of the HPA-axis, sympathetic activation, and systemic inflammation.

However, there are still unanswered questions concerning (1) whether physical exercise in early life can prevent or delay cognitive decline in later life, (2) the effectiveness of exercise programs for individuals across the life span and for those with neurological diseases, and (3) how much exercise is necessary to gain beneficial effects on cognitive health. This is a field of research that deserves more attention.

Link: https://doi.org/10.3389/fnbeh.2020.626769