Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
This content is published under the Creative Commons Attribution 4.0 International License. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/
- Support the Development of Rejuvenation Therapies: Become a SENS Patron and We Will Match Your Donations
- Increasing Life Expectancy Visualized as an Advancing Wave of Late Life Mortality Risk
- Assessing the Genetic Influence on Human Life Span
- Physical Activity and Aerobic Fitness Correlate with Lowered Mortality and Longer Lives
- Can Atherosclerosis be Prevented via Early, Large Reductions in LDL Cholesterol?
- Reviewing the Evidence for HSV1 to Contribute to Alzheimer's Disease
- Chrdl1 Loss of Function Mutation Increases Synaptic Plasticity in Mice
- Random Mutations in Nuclear DNA are Prevalent in Old Tissues
- Early Onset of Menopause Correlates with Shorter Life Expectancy
- Aging as the Failure of Youth-Maintenance Systems
- Judith Campisi on Senolytics
- Proposing a Better Approach to the Discovery of Calorie Restriction Mimetics
- Osteocalcin and RbAp48 Act via BDNF to Improve Memory in Aged Mice
- Senescent Cells and Damage Accumulation in Aging
- The Latest Data on Epigenetic Clocks Suggests that they are Not Yet Ready
Support the Development of Rejuvenation Therapies: Become a SENS Patron and We Will Match Your Donations
The SENS Research Foundation year end fundraiser has started. From now until the end of 2018, every new monthly donor will have the next year of their charitable donations to the SENS Research Foundation matched from our 54,000 challenge fund. The fund sponsors, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! challenge you to fund the development of rejuvenation therapies: sign up as a recurring donor, and we will match your donations for the next year.
Collectively, the SENS programs provide a path to comprehensive human rejuvenation. The SENS Research Foundation asks us to reimagine aging, to give our support to building a future in which being old does not have to mean being frail, sick, suffering, and diminished. This is not just theory. After years of effort, the work of our community of scientists, advocates, and philanthropists is paying off with the existence of working rejuvenation therapies that are well on their way to the clinic. The first rejuvenation therapies based on the SENS model, those that selectively destroy senescent cells, have been proven in mice and are presently undergoing heavily funded, rapidly expanding clinical development in multiple startup companies. Clinical trials in patients are underway.
So far, so good, but this is just the first step. The progress to date proves that the SENS vision of rejuvenation through damage repair is correct, but even as senescent cell clearance receives the attention and funding that it merits, a score of other equally important lines of research and development continue to languish, lacking resources. It is our job to provide those resources, the funding that can be used to bring these areas of research towards proof, widespread support, and active clinical development. The SENS Research Foundation has demonstrated its ability to make very good use of our charitable donations: you won't find a better way to change the world than this opportunity.
Reimagine Aging: the Campaign Begins Now
Thank you for your dedicated support of SENS Research Foundation's mission to end age-related disease. We know you share our passion and vision for a world with extended, healthy lifespans for all. How much human suffering would be alleviated if science and medicine could comprehensively treat the diseases of aging at their root cause?
Our donors are making this a reality. With your support, we are conducting and funding research, educating new scientists, and engaging in outreach to the public and industry partners. Research focuses on a unique damage-repair approach to treat diseases of aging. Education engages the next generation of rejuvenation biotechnology professionals. Outreach encourages and inspires the general public, policymakers, and academia to Reimagine Aging.
For more ways to donate, including how to receive tax benefits from the EU, visit our Ways to Donate page. From all of us at SRF, thank you! Your help is vital to moving our mission forward.
Increasing Life Expectancy Visualized as an Advancing Wave of Late Life Mortality Risk
Today's open access paper provides an interesting visualization of the slow upward trend in life expectancy that has taken place over the last 60 years. A plot of the distribution of human mortality by age over the last third of life results in a wave-like curve, peaking at around 90 years of age. But those are today's numbers. In the 1960s, the curve had much the same shape, but the peak was at 80 years of age. Life was shorter, but the distribution of mortality at the end of life was much the same.
This is the case despite large changes in the causes of death over this span of decades. Mortality risk due to heart disease has diminished greatly, for example, thanks to the advent of statins and similar treatments. The slow march of medicine - meaning control of infection and improved health throughout life, not just incrementally better ways to treat age-related disease - has resulted in life expectancy at birth increasing by two years every decade. Remaining life expectancy at 65 has increased by about a year with every passing decade.
These trends are now a matter of history, and will not continue as they have. The advent of senolytic therapies to selectively remove senescent cells, one of the causes of aging, will cause an upward leap in life expectancy at 65. Other rejuvenation therapies that arrive in the decades ahead will result in further gains. The era of slow, incidental increases in life span is over. The era of deliberately engineered longevity has started, but it will most likely take two decades or more for the results of present clinical development to start to appear in population-wide demographic data. There is a lot of work left to accomplished not just in development but also for distribution of rejuvenation therapies: senolytics already exist, but next to no-one is using them, for example. This must change.
Advancing front of old-age human survival
We conclude that an advancing old-age front characterizes old-age human survival in 20 developed countries. The long-term speed of the advancing front is ≃0.12 year per calendar year, about 3 years per human generation. The location of the survival front is the 25th percentile of mortality. Thus, the front implies that, e.g., age 68 years today is equivalent, in terms of mortality, to age 65 years a generation ago. Our findings echo aspects of an earlier proposal that mortality hazards have, over the years, shifted rigidly to older ages. Our analysis of percentiles makes no assumptions about the pattern of mortality at young or old ages and focuses on older deaths. However, our finding of a shifting front in the percentiles of death at old age is consistent with some patterns of shifts in old-age mortality hazards.
Our findings provide no support for an impending limit to human lifespan, certainly not at an age that affects the movement of the survival front (between the 25th and 90th percentiles). To the extent that we can rely on the long-term speeds of percentiles above the 90th, the oldest deaths are being compressed in some countries but definitely not in others. Here again we find no support for an approaching limit to human lifespan. Nor do our results suggest that endowments, biological or other, are a principal determinant of old-age survival. The advancing survival front that we find suggests that the effects of inequality on mortality may be much smaller among old-aged adults than among younger adults.
Our analyses use period life tables, not cohorts, and suggest that continued mortality improvement depends largely on period processes such as economic growth, investment and advances in health science research and practice, and increases in the age of transition to disability. Our results also constrain biological arguments about the causes of death, especially the plasticity of death rates in response to environmental factors. Our moving survival front is consistent with a plateau in mortality rates, but implies that the location and possibly the level of the plateau change over time.
Assessing the Genetic Influence on Human Life Span
The falling cost of gene sequencing allows for genetic data to be incorporated into studies of ever larger populations. At least hundreds of thousands of entire human genomes have been sequenced, and more selective sequencing has been undertaken for millions more. This data is now beginning to show up in epidemiological studies that tackle questions of health, choice, aging, and longevity.
What should we expect to see emerge from this scientific analysis? It seems fairly clear from the extensive existing evidence, data that results from many association studies carried out in search of gene variants correlated with longevity, that a large number of genes contribute to life span. Collectively these genes influence the highly complex relationship between the operation of metabolism and pace of aging, but the contribution to longevity resulting from any one gene is small.
Further, the contribution of a single gene to aging and longevity is usually strongly contingent on environmental factors or the presence of other gene variants. As a result, an association with longevity discovered in one study population is rarely replicated in others. Only a very few genes have exhibited a robust correlation with longevity in multiple studies, and their effect sizes are (with one exception) quite small.
When it comes to the overall interaction between genes and longevity, many lines of evidence lead the scientific community to believe that the genetic contribution to human variation in aging is smaller than the environmental contribution. Those environmental factors include lifestyle choices, burden of infection, and so forth. The study here reinforces that consensus, producing a model that predicts the difference in life expectancy for the best and worst human genomes to be somewhat less than the difference between a good lifestyle and a bad lifestyle established in other epidemiological studies.
Genetic Study Improves Lifespan Predictions and Scientific Understanding of Aging
Researchers set out to identify key genetic drivers of lifespan. In the largest ever genome-wide association study of lifespan to date, they paired genetic data from more than 500,000 participants in the UK Biobank and other cohorts with data on the lifespan of each participant's parents. Rather than studying the effects of one or more selected genes on lifespan, they looked across the whole genome to answer the question in a more open-ended way and identify new avenues to explore in future work.
Because the effect of any given gene is so small, the large sample size was necessary to identify genes relevant to lifespan with enough statistical power. Using this sample, the researchers validated six previously identified associations between genes and aging, such as the APOE gene, which has been tied to risk of neurodegenerative disease. They also discovered 21 new genomic regions that influence lifespan.
They used their results to develop a polygenic risk score for lifespan: a single, personalized genomic score that estimates a person's genetic likelihood of a longer life. Based on weighted contributions from relevant genetic variants, this score allowed the researchers to predict which participants were likely to live longest. "Using a person's genetic information alone, we can identify the 10 percent of people with the most protective genes, who will live an average of five years longer than the least protected 10 percent."
Living long and healthy lives is of great interest to us all, yet investigation into the genomic basis of lifespan has been hampered by limited sample sizes, both in terms of gene discovery and identification of longevity pathways. Applying univariate, multivariate, and risk factor-informed genome-wide association to 1,012,240 parental lifespans from European subjects in UK Biobank and an independent replication cohort, we validate previous associations near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, FOXO3A, 5q33.3/EBF1, ZW10, PSORS1C3, 13q21.31, and provide evidence against associations near CLU, CHRNA4, PROX2, and d3-GHR.
Our combined dataset reveals 21 further loci and shows, using gene set and tissue-specific analyses, that genes expressed in foetal brain cells and adult prefrontal cortex are enriched for genetic variation affecting lifespan, as are gene pathways involving lipoproteins, lipid homeostasis, vesicle-mediated transport, and synaptic function.
We next perform a lookup of disease SNPs and find variants linked to dementia, smoking/lung cancer, and cardiovascular risk explain the largest amount of variation in lifespan. This, and the notable absence of cancer susceptibility SNPs (other than lung cancer) among the top lifespan variants, suggests larger, more common genetic effects on lifespan reflect modern lifestyle-based susceptibilities. Finally, we create polygenic scores for survival in independent sub-cohorts and partition populations, using DNA information alone, into deciles of expectation of life with a difference of more than five years from top to bottom decile.
Physical Activity and Aerobic Fitness Correlate with Lowered Mortality and Longer Lives
Today I'll point out the results from recent research into the intersection between exercise and aging. It is well known that undertaking physical activity correlates with a lower risk of mortality and age-related disease, and though the details vary by age, this relationship holds up all the way into late life. Even modest levels of activity, such as cleaning and gardening and walking, appear to have a sizable impact on health and mortality risk.
When using human data researchers can typically only establish correlations between exercise and health, which leaves open the possibility that people who are more robust and would have lived longer anyway tend to exercise more often. However, in studies using mice it is quite clear that exercise is the cause of improved health and extends average (but not maximum) life span. It would be surprising to find that this was not the case in other mammals, given the degree of similarity in the cellular and biochemical responses to exertion.
The question of whether more exercise is better is an interesting one, and hard to quantify in humans. There is good evidence to suggest that the usual recommendation of 150 minutes per week is too low, for example. Elite athletes live significantly longer than the rest of the population, but it is unclear as to whether this is a reflection of that fact that only unusually robust individuals can manage to become professional athletes, or perhaps that the effect is mediated by wealth, status, or other confounding relationships. Exercise has a dose-response curve and it is presently thought that there is such a thing as too much of it as well as too little, though where exactly that line is drawn is far from settled. Exercise may be too indirect a measure, as one of the papers here suggests, and aerobic fitness may be the important determinant of mortality. For this measure, it seems that more is always better.
Better cardiorespiratory fitness leads to longer life
Researchers retrospectively studied 122,007 patients who underwent exercise treadmill testing between Jan. 1, 1991, and Dec. 31, 2014, to measure all-cause mortality relating to the benefits of exercise and fitness. The study found that increased cardiorespiratory fitness was directly associated with reduced long-term mortality, with no limit on the positive effects of aerobic fitness. Extreme aerobic fitness was associated with the greatest benefit, particularly in older patients (70 and older) and in those with hypertension.
The risk associated with poor cardiorespiratory fitness was comparable to or even exceeded that of traditional clinical risk factors, such as cardiovascular disease, diabetes, and smoking. The study's findings emphasize the long-term benefits of exercise and fitness, even to extreme levels, regardless of age or coexistent cardiovascular disease. Several recent studies have suggested associations between extreme exercise and certain adverse cardiovascular findings, such as atrial fibrillation and coronary artery disease. However, the newly published study found that extreme fitness provided additional survival benefit over more modest levels of fitness, and that extremely fit patients lived the longest.
"We were particularly interested in the relationship between extremely high fitness and mortality. This relationship has never been looked at using objectively measured fitness, and on such a large scale."
Physical Activity Lowers Risk of Death from Heart Disease
Physical activity includes walking and other gentle forms of exercise. It is proven to improve health. Physical activity can lower the risk of many chronic diseases, including type 2 diabetes, heart disease, several cancers, and depression. Exercise also can improve your ability to perform your daily activities and can lower your risk of death from heart disease. In frail older adults, physical activity has been shown to improve strength, balance, agility (the ability to move quickly and easily), walking speed, and muscle mass (the amount of muscle you have in your body). These are all key functions tied to frailty.
Researchers recently reviewed a number of studies about exercise in frail older adults. The review found a number of studies that showed exercise helped reduce falls, improved walking ability, improved balance or increased muscle strength. However, we still don't know whether physical activity can reduce death among frail older adults. Researchers thus recently designed a study to fill that knowledge gap by exploring whether physical activity could lower the high rate of death associated with frailty in older people.
The 3,896 study participants aged 60 years and older were selected according to sex and age. Information was collected at the participants' homes through personal interviews, and physical examinations were performed by trained personnel. Researchers assessed how much physical activity the participants did by asking whether they were generally inactive during their leisure time, or engaged in physical activity occasionally, several times a month, or several times a week.
Compared with robust participants, pre-frail and frail people had a higher risk of death from cardiovascular disease. However, being physically active was linked to a lower risk for death among pre-frail and frail individuals. What's more, deaths from cardiovascular disease in people who were physically active but also frail were similar to levels for pre-frail and inactive people. The researchers said their findings suggest that physical activity might partly reduce the increased risk of death associated with frailty in older adults.
Can Atherosclerosis be Prevented via Early, Large Reductions in LDL Cholesterol?
Atherosclerosis is a universally suffered condition of aging in which oxidized lipids are the seeds for ever-expanding fatty deposits in blood vessel walls. Blood vessels are progressively weakened and narrowed, and this ultimately leads to the catastrophic structural failure of a stroke or heart attack. Atherosclerosis is one of the largest single causes of death in our species.
Cholesterol is carried in the bloodstream, attached to low density lipoprotein (LDL) particles. Lacking any other viable approach to the condition, methods of reducing LDL cholesterol such as statin drugs are widely use to slow atherosclerosis. They reduce one of the inputs to the progression of the condition, the supply of cholesterol, but haven't been shown to produce any sizable reversal of established atherosclerotic lesions in humans. The animal evidence suggests that greater benefit may occur in the earlier stages of the disease, when it might be possible for lowered LDL cholesterol to allow repair mechanisms to catch up sufficiently to remove smaller, more recent lesions. In general, intervening early is a good idea: fixing smaller problems is easier than fixing larger ones. Researchers are now seeking to trial this concept in humans.
I think it remains the case, however, that any meaningful therapy for atherosclerosis must remove or at least significantly diminish the larger and more widespread lesions present in later stages of the condition. This sort of therapy will likely involve mechanisms capable of enhancing reverse cholesterol transport. This describes the way in which macrophages mine cholesterol from lesions and then hand it off to high density lipoprotein (HDL) particles that carry the cholesterol back to the liver. There are many places in which this process might be made more efficient: increased HDL particle count; improved cholesterol export in macrophages; greater macrophage resilience to cholesterol overload; and so forth.
Variants on most of these approaches have been shown to produce some degree of reversal of atherosclerosis in mice, as much as 50% reversal in some cases. Unfortunately, of these potential therapies, only increases in HDL particle numbers have been tried in humans. Those efforts didn't work well at all, which raises a number of interesting questions. There is some uncertainty as whether any of the other approaches presently in the pipeline will do any better in humans, as clearly the dynamics of the process must be substantially different between humans and animal models to produce such different results for the HDL particle trials.
Researchers suggest way to possibly eliminate artery-clogging condition
Researchers have proposed a unique study in humans to reduce the early onset of atherosclerosis, the buildup of the artery-clogging plaque that can lead to heart attacks and strokes. The proposed trial, CURing Early ATHEROsclerosis, or CURE ATHERO, would set out to determine if atherosclerosis in high-risk adults ages 25 to 55 might be reversed by using medicines called statins and PCSK9 inhibitors over the course of three years. "The idea is to get the cholesterol very low for a short period of time, let all the early cholesterol buildup dissolve, and let the arteries heal. Then patients might need to be retreated every decade or two if the atherosclerosis begins to develop again."
The proposal is a "very compelling idea" that might show whether older adults can avoid heart attacks and strokes by making sure they have low LDL and apo B levels earlier in their lives. "It's a very important question that we really need to answer, because we have therapies now to lower apo B lipoproteins and LDL cholesterol. We know that people who have low LDL cholesterol for genetic reasons have a very low risk of having cardiovascular events, so if we can replicate one of these genetic states and get people's LDL cholesterol really low in early adulthood, perhaps these people won't have downstream complications like heart attack and stroke."
Eradicating the Burden of Atherosclerotic Cardiovascular Disease by Lowering Apolipoprotein B Lipoproteins Earlier in Life
A new paradigm for preventing atherosclerotic cardiovascular disease (ASCVD) is needed. The most recent US data show the long-term decline in cardiovascular deaths has stopped, and has started to increase in the most at-risk populations.
Systemic approaches to improving lifestyle habits and better risk factor control are clearly needed. Given the difficulty of these endeavors to date, and the persistently high burden of ASCVD when risk factor modification is started later in adulthood, we propose a new paradigm for ASCVD prevention. We consider that it is now time to investigate whether intensively lowering plasma apolipoprotein (apo) B lipoprotein levels in younger and early midlife adults will regress earlier stages of atherosclerosis, thereby eliminating the risk of developing clinical ASCVD events later in life.
As a next step, we describe a proposed clinical trial to test early intervention to profoundly lower the concentration of low-density lipoprotein (assessed by its cholesterol component, LDL-C) and other apo B-containing lipoprotein in individuals aged 25 to 55 years who have image-documented preclinical atherosclerosis. Such a trial may provide the first direct evidence to support marked or even complete regression of early atherosclerosis in humans, and lay the ground work for definitive trials to support a new prevention paradigm of intensive regression therapy followed by intermittent retreatment for eradication of the clinical burden of ASCVD.
Reviewing the Evidence for HSV1 to Contribute to Alzheimer's Disease
Alzheimer's disease starts with a slow rise in levels of amyloid-β present in the brain, an imbalance between dynamic processes of creation and clearance. This produces a state of mild biochemical and cognitive dysfunction that sets the stage for the later, much more destructive phase characterized by chronic inflammation, deposition of altered tau protein, and cell death. The roots of Alzheimer's must lie in the early mechanisms, in the poorly studied initial years of the condition, that cause some people to accumulate amyloid-β at a faster pace. In recent years evidence has emerged for persistent viral infection to play a role. Amyloid-β is coming to be seen as an anti-viral mechanism, and its creation and aggregation is prompted by the presence of viral particles.
Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer's disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD.
Population data to investigate this epidemiologically, e.g., to find if subjects treated with antivirals might be protected from developing dementia - are available in Taiwan, from the National Health Insurance Research Database, in which 99.9% of the population has been enrolled. This is being extensively mined for information on microbial infections and disease. Three publications have now appeared describing data on the development of senile dementia (SD), and the treatment of those with marked overt signs of disease caused by varicella zoster virus (VZV), or by HSV. The striking results show that the risk of SD is much greater in those who are HSV-seropositive than in seronegative subjects, and that antiviral treatment causes a dramatic decrease in number of subjects who later develop SD.
It should be stressed that these results apply only to those with severe cases of HSV1 or VZV infection, but when considered with the over 150 publications that strongly support an HSV1 role in AD, they greatly justify usage of antiherpes antivirals to treat AD.
Chrdl1 Loss of Function Mutation Increases Synaptic Plasticity in Mice
Researchers here suggest that the protein chrdl1 plays an important role in the regulation of synaptic plasticity, the ability of the brain to generate new connections between neurons. Synaptic plasticity declines with age, and is important in cognitive function. There is thus considerable interest in ways to enhance plasticity, not just to turn back this aspect of aging, but also potentially as a form of enhancement therapy to improve memory or other aspects of the mind.
Researchers have shown that astrocytes - long-overlooked supportive cells in the brain - help to enable the brain's plasticity, a new role for astrocytes that was not previously known. The findings could point to ways to restore connections that have been lost due to aging or trauma. "To investigate this role, we used a lot of techniques in the lab to identify a signal made by astrocytes that's very important for brain maturation."
The signal turned out to be a protein astrocytes secrete called Chrdl1, which increases the number and maturity of connections between nerve cells, enabling the stabilization of neural connections and circuits once they finish developing. To further understand the role of Chrdl1, the team developed mouse models with the gene disabled by introduced mutations. These mice had a level of plasticity in their brains that was much higher than normal. Adult mice with the Chrdl1 mutation had brain plasticity that looked very much like that of young mice, whose brains are still in early stages of development.
Not much is known about the role of Chrdl1 in humans, but one study of a family with a Chrdl1 mutation showed they performed extremely well in memory tests. Other studies have shown the level of the gene encoding Chrdl1 is altered in schizophrenia and bipolar disorder, suggesting that Chrdl1 may have important roles in both health and disease. Future research by the team will dive deeper into the relationships between astrocytes and neurons and look for potential ways to use astrocytes as therapy. "We're interested in learning more about what the astrocytes are secreting into the brain environment and how those signals affect the brain. We plan to look at this relationship both early in development and in situations where those connections are lost and you want to stimulate repair, like after someone has had a stroke."
Random Mutations in Nuclear DNA are Prevalent in Old Tissues
Evolution requires happenstance mutation in order to progress, but too much of this random mutation leads to cancer or other forms of dysfunction sufficient to reduce reproductive fitness. The result is our present balance: enough mutation to make cancer a major cause of death, to ensure that mitochondria contribute to aging via mutation of mitochondrial DNA, and to produce some level of general dysfunction in aged tissues due to the accumulated mutational burden. The research noted here is one representative example of a range of research that seeks to quantify the degree to which our cells exhibit random mutational damage as we age. You might compare it with another set of results published recently on competition between mutations in skin, and how this paradoxically manages to suppress cancer risk.
Every person accumulates genetic changes, or mutations, throughout their lifetime. These mutations in normal tissue, called somatic mutations, are key to understanding the first steps to cancer and likely contribute towards ageing, but are uncharted territory due to technical limitations. For the first time, scientists have uncovered that on average, healthy cells in the oesophagus carry at least several hundred mutations per cell in people in their twenties, rising to over 2,000 mutations per cell later in life. Only mutations in a dozen or so genes seem to matter however, as these give the cells a competitive advantage allowing them to take over the tissue and form a dense patchwork of mutations.
The team used targeted and whole-genome sequencing to map groups of mutant cells in normal oesophageal tissue from nine individuals aged 20 to 75 years. The individuals' oesophageal tissues were considered healthy as none of the donors had a known history of oesophageal cancer, nor were taking medication for problems relating to the oesophagus. The study also casts new light on the mutations that are found in the squamous kind of oesophageal cancers. One mutated gene, TP53, which is found in almost all oesophageal cancers is already mutated in 5-10 per cent of normal cells, suggesting that cancer develops from this minority of cells.
In contrast, mutations in the NOTCH1 gene, known to control cell division, were found in nearly half of all cells of normal oesophagus by middle age, being several times more common in normal tissue than cancer. This observation suggests that researchers need to reconsider the role of some genes recurrently mutated in cancer in the light of mutations in normal tissue, and raises the possibility that the NOTCH1 mutation may even protect cells against cancer development. "This study shows that some genetic changes linked to cancer are present in surprisingly large numbers of normal cells. We still have a long way to go to fully understand the implications of these new findings, but as cancer researchers, we can't underestimate the importance of studying healthy tissue."
Early Onset of Menopause Correlates with Shorter Life Expectancy
Aging is a phenomenon affecting all organs and systems throughout the body, driven by rising levels of molecular damage. The variation in aging between individuals is largely determined by variations in the overall burden of such damage, the compound interest of small differences arising from lifestyle choices and happenstance such as infection in the first half of life. Thus for any given individual, manifestations and measures of aging tend to be fairly well correlated. That doesn't necessarily tell us anything about causation. So in this study, in which the researchers look at two very high level manifestations of aging, menopause and life span, there is probably no direct thread of causation at all. These are downstream manifestations of the summed effects of every cause of aging.
It is a well-accepted fact in the medical community that both type 2 diabetes and early onset of natural menopause may be associated with early death. Emerging evidence shows an association between age at menopause and diabetes, with studies reporting almost a two-fold increased risk of type 2 diabetes with early onset of menopause. To date, however, there are no other known studies that have quantified (calculated the number of years lived with and without diabetes) the combined association of early menopause and type 2 diabetes with life expectancy.
In this study involving 3,650 postmenopausal women, the difference in life expectancy was compared in women experiencing early, normal, and late menopause, as well as in those with and without diabetes. Compared with late menopause (defined as menopause that occurs at age 55 years and older), the difference in life expectancy for women who experienced early menopause (defined as menopause that occurs at age 44 years or younger) was -3.5 years overall and -4.6 years in women without diabetes. Compared with age at normal menopause (defined as menopause that occurs at 45-54 years of age), the difference in life expectancy for women who experienced early menopause was -3.1 years overall and -3.3 years in women without diabetes.
The authors suggest the need for future research to examine the mechanisms behind this association to help tailor prevention and treatment strategies that improve women's health across all age categories of menopause.
Aging as the Failure of Youth-Maintenance Systems
A group of scientists who are primarily involved in calorie restriction research here make the case aging to be caused in part by the declining activity of youth-maintenance programs, such as high levels of stem cell activity, high levels of the cellular repair processes of autophagy, and so forth. This is a novel viewpoint insofar as they wish to highlight this decline as something distinct from the matter of damage, and cordon it off as an area for particular study. This makes some sense from the perspective of calorie restriction and related interventions that slow aging via increased stress response activities, meaning more repair and more regeneration.
Why does maintenance of tissues fail with age? Those of us in the camp that sees aging as the result of accumulated molecular damage consider this decline to be the result of rising levels of molecular damage in cells and tissues. The programmed aging camp would no doubt suggest it to be part of an evolved program that actively limits life span. I think that the existence of metabolic waste products that are both damaging and resistant to clearance by our biochemistry tends to swing the argument in favor of aging as damage. One cannot just instruct cells to act in a more youthful fashion in order to reverse the accumulation of these waste products, which is the preferred approach for many in the programmed aging community.
Many theories have been proposed to explain the aging process ranging from the free radical theory of aging, to the disposability theory, and antagonistic pleiotropy theories. These were formulated to explain why organisms age and are consistent with the acceleration of damage and dysfunction as the force of natural selection declines. However, we can also consider aging to be the result of the end or at least of a partial inactivation of a "longevity program" whose scope is to maintain the organism in a youthful state. This is distinct from the more controversial "programmed aging" theory, in which the aging process has been selected to provide both genetic variability and the nutritional resources to promote fitness.
Although the existence a longevity program is very much consistent with the natural selection theory and may appear to be just another way to explain aging, it is not because it relates less to senescence and much more to a series of protection, repair, and replacement events aimed at keeping the organism young. I propose that this field can be termed "juventology" (the study of youth) from the Latin iuventus or "the age of youth."
For example, we know that S. cerevisiae grown in glucose medium can survive for ~6 days in a relatively low protection mode. However, when it is switched to water, stress resistance can increase several folds as does lifespan but also the period in which cells are able to reproduce and form colonies. Thus, there are clearly at least 2 longevity programs that can be selected by yeast cells and which are entered based on the type and level of nutrients in the medium.
This is a fundamental distinction from the "aging-centered" view for two reasons: (a) a longevity program based on the understanding of juventology, such as the alternative lifespan programs entered in response to fasting, may be independent or partially independent of aging. For example, the use of drugs and periodic fasting, both of which target the mTor-S6K and PKA pathways, can promote regeneration and rejuvenation. Thus, an organism could be aging at a higher rate and yet have a longer healthspan and lifespan by periodically activating regenerative and rejuvenating processes and (b) by shifting the focus from "old or older age" in which dysfunction generates high morbidity and mortality, to the period during which both morbidity and mortality are very low and difficult to detect.
For example, human diseases are rare before age 40, but very common after age 65, yet no specific field of science is focusing on how evolution resulted in a program that is so effective for the first 40 years of life and how that program may be extended by dietary, pharmacological, or other interventions.
Judith Campisi on Senolytics
As one of the authors of the initial SENS position paper, published many years ago now, Judith Campisi is one of the small number of people who is able to say that she was right all along about the value of targeted removal of senescent cells, and that it would prove to be a viable approach to the treatment of aging as a medical condition. Now that the rest of the research community has been convinced of this point - the evidence from animal studies really is robust and overwhelming - the senescent cell clearance therapies known as senolytics are shaping up to be the first legitimate, real, working, widely available form of rejuvenation therapy.
Why should we suddenly get excited about anti-aging drugs again?
There are now tools available to biomedical scientists that simply didn't exist when I was a graduate student or even a postdoc. So we're finally able to do experiments that were either considered impossible in some cases or were just dreams 20 or 25 years ago. The other thing that has changed is that the field of senescence - and the recognition that senescent cells can be such drivers of aging - has finally gained acceptance. Whether those drugs will work in people is still an open question. But the first human trials are under way right now.
How specifically does senescence contribute to aging?
The correct way to think about senescence is that it's an evolutionary balancing act. It was selected for the good purpose of preventing cancer - if cells don't divide, they can't form a tumor. It also optimizes tissue repair. But the downside is if these cells persist, which happens during aging, they can now become deleterious. Evolution doesn't care what happens to you after you've had your babies, so after around age 50, there are no mechanisms that can effectively eliminate these cells in old age. They tend to accumulate. So the idea became popular to think about eliminating them, and seeing if we can restore tissues to a more youthful state.
You've suggested that health care could be transformed by senolytic drugs, which eliminate senescent cells. That's a pretty broad claim.
If we think of aging as a driver for multiple age-related pathologies, the idea would be that a new generation of physicians - we call them geriatricians today - will take a much more holistic approach, and the interventions will also be more holistic. That's the idea-it would revolutionize the way we're thinking about medicine nowadays. And just to remind you, 80% of patients in the hospital receiving acute medical attention are over the age of 65. So the idea is that senolytics would be one weapon that geriatricians will have in their arsenal of weapons to treat aging holistically as opposed to one disease at a time.
Proposing a Better Approach to the Discovery of Calorie Restriction Mimetics
Calorie restriction slows aging and extends life span in near all species tested to date. The short term effects in humans are beneficial, and there is good evidence for the practice of calorie restriction to reduce the risk of age-related disease. The size of the effect on life span is much smaller in long-lived mammals than is the case in short-lived mammals, unfortunately, as is the case for all approaches based on increased activity of stress response mechanisms. Nonetheless, there is considerable interest in the discovery and development of calorie restriction mimetics, compounds that provoke some of the same beneficial alterations in metabolism as occur in calorie restricted individuals. So far this has been a painfully slow and expensive process, and thus it is entirely understandable that some groups are working on ways to improve the efficiency of this part of the field of aging research. Even so, when the benchmark is resveratrol, a noted failure, it seems hard to imagine this line of work producing meaningful results when it comes to human longevity. Stress response upregulation is a poor approach to age-related degeneration when compared to targeted repair of the biochemical damage that causes aging.
Caloric restriction (CR) is defined as a reduction of caloric intake by 30-40% of ad libitum consumption, without causing malnutrition. CR can cause lifespan extension by triggering a shift from a physiological state of proliferation and growth, to repair and maintenance. Studies have shown that CR reduces oxidative damage, retards age-related functional decline such as deteriorations in DNA repair capacity, and causes a 30% increase in maximal lifespan of mammals. Nevertheless, the amount and duration of CR necessary to extend lifespan is not practical in humans. A feasible solution lies in developing a CR mimetic that can directly target biochemical pathways affected by CR and similarly achieve lifespan extension.
Natural products represent a good starting point for drug discovery, and there is great interest in synthesizing analogs of these compounds in order to explore the mechanism of action, and enhance bioactivity and bioavailability. Polyketides are functionally and structurally diverse secondary metabolites produced in bacteria, fungi, and plants. Many of these bioactive natural products have significant medical applications. Because of the chemical and structural complexity of polyketides and their derivatives, chemical synthesis is difficult. Current research in the engineering and structural characterization of polyketide synthases (PKSs) has facilitated their use as biocatalysts to generate novel polyketides, which can serve as potential drug leads.
The conventional way of anti-ageing drug screening is via lifespan assays. However, lifespan assays are time-consuming and impractical for screening a large library of bioactive compounds. This study aims to develop a medium throughput screening methodology by conducting mitochondrial function assays on C. elegans exposed to various compounds using an Extracellular Flux Analyzer. By periodically introducing pharmacological agents such as electron transport chain inhibitors to manipulate mitochondrial activity and respiratory function, the mitochondrial biology of C. elegans can be examined to establish a correlation between oxygen consumption rates, CR mimetics, and lifespan extension.
Here, we show that by establishing a combinatorial biosynthetic route in Escherichia coli and exploring the substrate promiscuity of a mutant PKS from alfalfa, 413 potential anti-ageing polyketides were biosynthesized. In this approach, novel acyl-coenzyme A precursors were utilized by PKS to generate polyketides which were then fed to Caenorhabditis elegans to study their potential efficacy in lifespan extension. It was found that CR mimetics like resveratrol can counter the age-associated decline in mitochondrial function and increase the lifespan of C. elegans. Using the mitochondrial respiration profile of C. elegans supplemented for 8 days with 50 μM resveratrol as a blueprint, we can screen our novel polyketides for potential CR mimetics with improved potency. This study highlights the utility of synthetic enzymology in the development of novel anti-ageing therapeutics.
Osteocalcin and RbAp48 Act via BDNF to Improve Memory in Aged Mice
Expression of RbAp48 diminishes with aging, and increased expression in the dentate gyrus improves memory in aged mice. Similarly, infusions of osteocalcin reduce the detrimental effects of aging on memory in mice. Researchers here demonstrate a link between these two approaches, showing that both RbAp48 and osteocalcin operate via BDNF, well known to be associated with cognitive function over the course of aging. This sort of finding is quite common. All cellular mechanisms involve numerous proteins and can thus be influenced at many points. Research groups tend to independently discover various different approaches, and only later are they understood to involve the same underlying targets.
Alzheimer's disease changes the brain in different ways than does age-related memory loss, a milder, though far more common, memory disorder. Alzheimer's disease begins in a part of the brain called the entorhinal cortex, which lies at the foot of the hippocampus. Age-related memory loss, by contrast, begins within the hippocampus itself, in a region called the dentate gyrus.
In 2013, researchers discovered that a deficiency in the RbAp48 protein is a significant contributor to age-related memory loss but not Alzheimer's. Research has shown that RbAp48 levels decline with age, both in mice and in people. This decline can be counteracted; when researchers artificially increased RbAp48 in the dentate gyrus of aging mice, the animals' memories improved. In 2017, the researchers found another way to improve the memories of mice. Infusions of osteocalcin, a hormone normally released by bone cells, had a positive effect on memory.
A new study connects osteocalcin and RbAp48, suggesting that the key driver of the memory improvements lay in the interplay between these molecules. In a series of molecular and behavioral experiments, the team found that RbAp48 controls the expression levels of BDNF and GPR158, two proteins regulated from osteocalcin. This chain of events appears to be critical; if RbAp48 function is inhibited, osteocalcin infusions have no effect on the animals' memory. Osteocalcin needs RbAp48 to kick start the process.
This complex sequence of molecular signals is entirely different from those associated with Alzheimer's disease. These findings also provide further evidence in favor of what may be the best way to stave off, or even treat, age-related memory loss in people: exercise. Studies in mice have shown that moderate exercise, such as walking, triggers the release of osteocalcin in the body. Over time, osteocalcin may make its way to the brain, where it encounters RbAp48. Eventually, this could have a long-term, positive effect on memory and the brain.
Senescent Cells and Damage Accumulation in Aging
This open access review of cellular senescence in aging is perhaps noteworthy for being authored in part by Vadim Gladyshev, one of the more pessimistic researchers in our community. Simplified a little, his opinion is that aging and metabolism are too complex and poorly understood to hope for rapid progress towards rejuvenation and life extension in our lifetimes. He is not in agreement with the proposition that one can bypass the requirement for greater understanding of aging by targeting the root causes of aging - one of which is the accumulation of senescent cells - as I don't think he considers the SENS portfolio of causes of aging sufficiently proven. It is thus interesting to see him engage in detail with the topic of cellular senescence, particularly given the past few years of promising results in mice due to senolytic therapies capable of selectively destroying these cells.
Some animals are characterized by the so-called negligible senescence, such as a species within the genus of Cnidaria - Hydra, although it is known that their individual cells do age. This apparent nonaging phenotype can be achieved by replacing cells that accumulated damage over time with new cells generated from abundant stem cells that can give rise to any cell type in the body. However, this nonaging strategy is not applicable to the great majority of organisms with specialized, nonreplaceable cells and structures. When organisms are unable to replace cells at will or dilute damage, intracellular damage accumulates, exerting its deleterious effect on the host cell as well as other cells, impairing their function and ultimately contributing to age-related diseases and to aging itself.
The macroscopic age-associated changes in organisms are so obvious and severe that identifying their molecular bases would seem to be an easy task. Yet, all the research conducted so far has not led to the unambiguous identification of the causal factors orchestrating aging.
With recently published evidence, the role of cellular senescence in organismal aging has become increasingly clear. The phenomenon of cellular senescence has a special meaning in the context of damage accumulation in aging. Cells triggered to senesce by damaging insults exhibit higher basal levels of damaged macromolecules than healthy cells and also generate damage at a higher rate. This notion posits senescent cells as organismal carriers of damage. It is especially relevant for the irreparable forms of damage such as telomere-associated breaks and lipid-protein aggregates of lipofuscin.
Kinetics of senescent cell accumulation in response to lifespan-modulating interventions differs from the kinetics of irreparable and reparable types of damage. This is due to yet another layer of complexity in the regulation of senescent cell population in vivo that is mediated by the immune system. Subjected to a life-extending intervention, an organism can remove senescence-related damage, in contrast to other types of irreparable damage. A change from life-extending to life-shortening conditions does not, however, abolish the beneficial effects of the former. As shown for calorie restriction, animals on short-term calorie restriction maintain the status of low senescent cell abundance after the end of the treatment.
Accumulation of senescent cells is an integral part of the damage accumulation process. Senescent cells then emerge as causal to age-related diseases. This model explains the recently published evidence that elimination of senescent cells can alleviate multiple age-related diseases and increase health span but does not greatly affect the rate of aging/maximum lifespan. As senescent cells contain high levels of irreparable damage, we do not imply that a certain effect on the rate of aging is impossible. However, we argue that elimination of senescent cells is unlikely to be the intervention that would very significantly prolong human maximum lifespan.
The Latest Data on Epigenetic Clocks Suggests that they are Not Yet Ready
An epigenetic clock is a weighted measure of DNA methylation at specific sites on the genome. The best such clocks correlate well with chronological age, and come with additional evidence to suggest that they also correlate well with biological age, the burden of damage that leads to dysfunction. Study populations with age-related disease, or known to have higher risks of age-related disease, also have higher ages as measured by an epigenetic clock.
Unfortunately it remains unclear as to what exactly is being measured by these epigenetic changes. They are far downstream of the damage that causes aging, and there is no clear line of cause and consequence to connect the two. That presents a challenge to those who wish to use epigenetic clocks as a way to rapidly evaluate potential rejuvenation therapies at low cost. Without knowing what the clock measures, the result is not actionable. It is quite possible that any given clock only reflects some of the root causes of aging, or some failing organ systems, and not all of them.
The results here, showing varied outcomes when epigenetic clocks are used to assess mice undergoing a variety of approaches to slow aging, suggest that epigenetic clocks are not yet ready for use in this way. Much more work remains to build clocks that can be used in confidence to quantify the performance of potential rejuvenation therapies, most of which will be bringing new mechanisms to the table, approaches that will not have been calibrated against epigenetic measures in any meaningful way.
Our understanding of age-related epigenetic changes in DNA methylation in humans has progressed rapidly with the technical advancement of genomic platforms. The correlation between chronological age and DNA methylation over the course of an entire lifespan is strong. Recent studies have taken advantage of this relationship to accurately estimate chronological age based on the methylation levels of multiple CpG dinucleotides. For example, the human multi-tissue epigenetic age estimation method combines the weighted average of DNA methylation levels of 353 CpGs into an age estimate that is referred to as DNAm age or epigenetic age.
Most importantly, we and others have shown that human epigenetic age relates to biological age, not just chronological age. This is demonstrated by the finding that the discrepancy between DNAm age and chronological age (what we term "epigenetic age acceleration") is predictive of all-cause mortality even after adjusting for a variety of known risk factors.
We combined hundreds of new DNA methylation samples collected from several mouse tissues with publicly available data from previous studies of mouse DNA methylation. We compared clocks built with different regression methods using hundreds of thousands of CpGs as input as well as a clock constructed from a limited set of mammalian-conserved CpGs. We evaluated the performance of these clocks across samples and tissues. We applied the most accurate clock to samples from previous longevity studies of mice to measure the effects of these interventions on epigenetic aging.
We demonstrate that these data enable construction of highly accurate multi-tissue age estimation methods (epigenetic clocks) for mice that apply to the entire life course (from birth to old age). We demonstrate that these clocks perform well on new tissues not included in the training of the clock by performing tissue exclusion cross-validation. This gives us confidence that these clocks will work on new samples from other tissue types as well.
Our study leads to several novel insights. First, our first prototype of an age estimator based on fewer than 1000 highly conserved CpGs demonstrates that it will be feasible to build highly accurate DNAm age estimator on the basis of highly conserved CpGs. Second, we find that epigenetic clocks that are optimal for estimating age (namely those based on elastic net regression) may be inferior to less accurate clocks (based on ridge regression) when it comes to gold standard anti-aging interventions. Only our ridge regression clock manages to corroborate most of the previously reported findings, e.g. only the ridge clock showed that dwarf strains show slower epigenetic aging relative to wild-type strains. The anti-epigenetic aging effects of calorie restriction are highly robust and could be observed with all clocks. However, none of our clocks managed to detect an anti-aging effect of rapamycin.
These results suggest that the multi-tissue ridge regression DNA methylation clock is most useful in assessing "biological age" for a variety of treatments, experimental interventions, and genetic backgrounds. However, the elastic net clocks are better for assessing chronological age. Overall, this study demonstrates that there are trade-offs when it comes to epigenetic clocks in mice. Highly accurate clocks might not be optimal for detecting the beneficial effects of anti-aging interventions.