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- Advocating for Senolytics to Prevent Accelerated Aging Resulting from Cancer Treatment
- Mitochondrial Complex I Subunit Protein Abundance Correlates with Mammalian Species Longevity
- A Biomarker of Aging Based on Protein Glycosylation Patterns
- Transplanting Gut Microbes from Old Rats to Young Rats Produces Inflammation and Cognitive Decline
- On Nutraceutical Senolytics
- Control of Blood Pressure Reduces Risk of Atrial Fibrillation
- SENS Research Foundation on COVID-19 and Aging
- Physical Activity Slows the Consequences of Aging
- Plasma from Young Rats Reduces Epigenetic Age Measures and Senescent Cell Burden in Old Rats
- Increased Levels of IL-4 Observed in Macular Degeneration
- Ten Weeks of Resistance Training in 60-Year-Olds Doubles NAD+ Levels in Muscle Tissue
- Repair of Mitochondrial DNA Damage as Potential Treatment for Cardiac Aging
- Failing Mitophagy in the Progression of Aging
- Early Life Epigenetic Changes can Set the Stage for Later Life Metabolic Dysfunction
- Alk Inhibitors to Slow Aging
Advocating for Senolytics to Prevent Accelerated Aging Resulting from Cancer Treatment
Chemotherapy and radiotherapy remain the presently dominant forms of cancer treatment. Immunotherapies are making slow inroads, but remain a minority of all treatments. Both chemotherapy and radiotherapy kill cells and force cells into senescence, cancerous cells and otherwise. They are a balance struck between killing the cancer and killing healthy tissue, and are are not pleasant at all for the patient. Cancer survivors have a significantly reduced life expectancy, as large as that resulting from life-long smoking, and evidence strongly suggests that this is due to a significantly increased burden of >senescent cells left behind following treatment.
Cells become senescent for many reasons, including the DNA damage and environmental toxicity produced by chemotherapies and radiotherapies. Senescence is a state of growth arrest in which cells bloat, cease to replicate, and begin to secrete an inflammatory mix of signals intended to attract immune cells. In a youthful, healthy metabolism, senescent cells are created constantly and quickly destroyed. In older people, more senescent cells are created and the processes of destruction become less efficient. Senescent cells accumulate, and their inflammatory signaling degrades tissue and organ function. This accumulation is one of the causes of degenerative aging.
In this sense, chemotherapy and radiotherapy cause accelerated aging. That is a considerably better option than death by cancer, but it may soon be reversible, rather than a fact of life than one must accept. Senolytic therapies capable of selectively destroying some fraction of the senescent cells present in tissue are now a reality, under active development, while some of the early senolytic drugs are readily available on the global market. These have not yet been applied to cancer patients in human trials of their senolytic effects, but that is only a matter of time. The cancer research community is most interested in finding ways to reduce the long-term impact of cancer treatment.
Strategies to Prevent or Remediate Cancer and Treatment-Related Aging
The rapidly aging U.S. population coupled with improved cancer survival rates has led to predictions of unprecedented growth in the number of cancer survivors over the next decade. Unfortunately, many modalities used to cure or control cancer damage healthy tissue, leading rate of functional decline) or accentuate the aging process (e.g., paralleled “normal” aging trajectory with weakened reserve). Data suggests that cancer survivors treated with adjuvant therapies are at risk for early onset of multimorbidity commonly seen in older patients. Estimates indicate that up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with cancer- and treatment-related comorbidities, including frailty, sarcopenia, cognitive impairment, and/or subsequent neoplasms. Adult cancer survivors report engaging in healthy behaviors at levels similar to adults with no history of cancer, and are more likely to adhere to physical activity recommendations. However, there are limited data on how physical activity and other strategies mitigate age-related conditions for cancer survivors.
Aging involves multifaceted, interdependent biological processes that can be altered by cancer and its treatments. The Geroscience Hypothesis postulates that many age-related conditions can be slowed or delayed by targeting hallmarks of aging (e.g., genomic instability, stem cell exhaustion, cellular senescence, inflammation, mitochondrial dysfunction, and epigenetic alterations). Given the complementarity of hallmarks that undergird aging, cancer, and cancer treatments, geroscience-guided interventions might delay or avert the age-related conditions observed in cancer survivors.
To consider emerging strategies that might prevent, mitigate or reverse cancer- and treatment-related aging consequences, the National Cancer Institute (NCI) convened the second of two think tanks under the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Emphasis was placed on therapies linked to age-related conditions or underlying aging processes (hallmarks of aging) that could be potential targets for interventions. Although several age-related processes provide potential targets for interventions, meeting discussions focused on cellular senescence. Cellular senescence is a cell fate that includes an irreversible proliferative arrest. Senescent cells accumulate in multiple tissues, and interestingly, transplanting small numbers of senescent cells into young animals induces frailty and age-related disease. Senescent cells also develop a pro-inflammatory senescence-associated secretory phenotype (SASP) that can disrupt tissue and immune function and create a permissive microenvironment for cancer growth.
Senescent cells are a promising target for aging interventions since these cells do not divide and can be eliminated by intermittent dosing using drugs with short half-lives. The SASP is also modifiable: it can be up- or down-regulated by hormones, pathogens, and drugs. Rapamycin, a mTOR inhibitor, is a promising agent that has been implicated in both aging and senescence. Rapamycin fed to older mice was shown to delay aging and extend lifespan. Senolytics have also achieved success in recent pre-clinical studies; notably, several senolytics are repurposed cancer drugs. The first trial in humans, a pilot, open-label study of dasatinib plus quercetin for idiopathic pulmonary fibrosis, a progressive, fatal, senescence-driven disease, was recently published. After nine doses over three weeks, participants showed improved physical function one-week later. If shown to be safe and effective in larger trials, the hope is that mTOR inhibitors and senolytics can be tested as preventatives of age-related conditions in cancer populations. Research is needed to determine the safety and efficacy of dosing intervals, and systemic, as opposed to local, administration.
Mitochondrial Complex I Subunit Protein Abundance Correlates with Mammalian Species Longevity
The gerontology community is most interested in identifying and quantifying the mechanisms that determine species longevity. Why do different mammalian species have radically different life spans, from the year of a shrew to the centuries of large whales? Some inroads have been made into which portions of cellular metabolism are likely contributing to sizable life span differences, but there is no map of relative contributions or exhaustive list of mechanisms – this is a project that still has a long way to go before completion.
Will knowing more about species life span determination help in producing interventions to increase longevity in our species? This may or may not be the case. There is no particular reason why the important factors in species life span must correlate well with the classes of therapy that will produce rejuvenation. A given species will accumulation forms of molecular damage and dysfunction at a given pace, and effective periodic repair of that damage may well involve completely different mechanisms to those that determine the rate at which damage accumulates.
One area of overlap between mechanisms known to be of interest to species longevity and mechanisms known to be of interest to aging within a species is the structure and function of mitochondria. Mitochondrial dysfunction is prevalent in aging, for reasons that appear to involve an imbalance of fusion and fission of mitochondria, and a consequent failure of the quality control mechanism of mitophagy. Equally, mitochondrial DNA damage can produce mutant mitochondria that overtake cells and cause them to export damaging reactive molecules into surrounding tissue. In the study of aging and life span by species, researchers have shown that mitochondrial composition and metabolic rate correlate well with species life span, giving rise the the membrane pacemaker theory of aging. Some species have mitochondria that are more resilient to oxidative damage, which can slow the onset of dysfunction with aging.
Today’s open access paper is an interesting addition to this body of literature. Researchers show that some components of mitochondrial machinery vary in abundance in ways that correlate with mammalian species life span. This seems likely to affect the generation of oxidative molecules by mitochondria, and thus also alter the balance of oxidative damage and mitochondrial dysfunction. This part of the field is still very much a collection of correlations and hypotheses, however. It is quite possible to argue for other interpretations of what is observed, or to expect that more data might upturn an existing consensus.
Low abundance of NDUFV2 and NDUFS4 subunits of the hydrophilic complex I domain and VDAC1 predicts mammalian longevity
Complex I (Cx I) (NADH-ubiquinone oxidoreductase) is an electron entry point in the mitochondrial respiratory electron transport chain (ETC). Cx I catalyses NADH oxidation reducing ubiquinone to ubiquinol, importantly contributing to the proton motive force used to synthesize ATP by the oxidative phosphorylation. Cx I also produce reactive oxygen species (ROS), initially superoxide radicals, which can damage all cellular components. Although at least 11 sites producing ROS have been identified, Cx I and complex III (Cx III) are conventionally recognized as the major sources of ROS at the ETC. Mitochondrial ROS production (mitROSp) has been considered one of the main effectors responsible for aging and longevity.
Low rates of mitROSp have been described in many long-lived mammalian and bird species. These studies generally demonstrated the existence of a negative correlation between mitROSp and longevity. Among the two main ROS generating ETC complexes, the low ROS production of various long-lived species has been localized at Cx I. Interestingly, different pro-longevity nutritional and pharmacological interventions like dietary restriction (DR) and methionine restriction, and rapamycin treatment have been also associated with decreased mitROSp at Cx I.
Mammalian Cx I is the largest component of the ETC built of 45 different subunits in mammals. Among the 14 core subunits, the 7 mitochondrial-encoded ND subunits are present in the hydrophobic membrane domain, and the other 7 nuclear-encoded (NDUF) subunits are present in the hydrophilic matrix domain. The 31 supernumerary NDUF accessory subunits are also nuclear coded. However, it is totally unknown if some particular Cx I subunits, especially some NDUF subunits of the Cx I hydrophilic domain, could be involved in the determination of the longevity-related low complex I ROS production of long-lived animal species.
The present study follows a comparative approach to analyse Cx I in heart tissue from 8 mammalian species with a longevity ranging from 3.5 to 46 years. Gene expression and protein content of selected Cx I subunits were analysed. Our results demonstrate: 1) the existence of species-specific differences in gene expression and protein content of Cx I in relation to longevity; 2) the achievement of a longevity phenotype is associated with low protein abundance of subunits NDUFV2 and NDUFS4 from the matrix hydrophilic domain of Cx I; and 3) long-lived mammals show also lower levels of VDAC (voltage-dependent anion channel) amount. These differences could be associated with the lower mitochondrial ROS production and slower aging rate of long-lived animals and, unexpectedly, with a low content of the mitochondrial permeability transition pore in these species.
A Biomarker of Aging Based on Protein Glycosylation Patterns
Today I’ll note the development of a commercial aging clock based on glycosylation patterns of immunoglobulin G, a marker for the inflammatory status of the immune system, by startup biotech company GlycanAge. There are at present any number of approaches to measuring biological age, the burden of cell and tissue damage that leads to dysfunction. Stage of development varies widely, with the most work to date being on clocks based on changes in DNA methylation. There are also clocks that use protein levels in blood, weighted combinations of simple measures such as grip strength, and other approaches besides these. The important goal in these efforts is to produce a measure that can quickly be applied before and after a potential intervention to quantify the degree to which it reverses aging. A generally accepted, fast, cheap measure of age would greatly accelerate development of rejuvenation therapies, and might finally focus more research attention on repair-based interventions that have a greater chance of producing large effect sizes.
That still lies a way in the future, however. The challenge with near all of these clocks is that they are constructed by comparing data that is far downstream of the causes of aging against outcomes such as mortality risk. Thus there is no good understanding of what exactly it is that these biomarkers of aging are actually measuring, under the hood. The glycosylation clock is more clear than most, in that it is very directly an assessment of the chronic inflammation of aging, but even then it is a challenge to say which underlying causes of aging are more or less important in that outcome. The situation is much murkier for other clocks.
This lack of knowledge means that a clock must be calibrated against each potential intervention, in the slow, hard way, by waiting to assess lifespan, in order to ensure that it is a valid test. This somewhat defeats the point of the exercise, to make development faster for new interventions. Further, it means that most of the commercially available tests are not actionable: the test will produce a number, but that number says nothing about what might be done to change it. The glycosylation clock is at least ahead of the game on that front, pointing directly to whatever approaches are known to reduce chronic inflammation, but this may or may not still be somewhat disconnected from other processes of aging.
Start-up claims first commercial glycan-based age test
GlycanAge is a British-Croatian start-up focused on analysing glycosylation patterns to deliver what it claims is the “most accurate” measure of biological age. Glycans are complex sugars that contribute significantly to the structure and function of the majority of proteins. Changes in glycans have been reported in many inflammatory diseases, where they reflect disease activity, or in some cases even precede the development of disease.
The company, leveraging patents from leading glycomics research lab Genos, has developed a direct-to-consumer glycan test kit that measures biological age and chronic low grade systemic inflammation. When the company first started in 2016, it worked using plasma samples, which was expensive and hard to scale commercially, but it has since developed a dry blood spot based test that delivers the same results.
“Telomeres are DNA timers that limit the lifespan of a single cell. On the individual cell level, telomeres are the best marker of aging. However, we are composed of trillions of cells and each of them has different age and expected lifespan. GlycanAge is different because it measures your immunoglobulin G glycosylation, which directly correlates with the level of inflammation in your body. It will give you information about the immune balance of your organism that changes with age, health and life circumstances.”
GlycanAge is a science-based test that will accurately determine your biological age. This is a first commercial glycan-based test that will put a single number to your health. Glycans are complex sugar molecules (carbohydrates), and one of the four main building blocks of life. They are involved in almost every process in our body.
More than half of all our proteins are glycosylated, with their glycan parts often playing an essential functional role. Glycans are crucial for the functioning of our immune system. Glycans attached to the antibodies modulate their activity and determine if they will have a pro-inflammatory or anti-inflammatory function. Thus, it is not surprising that glycan profiles can serve as a measure of an individual’s health. The GlycanAge test looks at the glycosylation pattern of the immunoglobulin G (IgG) molecule. IgG is the most prevalent antibody type in our blood and especially important in controlling inflammation and pathogens.
Immunoglobulin G (IgG), the most prevalent antibody type in our blood, is always glycosylated – meaning it has glycans attached to it. The type of the glycan group attached to the IgG determines if IgG will enhance or reduce inflammation. Since inflammation can exhaust our resources to keep the body in good health, low level of inflammation was shown to be a predictor of successful ageing. Therefore, IgG glycosylation is also a good measure of biological age.
Transplanting Gut Microbes from Old Rats to Young Rats Produces Inflammation and Cognitive Decline
Today’s open access paper is interesting on two counts. Firstly as one of a number of studies in recent years examining the effects of age-related changes in the gut microbiome via fecal transplantation between young and old animals. Secondly, it suggests that negative effects on cognitive function resulting from these changes is mediated by chronic inflammation generated by the interaction of harmful gut microbes with the immune system.
There is a growing interest in the age-related shift in microbial populations in the gut. Researchers have identified some important metabolites that are generated at lower levels in older people as a result of loss of beneficial microbes. These include butyrate, propionate, and indole. Supplementation is a possibility, but this is by no means a comprehensive list, and that will not solve all of the other issues, such as growing populations of harmful microbes aggravating the immune system to generate chronic inflammation. Fixing the balance of populations is the more sensible path forward, and given sufficient funding for development and trials, the medical community might deploy fecal microbial transplantation from young to old as an intervention.
It is quite unclear as to why microbial populations change for the worse with age. The direction of causation between immune dysfunction and a worse gut microbiome might be in either direction. The earliest significant changes occur around age 35, which seems far too young for any of the obvious mechanisms of aging to be producing meaningful pathology. There are many potential contributing causes in later life, including the aforementioned immune dysfunction, dietary changes, lack of exercise, and declining tissue function of the intestines. Establishing which of these causes are actually important is very much a work in progress.
Age-related shifts in gut microbiota contribute to cognitive decline in aged rats
The human gastrointestinal tract harbors a complex and dynamic population of microorganisms, referred to as gut microbiota. The gut microbiota is very important for the development and homeostasis of the body; it regulates intestinal motility and gastrointestinal barrier, host energy metabolism and mitochondrial function, as well as immune responses and the central nervous system. In adulthood, the microbiota reaches a relative equilibrium, and does not significantly change under stable environmental and health conditions. Generally, the phyla Bacteroidetes and Firmicutes dominate the intestine for adulthood. However, with an increasing age, the gut microbiota undergoes a profound remodeling. Researchers have shown that the gut microbiota of the elderly is substantially different from the younger adults, and correlates with frailty. However, given our current inability to delineate the most significant effector mechanisms involved in the host-microbiota interactions over a lifetime, it is difficult to tease apart causality from correlation.
Although some animal studies indicated that the gut microbiota affects learning and memory, these reports were based on special animal models, such as germ-free (GF) mice, or on various artificial interventions that change the gut microbiota, such as pathogenic bacterial infection, probiotics, and antibiotics. Since the aging process and aging biological characteristics were not considered in these studies, they were not able to uncover the association between gut microbiota and cognitive function under normal aging process. Given these findings, we hypothesized that alterations in the gut microbiota contribute to cognitive decline in aging. In this study, we transplanted the gut microbiota from aged rats to young rats by using the fecal microbiota transplantation (FMT) technique, to observe whether the reshaped gut microbiota can cause a shift in cognitive behavior, brain structure, and functions in the young recipient rats. To our knowledge, this is the first study that investigates the effect of gut microbiota on cognitive decline in normal aging process.
Results showed that FMT impaired cognitive behavior in young recipient rats; decreased the regional homogeneity in medial prefrontal cortex and hippocampus; changed synaptic structures and decreased dendritic spines; reduced expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor NR1 subunit, and synaptophysin; increased expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE). All these behavioral, brain structural and functional alterations induced by FMT reflected cognitive decline. In addition, FMT increased levels of pro-inflammatory cytokines and oxidative stress in young rats, indicating that inflammation and oxidative stress may underlie gut-related cognitive decline in aging. This study provides direct evidence for the contribution of gut microbiota to the cognitive decline during normal aging and suggests that restoring microbiota homeostasis in the elderly may improve cognitive function.
On Nutraceutical Senolytics
Nutraceuticals are compounds derived from foods, usually plants. In principle one can find useful therapies in the natural world, taking the approach of identifying interesting molecules and refining them to a greater potency than naturally occurs in order to produce a usefully large therapeutic effect. Unfortunately, in practice the nutraceutical industry is a largely a lazy one, in which entrepreneurs take advantage of a short path to market, and a lack of interest among consumers in whether or not products actually work, in order to repackage cheap ingredients into expensive brands that have minimal, unreliable, or even no beneficial effects.
In today’s open access paper, researchers discuss the potential for nutraceutical research and development to produce useful senolytic compounds. A senolytic therapy is one that selectively kills senescent cells in aged tissues, thus reversing aspects of aging by removing the inflammatory, harmful signaling of these cells. This class of therapy has performed well in animal models, and early human trials continue to produce promising outcomes.
Any survey of nutraceutical development is, as noted above, going to include a lot of useless, overhyped lines of work. Just because a mechanism exists doesn’t mean that the mechanism produces a large enough benefit to be therapeutic, and tiny to nonexistent effect sizes are characteristic of nutraceutical development. It is safe to tune out any time compounds in green tea are mentioned, for example. Still, some plant extract senolytics, such as fisetin and piperlongumine, do appear to have interestingly large effects in animal studies – even similarly sized to the small molecule chemotherapeutic senolytics. Whether they do as well in human trials remains to be seen, but making the attempt is not unreasonable based on the animal data.
An Appraisal on the Value of Using Nutraceutical Based Senolytics and Senostatics in Aging
Recent studies argue for a pathogenic role of senescent cells, which contribute to a range of aging related diseases, such as osteoarthritis, cardiovascular disease, and cataract. Senescent cells are found in aging related cognitive decline but also in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Therefore, the possible application of senolytics in a wide range of clinical scenarios is becoming an attractive concept. Senolytics could be used as a preventative in the elderly, as a supplement to clear senescent cells to thus improve or maintain tissue and organ health. They are also being looked at as an adjuvant cancer therapy, with the aim of clearing treatment-induced senescent cells and thus reducing the probability of relapse.
Synthetic compounds with senolytic or senostatic properties can be effective, however, they are not specific, and systemic side effects can be severe and deleterious to healthy cells. Hence, a movement toward the research of natural based compounds (nutraceuticals) with potential anti-senescence properties has begun. Nutraceuticals are bioactive compounds derived from food, including plant material, with physiological benefits in the prevention or treatment of disease. For instance, polyphenols, found in high abundance in plants, are bio-active compounds with anti-oxidant and anti-inflammatory properties making them potential senostatics by negating the pro-oxidant and pro-inflammatory signaling of senescent cells. The aim remains to find potential anti-aging therapies that are effective but exhibit minimal side effects, and some natural plant-based compounds could fit this criterion.
In vitro, two olive phenols called hydroxytyrosol (HT) and oleuropein aglycone (OLE) have shown to counteract senescence via significant reductions in SA-β-Gal staining, p16 levels, and senescence-associated secretory phenotype (SASP) levels in human lung fibroblasts and neonatal human dermal fibroblasts. Catechin is a tannin found in green tea that exists in multiple forms, including Epigallocatechin gallate (EGCG). Research investigating the effects of EGCG against replicative senescence in cells has shown the potential senostatics effects of the nutraceutical. Fisetin is bioactive flavonol molecule. Naturally aged C57BL/6 mice treated orally at 22-24 months with 100 mg/kg fisetin for 5 days showed a reduction in senescent cells in white adipose tissue. Additionally, fisetin treatment at 85 weeks of age significantly prolonged life-span of these mice by an additional 3 months. Resveratrol treatment in endothelial progenitor cells (EPCs) also showed prevention of replicative senescence. However, when a large-scale in vivo study of resveratrol in genetically heterogenous (outbred) mice was conducted in parallel with rapamycin treatment, analysis of activity showed that there was no significant difference between control and resveratrol-treated mice.
For senolytics to be widely used in aged but otherwise healthy populations to prevent tissue dysfunction, unwanted side effects have to be kept to the minimum. The use of nutraceutical based senolytics could result in fewer complications, while retaining anti-senescent effects. Despite promising in vitro reports, the data on the in vivo efficacy of nutraceutical senolytics is still sparse and, in some cases, contradictory. Thus, more research is still needed to determine whether they could be an attractive alternative to the most used chemical senolytics, such as dasatinib + quercetin, which have shown promising results in preliminary short-term clinical trials.
Control of Blood Pressure Reduces Risk of Atrial Fibrillation
Raised blood pressure with age, hypertension, strongly correlates with cardiovascular disease risk and overall mortality. Hypertension is an important downstream mechanism in aging, a way in which low level biochemical damage – such as cross-linking that stiffens blood vessel walls, or inflammation that produces dysfunction in smooth muscle cells – gives rise to pressure damage to sensitive tissues throughout the body. Hypertension accelerates the progression of atherosclerosis, the development of fatty deposits that weaken and narrow blood vessels, and is associated with a greater risk of atrial fibrillation, an abnormal heart rhythm. This latter correlation may be due to the way in which hypertension produces changes in the structure of the heart, such as a growth and weakening of heart muscle.
Intensive blood pressure control may reduce the risk of atrial fibrillation (AFib), an irregular heartbeat that can lead to serious complications such as stroke, heart failure, and heart attacks. Researchers found that lowering a systolic blood pressure to less than 120 resulted in a 26% lower risk of AFib compared to systolic blood pressure of less than 140.
This analysis, using data from the National Institutes of Health Systolic Blood Pressure (SPRINT) trial, included 8,022 study participants who were randomized into one of two groups: 4,003 participants in an intensive blood pressure control group (target less than 120 mm Hg) and 4,019 participants in a standard lowering group (target less than 140 mm Hg).
Participants were followed for up to five years. During that time, only 88 AFib cases occurred in the intensive blood pressure lowering group while 118 cases occurred in the standard blood pressure lowering group. Researchers showed that the benefit of intensive blood pressure lowering on reducing the risk of AFib was similar in all groups of the participants regardless of sex, race, or levels of blood pressure.
SENS Research Foundation on COVID-19 and Aging
SENS Research Foundation here explains why COVID-19, like near all infectious disease, is far worse for the old. It isn’t just a matter of the decline of immune function, though that is the bulk of it. Older people have a greater burden of damage and dysfunction that makes them less resilient in many other ways. Rising mortality due to infectious disease with age is the result of both (a) a greater likelihood of severe infection due to immune aging, and (b) that the individual is less likely to survive a severe infection due to general frailty. Tens of thousands die every year in the US from seasonal influenza; that is largely ignored, taken as a fact of life when considered at all. But the research and medical communities are on the verge of being able to reverse the consequences of aging, to develop rejuvenation therapies that will improve immune function and resilience in the old. This work needs greater support than it presently receives if we are to see significant progress over the next decade.
Through all the daily updates on the sick and the dead, on testing and hospital capacity and changing public health guidance, there remains one constant: by far the greatest predictor of death from the COVID-19 pandemic is age. The so-called comorbidities predisposing patients to death from COVID-19 – chronic lung diseases, damaged kidneys and hearts, high blood pressure, diabetes – are themselves aspects of aging, erupting in their distinctive ways in particular tissues. Flattening this “demographic curve” of degenerative aging would reduce COVID-19 to a disease similar in impact to an average recent flu season (and make future flu seasons less deadly), while also putting an end to the staggering toll of age-related death and debility that ticks on in the background even now, day in and day out, pandemic or none.
The most obvious link between aging and COVID-19 is the aging of the immune system, or immunosenescence. Older people mount a much weaker and less complete immune response to both infection and vaccine, even as they suffer increasingly from overactive parts of the immune response, including autoimmunity and chronic inflammation. In today’s pandemic, COVID-19 patients suffer from an exhaustion of natural killer (NK) and CD8+ (“killer”) T-cells. Whereas T-cells and B-cells are specialists, focused on eliminating specifically-identified threats (such as cells infected with specific viruses), NK cells are sentinels patrolling the perimeter of a military camp, on the lookout for anything that looks like it doesn’t belong. Long before the pandemic hit, we knew that NK cells lose much of their effectiveness with age, meaning that aging people already come into the fight against infections like SARS-CoV-2 with these critical early responders weakened.
We’ve known for a while that the age-related loss of lung function is a massive driver of risk of death from pneumonia. Aging people not only have fewer functional alveoli available, but progressively lose the ability to inhale and exhale deeply to compensate for alveoli taken offline by the infection. Continuing research suggests that eliminating senescent cells in the lung may preserve and restore youthful lung function, leaving the lungs better prepared to endure the attack of the SARS-CoV-2 virus and other causes of pneumonia. Senolytic drugs, which selectively kill senescent cells, have been shown to reverse lung fibrosis and other tissue fibrosis in aging mice. Studies in aging mice demonstrate that ablating senescent cells restores youthful lung compliance, suggesting an opportunity to do the same with other senescent-cell elimination strategies, such as restoring the ability of NK cells to eliminate them from tissues.
Like the pandemic, aging touches all of us. It creeps silently through our tissues, progressively crippling our minds and bodies, and eventually killing us if we don’t die first of accident, violence, or other abrupt age-independent causes. In COVID-19, the damage caused by aging is the largest factor in determining who lives and who dies, even if the trigger was pulled by a virus spread by globalization. The need for rejuvenation biotechnologies as part of medicine has never been clearer, and so we strengthen our resolve. Restoring our cells and tissues to youthful vigor will allow us to step out of our ancient lockdown and into a bright future.
Physical Activity Slows the Consequences of Aging
We live in a world in which most people do not undertake anywhere near the level of physical activity that is optimal. Thus adding greater physical activity as a lifestyle choice appears very beneficial. There is a great deficiency, one that has serious consequences to health, and fixing that deficiency is touted as a successful intervention. But in reality, the situation is one in which most people harm their long term health through a form of self-neglect. This era of cheap calories and comfort is a time of vast benefits for humanity – but it has a few downsides, and this is one of them.
This meta-analysis showed a protective effect of physical activity to successful aging among the middle-aged and older adults. The protective effect of physical activity to successful aging was larger on the younger group than the older group. Being physically active in earlier life is beneficial to successful aging in later life. However, the effect of physical activity on successful aging decreased as time elapsed. Physically active middle-aged and older adults were more likely to age successfully than sedentary adults (odds ratio 1.64). The effect of physical activity was stronger in the younger group (odds ratio 1.71) than on the older group (odds ratio 1.54). The protective effect of physical activity reduced annually by approximately 3%.
Physical activity prevents the development of many chronic diseases, including metabolic syndrome, type 2 diabetes, coronary artery disease, hypertension, stroke, dyslipidemia, cognitive impairment, depression, osteoarthritis, osteoporosis, colon cancer, breast cancer, non-alcoholic fatty liver disease, and sarcopenia. Physical activity also increases longevity and survival. For middle-aged and older people, a dose-response relationship was found between physical activity and decrease in mortality. Compared with sedentary older people, physically active older adults were more likely to remain living independently. Physical activity in old age preserves the cognitive and physical functions. These previous findings supported the main finding of the present meta-analysis.
Physical activity is a protective factor of successful aging in the middle-aged and older adults. Although some included studies showed a weak association between physical activity and successful aging, most studies reported a consistent positive relationship. Further research is warranted to establish the dose-response relationship between physical activity and successful aging as well as to reduce the effects of time.
Plasma from Young Rats Reduces Epigenetic Age Measures and Senescent Cell Burden in Old Rats
This study is interesting on a few counts. Firstly, transfusion of old individuals with plasma from young individuals has failed to produce usefully large benefits in human trials, and the evidence in mice looks similarly shaky. Yet here, in rats, benefits are observed with a specific approach to producing a plasma fraction for use in therapy. The authors do not divulge details regarding the methodology of production, as they intend commercial development in the near future. Secondly, it connects epigenetic age reduction with reduction in senescent cell burden. It is worth noting that the epigenetic clocks used here to assess biological age are new, not existing clocks, however. The reduction in senescent cells is thus the more interesting measure to result from the study. As a final note, only a small number of rats were used in the plasma transfusion portion of the study, so this is very much a result that requires replication.
Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data.
We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.
Increased Levels of IL-4 Observed in Macular Degeneration
The wet form of age-related macular degeneration involves an excessive growth of blood vessels behind the retina, disrupting structure to produce a progressive and presently irreversible loss of vision. Researchers here point out a role for IL-4 in this process, though the mechanisms involved are probably a fair way downstream from the causes of chronic inflammation and immune system dysfunction that spur the development of macular degeneration. Sometimes it is a possible to find a good place to sabotage the development of pathology that is distant from the root causes, but the odds are not favorable. More commonly, later stage intervention is the path to only marginally effective therapies.
Scientists have identified an unexpected player in the immune reaction gone awry that causes vision loss in patients with age-related macular degeneration (AMD). The findings suggest that an immune-stimulating protein called interleukin-4 (IL-4) and its receptor may be promising targets for new drugs to treat AMD, a common form of age-related vision loss. In patients with AMD, inflammation in the eye triggers excessive growth of new blood vessels in the center of the retina. This process damages the photoreceptors in the eye and leads to progressive vision loss.
The team measured levels of IL-4 in the eyes of 234 patients with AMD and 104 older individuals undergoing surgery for cataracts. They found that those with AMD had higher levels of IL-4 than those undergoing surgery. Next, they found that IL-4 was also elevated in mice with a condition that mimics AMD. To determine if IL-4 was helping or harming the animals, they administered them with IL-4 and found that it increased the excessive growth of blood vessels in the eye. An antibody that blocks IL-4 production reduced this blood-vessel growth. Mice with the AMD-like condition that were genetically engineered to lack IL-4 also had less blood-vessel growth.
“Our results show that IL-4 plays a crucial role in excessive blood-vessel growth by recruiting bone marrow cells that aid this growth to the lesion in the eye. These results were surprising and suggest that normally helpful immune responses can instead cause more harm,. As IL-4 plays a key disease-promoting role in AMD, it may serve as a target for new treatments to treat this condition.” Normally, bone marrow cells help the body repair damaged tissues, while IL-4 helps suppress excessive blood vessel growth.
Ten Weeks of Resistance Training in 60-Year-Olds Doubles NAD+ Levels in Muscle Tissue
When looking at any of the work presently taking place on improving metabolism in older individuals, whether by stress response upregulation, or by improving mitochondrial function, it is always worth checking the human data, where it exists, to compare the effect size with that of exercise. This open paper is a useful resource when comparing exercise to the class of approaches that fairly directly increase levels of NAD+/NADH. These molecules are involved in mitochondrial function, and for various reasons – decline in recycling, decline in synthesis – become less available with age.
A number of supplements and treatments are on the market or under development to increase NAD+ levels in older people, and an initial human trial has been published for nicotinamide riboside. In that trial, nicotinamide riboside supplementation boosted NAD+ by 60% or so in immune cells from a blood sample. In the paper here, NAD+ was more than doubled in muscle cells following ten weeks of resistance training, restoring levels in older people to that of collage-aged individuals. This is not an apples to apples comparison, but worth considering while thinking about the present enthusiasm for NAD+ upregulation. The long term effects of exercise and resistance training are quite well catalogued, and while beneficial, do not greatly extend life.
Nicotinamide adenine dinucleotide (NAD+) is a metabolite involved in numerous biochemical reactions. In particular, NAD+ is involved with electron transport where the reduced form (NADH) transfers electrons to other substrates and intermediates of metabolism. There is enthusiasm surrounding the role that tissue NAD+ concentrations play in the aging process, and researchers have determined skeletal muscle NAD+ concentrations are lower in older rodents and humans. These findings have led some to suggest that the age-associated loss in skeletal muscle NAD+ levels contributes to mitochondrial dysfunction. NAD+ biosynthesis can be catalyzed through the salvage/recycling pathway, and nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in this pathway. Beyond its involvement with redox reactions, NAD+ binds to and activates a class of enzymes that possess deacetylase activity called sirtuins (SIRTs).
Endurance training appears to be capable of increasing skeletal muscle markers related to NAD+ and SIRT signaling. For instance, endurance training in rodents and humans has been shown to modulate SIRT1 and SIRT3 protein levels and increase the activity of these enzymes in skeletal muscle. Additionally, skeletal muscle NAMPT protein levels have been reported to be higher in endurance-trained athletes versus untrained individuals. However, there is a paucity of research examining these biomarkers in response to resistance training. It remains plausible that resistance training can increase skeletal muscle markers related to NAD+ biosynthesis and SIRT signaling, and this may be an involved mechanism in facilitating training adaptations.
Given the paucity of data in this area, we sought to examine the effects of resistance training on skeletal muscle NAD+ concentrations as well as NAMPT protein levels, SIRT1/3 protein levels, and markers of SIRT activity in middle-aged, overweight, untrained individuals. In the middle-aged participants, the 10-week training intervention: i) promoted training adaptations (i.e., increased strength and localized hypertrophy), ii) robustly increased muscle NAD+ and NADH concentrations, iii) modestly (but significantly) increased NAMPT protein levels and global SIRT activity, and iv) robustly increased citrate synthase activity levels in muscle suggesting mitochondrial biogenesis occurred. This is the first evidence to suggest resistance training in middle-aged individuals restores muscle NAD+ and NADH concentrations to levels observed in recreationally-trained college-aged individuals.
Repair of Mitochondrial DNA Damage as Potential Treatment for Cardiac Aging
Mitochondrial DNA damage is a contributing cause of aging, and researchers here look at this issue in the context of the aging of heart tissue. Mitochondria are the power plants of the cell, a herd of bacteria-like structures that contain their own small genome, and work to produce the chemical energy store molecule adenosine triphosphate. This is an energetic process that produces oxidative molecules as a byproduct, capable of damaging cellular machinery and requiring maintenance and antioxidant processes as a defense. Mitochondria are destroyed by the quality control mechanism of mitophagy when damaged, and replicate to make up their numbers.
Some forms of mitochondrial DNA damage can subvert quality control and lead to problem cells overtaken by broken mitochondria, exporting harmful reactive molecules into the surrounding tissue. Ways to repair or replace damaged mitochondrial DNA will likely turn back aspects of aging by removing a source of damage and dysfunction, but the various approaches to this challenge are as yet still comparatively early in the development process.
Cardiac aging resulting in defects in cardiac mitochondrial function centers on the mitochondrial DNA (mtDNA) damage. The mechanisms of the alterations in the aging heart mainly involve mitochondrial dysfunction, altered autophagy, chronic inflammation, increased mitochondrial oxidative stress, and increased mtDNA instability.
Reactive oxygen species (ROS) play a pivotal role in healthy cellular and mitochondrial signaling and functionality. However, if unchecked, ROS can mediate oxidative damage to tissues and cells, leading to a vicious cycle of inflammation and more oxidative stress. Meanwhile, mitochondria, the major source of ROS, are thought to be particularly vulnerable to oxidative damage. Because of its richness in mitochondria and high oxygen demand, the heart is at high risk of oxidative damage. The most supportive evidence of the central role of mitochondrial ROS in the aged heart is that overexpression of catalase targeted to mitochondria attenuates cardiac aging.
A growing body of evidence suggests that there is increasing oxidative damage to mitochondrial DNA in cardiac aging. Because of the histone deficiency, limited DNA repair capabilities, and proximity of mtDNA to the site of mitochondrial ROS generation, mtDNA can suffer various types of damage, including mtDNA point mutations, mtDNA point deletions, and decreased mtDNA copy number (mtDNA-CN). The continuous replicative state of mtDNA and existence of the nucleoid structure render mitochondria vulnerable to oxidative damage and mutations.
DNA polymerase gamma (DNA Pol γ) plays a vital role in mtDNA replication. DNA Pol γ has two main functions: mtDNA synthesis and proofreading. Recent studies report that ROS reduces the proofreading ability of Pol γ, causing replication errors. Thus, oxidation aggravating mtDNA mutations causes replication errors, which indirectly cause mtDNA damage. This proves that mtDNA mutations are largely random, and Pol γ oxidation is likely to account for mtDNA mutations in aging. Therefore, mtDNA mutation may be highly associated with heart aging, and the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.
Failing Mitophagy in the Progression of Aging
Mitochondria, the power plants of the cell, decline in function with age. This contributes to the development of age-related conditions, particularly in energy-hungry tissues such as muscle and brain. An important proximate cause of this failure is disruption of mitophagy, a form of the cellular maintenance process of autophagy that recycles damaged mitochondria. This in turn might be due to an imbalance of fission and fusion of mitochondria, leading to large mitochondria that are resistant to mitophagy. It may also be due to various dysfunctions in mechanisms of autophagy that emerge in old tissues. The underlying causes below that level are poorly understood, but interventions that enhance autophagy are one possible starting point for the development of therapies to improve faltering mitochondrial function in older people.
A decline in mitochondrial function is a hallmark of the aging process and is connected to other aging hallmarks such as telomere dysfunction, genome instability, and cellular senescence. However, it remains largely unclear how these processes are interconnected and finally provoke disruption of the cellular and tissue integrity. There is accumulating evidence that mitophagy impacts health- and lifespan in different model organisms. The effect of changes in mitophagy on health- and lifespan has been particularly demonstrated by using the model organisms C. elegans and D. melanogaster. Several genetic studies in D. melanogaster revealed that the overexpression of mitochondrial and mitophagy genes leads to increased health- and/or lifespan. For instance, the overexpression of the mitochondrial fission protein dynamin-related protein 1 (DRP1) increased the lifespan along with a prolonged healthspan in flies.
An increasing number of human diseases have been associated with impaired mitophagy, thus, interventions that modulate mitophagy may provide the possibility of counteracting disease development or progression. In recent years, multiple small molecules as well as lifestyle interventions have been shown to modulate autophagy, thereby causing health- and lifespan benefits in different organisms. Due to the dependency on core autophagy regulators, mitophagy is modulated by most of the classic autophagy inducers such as the mTOR inhibitor rapamycin, the AMP-activated protein kinase (AMPK) activator AICAR, as well as caloric restriction and exercise.
Mitophagy is emerging as a central process preserving organismal and, especially, neurological health. Since most trials targeting age-associated neurodegeneration in the last decades have been disappointing, new pharmaceutical avenues are direly needed. Here, mitophagy stimulators could play a key role. Indeed, several clinical trials are underway testing the efficacy of mitophagy modulating compounds and the outcome of these studies will undoubtedly prove critical for the future translatability of the field. Nonetheless, the regulatory mechanism of mitophagy and its contribution to age-associated diseases still remains elusive and potential issues with artificially augmenting mitophagy have not been considered. However, given the central role of mitophaging in multiple age-related pathologies it appears highly likely that these new promising approaches may present possible interventions in age-associated diseases. The future is bright!
Early Life Epigenetic Changes can Set the Stage for Later Life Metabolic Dysfunction
Epigenetic markers on DNA determine the pace and timing of protein production, and are thus one of the important influences on cell and tissue function. Cells adjust their epigenetic programs in response to the surrounding environment, but alterations can be lasting. It is thought that environmental influences on epigenetic programming of cellular behavior that occur in childhood set the stage for faster or slower onset of metabolic dysfunction in later life, once cell and tissue damage starts to accumulate. Researchers here provide a proof of principle of this process in rats.
Environmental exposures during early life exert a profound influence on developing organs, which can affect health across the life-course, and even transgenerationally. The adverse health impact of these exposures is thought to be mediated by reprogramming of normal physiologic responses, and forms the basis of the developmental origins of health and disease (DOHaD) paradigm. Fetal over- or under-nutrition has been linked to metabolic dysfunction in adulthood and increased risk for metabolic diseases including obesity, diabetes, and metabolic syndrome. Besides nutritional stressors, early-life exposures to environmental chemicals, including endocrine-disrupting chemicals (EDCs), can influence health and disease susceptibility across the life-course.
EDCs are defined as exogenous chemicals, or mixture of chemicals, that interfere with hormone action and many have been shown to impact metabolic function, and increase disease risk in metabolic organs such as the liver. Recently, the epigenetic machinery has emerged as a target for EDCs and other environmental exposures. When this machinery is perturbed early in life, the resulting epigenetic alterations can persist long after the initial environmental insult (often referred to as developmental reprogramming). Accordingly, research on the causes of the epidemic rise in metabolic diseases has expanded beyond genetics, over-nutrition, and energy expenditure to include the role of early-life EDC exposures. However, little is known about what determines vulnerability to early-life exposures, or specific targets and pathways linking developmental reprogramming by early-life exposures to later-life metabolic dysfunction.
Using a rat model for exposure to an endocrine disrupting chemical (EDC), we show that early-life chemical exposure causes metabolic dysfunction in adulthood and reprograms histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature. This epigenomic reprogramming persists long after the initial exposure, but many reprogrammed genes remain transcriptionally silent with their impact on metabolism not revealed until a later life exposure to a Western-style diet. Diet-dependent metabolic disruption was largely driven by reprogramming of the Early Growth Response 1 (EGR1) transcriptome and production of metabolites in pathways linked to cholesterol, lipid, and one-carbon metabolism.
Alk Inhibitors to Slow Aging
A number of receptor tyrosine kinases are implicated in areas of metabolism known to influence the pace of aging in short-lived laboratory species. Researchers here investigate Alk, a receptor tyrosine kinase previously understudied in this context. It isn’t clear that this will do any better as a basis for human therapies. In general this class of efforts to manipulate metabolism produces diminishing returns as species life span increases. Short-lived worms, flies, and mice exhibit a life span that can vary widely in response to environmental circumstances and changes in metabolism. We long-lived humans do not.
Inhibition of signalling through several receptor tyrosine kinases (RTKs), including the insulin-like growth factor receptor and its orthologues, extends healthy lifespan in organisms from diverse evolutionary taxa. This raises the possibility that other RTKs, including those already well studied for their roles in cancer and developmental biology, could be promising targets for extending healthy lifespan. Here, we focus on anaplastic lymphoma kinase (Alk), an RTK with established roles in nervous system development and in multiple cancers, but whose effects on aging remain unclear.
We find that several means of reducing Alk signalling, including mutation of its ligand jelly belly (jeb), RNAi knock-down of Alk, or expression of dominant-negative Alk in adult neurons, can extend healthy lifespan in female, but not male, Drosophila. Moreover, reduced Alk signalling preserves neuromuscular function with age, promotes resistance to starvation and xenobiotic stress, and improves night sleep consolidation. We find further that inhibition of Alk signalling in adult neurons modulates the expression of several insulin-like peptides, providing a potential mechanistic link between neuronal Alk signalling and organism-wide insulin-like signalling. Finally, we show that TAE-684, a small molecule inhibitor of Alk, can extend healthy lifespan in Drosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.