Fight Aging!

OneSkin Technologies is one of the first generation of startup biotech companies in the longevity industry; you'll find an overview of their programs and technology in an interview with founder Carolina Reis last year. In summary, OneSkin works on both improved models of aging skin, and topical senolytic compounds capable of selectively destroying the senescent cells thought to be responsible for a sizable fraction of skin aging in later life. Unlike other companies in the longevity industry, the OneSkin staff is focused on the cosmetics regulatory path to market. This is in some ways more limited, and in other ways much cheaper and faster than the standard investigational new drug approach with the FDA.

Today's news is more on the modelling front of the company's efforts, in that OneSkin has developed a DNA methylation clock for age assessment in skin. DNA methylation is a form of epigenetic mark on DNA, an adjustment as to whether or not a gene will be expressed to produce the protein that it encodes. These marks shift constantly in response to circumstances, but some changes are characteristic of aging. The first epigenetic clock to assess chronological age, and which showed acceleration of the epigenetic age in people with greater mortality risk, was developed a decade ago. Considerable effort since then has gone into producing ever more varied (and sometimes better) assessments of biological age.

Evidence to date has suggested that different organs age at different rates, or at least that the epigenetic response to the molecular damage of aging is consistently different in different tissues. This means that tissue specific epigenetic clocks are probably necessary as this technology becomes used in practical ways. The primary obstacle to that practical use is that there is all too little connection between these epigenetic marks and the known mechanisms and processes of aging. It is very unclear, in advance, as to whether any specific intervention or mechanism should be expected to change a measurement of epigenetic age, or, when changes are observed, whether those changes are meaningful. So the clocks must be calibrated for use with any specific intervention - and that is very much an ongoing process in its earliest stages at best.

OneSkin launches MolClock, the first skin-specific molecular clock to determine the biological age of human skin

OneSkin is excited to share our new application programming interface (API), MolClock, the first ever skin-specific molecular clock designed to determine the chronological age of human skin. MolClock has the potential to drastically transform how scientists measure an individual's skin molecular age which indicates one's overall health, and the efficacy of skin products and interventions from a molecular level. While OneSkin owns the proprietary rights of MolClock, the tool is available for free and public use in an effort to forward the study of molecular aging and longevity research for scientists everywhere.

"The algorithm behind MolClock was constructed using machine learning to detect important epigenetic alterations that occur in our skin as we age. To train and test the MolClock algorithm, we used over 500 human skin samples and over 2,000 DNA methylation (DNAm) markers, achieving a highly accurate DNAm age predictor. MolClock allows us to predict the molecular age of someone's skin based on their methylation profiles, which correlates strongly with one's chronological age. Exceptions occur when there are ongoing processes that influence one's DNAm age such as diseases including cancer and psoriasis, inflammatory disorders, and environmental exposures or lifestyle influences, such as smoking and obesity, which in most cases, will promote an acceleration of aging and increase the skin molecular age. Therefore, the DNAm age predicted by our tool is a highly accurate indicator of overall skin health."

Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

DNA methylation (DNAm) age constitutes a powerful tool to assess the molecular age and overall health status of biological samples. Recently, it has been shown that tissue-specific DNAm age predictors may present superior performance compared to the pan- or multi-tissue counterparts. The skin is the largest organ in the body and bears important roles, such as body temperature control, barrier function, and protection from external insults. As a consequence of the constant and intimate interaction between the skin and the environment, current DNAm estimators, routinely trained using internal tissues which are influenced by other stimuli, are mostly inadequate to accurately predict skin DNAm age.

In the present study, we developed a highly accurate skin-specific DNAm age predictor, using DNAm data obtained from 508 human skin samples. Based on the analysis of 2,266 CpG sites, we accurately calculated the DNAm age of cultured skin cells and human skin biopsies. Age estimation was sensitive to the biological age of the donor, cell passage, skin disease status, as well as treatment with senotherapeutic drugs.

There is very mixed data for the ability of electromagnetic stimulation to improve cognitive function. One recent study suggests that this is because the way in which such stimulation is applied, the details of frequency, power, timing, and so forth, matters greatly. There is no one obvious way to go about this form of intervention, and most studies differ in any number of details that may or or may not turn out to be important given a better understanding of the underlying mechanisms. The small study here is an example of a case in which improved memory function is demonstrated in older people - which might be compared to other, similar studies in which no benefit was observed.

Source memory is one of the cognitive abilities that are most vulnerable to aging. Luckily, the brain plasticity could be modulated to counteract the decline. The repetitive transcranial magnetic stimulation (rTMS), a relatively non-invasive neuro-modulatory technique, could directly modulate neural excitability in the targeted cortical areas. Here, we are interested in whether the application of rTMS could enhance the source memory performance in healthy older adults. In addition, event-related potentials (ERPs) were employed to explore the specific retrieval process that rTMS could affect.

Subjects were randomly assigned to either the rTMS group or the sham group. The rTMS group received 10 sessions (20 min per session) of 10 Hz rTMS applying on the right dorsolateral prefrontal cortex (i.e., F4 site), and the sham group received 10 sessions of sham stimulation. Both groups performed source memory tests before and after the intervention while the electroencephalogram (EEG) was recorded during the retrieval process. Behavioral results showed that the source memory performance was significantly improved after rTMS compared with the sham stimulation; ERPs results showed that during the retrieval phase, the left parietal old/new effect, which reflected the process of recollection common to both young and old adults, increased in the rTMS group compared with the sham stimulation group, whereas the late reversed old/new effect specific to the source retrieval of older adults showed similar attenuation after intervention in both groups.

The present results suggested that rTMS could be an effective intervention to improve source memory performance in healthy older adults and that it selectively facilitated the youth-like recollection process during retrieval.

Link: https://doi.org/10.3389/fpsyg.2020.01137

There is good mechanistic evidence for the bacteria responsible for gum disease, periodontitis, to contribute directly to age-related inflammation in the heart, brain, and other organs, and thus raise the risk of suffering cardiovascular disease, Alzheimer's disease, and numerous other conditions that are accelerated by chronic inflammation. In the case of Alzheimer's disease, is the effect size due to periodontitis large enough to care about in comparison to other contributing causes, however? Some research suggests that the increase in risk of Alzheimer's is modest, but this is still a point that can be argued either way.

Alzheimer's disease (AD) is the most common cause of dementia, and it exhibits pathological properties such as deposition of extracellular amyloid β (Aβ) and abnormally phosphorylated tau in nerve cells and a decrease of synapses. Conventionally, drugs targeting Aβ and its related molecules have been developed on the basis of the amyloid cascade hypothesis, but sufficient effects on the disease have not been obtained in past clinical trials. On the other hand, it has been pointed out that chronic inflammation and microbial infection in the brain may be involved in the pathogenesis of AD.

Recently, attention has been focused on the relationship between the periodontopathic bacterium Porphylomonas gingivalis and AD. P. gingivalis and its toxins have been detected in autopsy brain tissues from patients with AD. In addition, pathological conditions of AD are formed or exacerbated in mice infected with P. gingivalis. Compounds that target the toxins of P. gingivalis ameliorate the pathogenesis of AD triggered by P. gingivalis infection. These findings indicate that the pathological condition of AD may be regulated by controlling the bacteria in the oral cavity and the body. In the current aging society, the importance of oral and periodontal care for preventing the onset of AD will increase.

Link: https://doi.org/10.2147/JIR.S255309

In a few recent scientific publications, the authors examined the differences in incidence of age-related disease and mortality in populations with differing levels of plant versus animal dietary protein intake. The closer to a vegan diet one approaches, the lower the risk of disease and mortality. There is already plenty of evidence for this outcome in the literature, although, as in all such things, the outstanding questions revolve around which of the possible mechanisms are the important ones.

For example, it should be expected that a lesser intake of animal protein will lower inflammation throughout the body. But does this effect really matter in comparison to the physiological response to the lower intake of calories one sees in people who adopt plant-based diets? Given the strength of the effects of calorie intake on long-term health, it is a very reasonable to make the argument that the bulk of the benefits of a vegan diet arise because of a lower calorie intake. Fewer calories means less visceral fat, greater operation of stress response mechanisms such as autophagy, and so forth. This adds up over the years.

Plant-Based Diets Promote Healthful Aging

Researchers reviewed clinical trials and epidemiological studies related to aging and found that while aging increases the risk for noncommunicable chronic diseases, healthful diets can help. The authors cite studies showing that plant-based diets rich in fruits, vegetables, grains, and legumes: reduce the risk of developing metabolic syndrome and type 2 diabetes by about 50%; reduce the risk of coronary heart disease events by an estimated 40%; reduce the risk of cerebral vascular disease events by 29%; reduce the risk of developing Alzheimer's disease by more than 50%.

Association Between Plant and Animal Protein Intake and Overall and Cause-Specific Mortality

In this analysis of a large prospective cohort of 416,104 men and women in the US with 16 years of observation, we found higher plant protein intake was associated with reduced risk of overall mortality, with men and women experiencing (respectively) 12% and 14% lower mortality per 10 g/1000 kcal intake increment (5% lower mortality per standard deviation increment). The inverse association was apparent for cardiovascular disease and stroke mortality in both sexes, was independent of several risk factors, and was evident in most other cohort subgroups.

Replacement of 3% energy from various animal protein sources with plant protein was associated with 10% decreased overall mortality in both sexes. Of note, substitution analyses suggested that replacement of egg protein and red meat protein with plant protein resulted in the most prominent protective associations for overall mortality, representing 24% and 21% lower risk for men and women, respectively, for egg protein replacement, and 13% and 15% lower risk for men and women for red meat protein replacement. The effect sizes of these risk estimates were small.

In this study, researchers show that small extracellular vesicles can influence the functional status of old tissues. These vesicles are membrane-bound packages of molecules that are used by cells as a form of communication, constantly secreted and taken up. Delivery of vesicles isolated from young tissues (or normal, non-senescent cells) improves function and suppresses the markers of cellular senescence in aged tissues, while delivery of vesicles isolated from old tissues (or senescent cells) degrades the function of young tissues by encouraging cellular senescence. The authors postulate a signaling environment in every tissue that slowly tips towards favoring cellular senescence and dysfunction as aging progresses. Delivering suitable vesicles in large enough numbers, and for a long enough period of time, should tip the balance back - though it is an open question as to how long the benefits would last, given the other aspects of aging still extant and still driving dysfunction.

A few decades ago, the notion of rejuvenation or amelioration of aging seemed unfeasible. However, in the last decades, the concept of parabiosis re-emerging and the rejuvenating cellular and tissue plasticity acquired by induced pluripotent stem cells have changed our views on the subject. Interestingly, we previously found that small extracellular vesicles (sEVs) isolated from senescent cells induce paracrine senescence in proliferating cells. In this study, we are describing that sEVs derived from fibroblasts isolated from young human healthy donors (sEV-Ys) ameliorate senescence in old recipient cells and old mice. Thus, there seems to be a crosstalk between both cells types via EVs; EVs inducing senescence in young cells and EVs preventing senescence in old cells. We believe this situation is what really happens in vivo.

It is known that the tissue holds a mixture of senescent and proliferating cells. We believe that the predominance of functionality between sEV-Ys and sEVs derived from senescent cells will depend on the proportion of each cell present in the tissue. When the majority of cells existing in the tissue are senescent cells, the tissue homeostasis becomes compromised as there is transmission of paracrine senescence; however, during the earlier stages of aging or during tissue damage, when there are still plenty of proliferating cells, these can "repair" tissue dysfunction by ameliorating the senescent phenotype of damaged cells through soluble factors and via sEVs as shown in this study.

Although it is tempting to speculate that according to our results sEV-Ys have rejuvenating potential to young tissues in old mice, we must be cautious to reach such conclusions as more experimental data would be needed. However, we cannot deny that sEV-Ys are helping damaged tissues to repair, which is also a very attractive tool. It would be interesting to perform longer-term experiments to determine the time period by which sEV-Ys can have rejuvenating or repairing functions.

Link: https://doi.org/10.1016/j.cmet.2020.06.004

Studies based on the transfer of blood or plasma from young mice to old mice are resulting in a number of interesting discoveries regarding important differences in the cell signaling environment that occur with age. Whether it is possible to exploit this knowledge to produce significant gains in human health remains an open question. Early tests of plasma transfer did not produce compelling results, while efforts focused on specific proteins have yet to reach the point of clinical trials. The research noted here is illustrated of many lines of inquiry presently underway, in which a novel signal molecule is identified and shown to produce benefits in old mice. It is unusual in that it turned up a molecule that doesn't in fact change with age, but is related to the effects of exercise on brain health.

Researchers collected plasma from either 6- or 18-month-old mice that were allowed to run on a wheel, and injected that into 18-month-old sedentary mice eight times over three weeks. The shots upped BDNF in the brain by a quarter, neurogenesis by half, and also improved the old mice's performance in the radial arm water maze and contextual fear conditioning tests.

To find the factors responsible, the authors analyzed the plasma of exercising mice by mass spectrometry. They identified 12 proteins that were consistently elevated by exercise in both age groups. They were mostly metabolic proteins made by the liver. Among the dozen, Gpld1 and serum paraoxonase 1 stood out as key. Each is involved in numerous metabolic processes, such as cholesterol efflux, hormone response, and processing ammonium, ethanolamine, and organic hydroxy compounds.

Overexpressing serum paraoxonase 1 in old mice did them no good. In contrast, overexpression of Gpld1 elevated the mice's hippocampal BDNF by 40 percent and nearly tripled their neurogenesis. One to two months later, the rodents did better on the radial-arm water maze, Y maze, and object-recognition tests. This was a surprise, since Gpld1 had not been linked previously to aging or cognition. In fact, its expression does not change with age in mice, the authors found. It goes up in the liver, but not other organs, after exercise. Its expression does not rise in the hippocampus after exercise.

How, then, might Gpld1 help the brain? Using a tagged construct, the authors found that very little of the enzyme gets past the blood-brain barrier, suggesting that it somehow exerts its effects from outside. How Gpld1 does this is still a mystery, but it may act by dampening peripheral inflammation, and that that may influence neuroinflammation.

Link: https://www.alzforum.org/news/research-news/liver-enzyme-levitates-exercise-spurs-learning-old-mice

Measures of biological age based on epigenetic marks, protein levels, transcriptomic profiles, and similar collections of biological data are proliferating rapidly. The first epigenetic clock, a weighted combination of DNA methylation status at numerous CpG sites, is barely a decade old. The results correlate quite tightly with chronological age, but it was quickly established that people with epigenetic ages greater than chronological age tend to exhibit a greater risk of mortality and presence of age-related disease, and vice versa. More clocks followed, and the diversity of data used to generate these assessments of age increased along the way.

All of these approaches to measuring the burden of age suffer the same issue: they are disconnected from the well established causative mechanisms of aging, from cellular senescence to mitochondrial dysfunction. It is near entirely unknown as to how the specifics of the epigenome, proteome, or transcriptome used in these clocks are determined by mechanisms of aging. The clocks produce an outcome, but there is no way to predict in advance how the outcome will change in response to specific interventions, or whether such changes are in any way an accurate reflection of the impact of an intervention on aging.

For example, perhaps some clocks are largely measures of inflammatory status and downstream effects of chronic inflammation. Interventions that reduce inflammation would produce impressive results, while others would not. But inflammation is only one aspect of aging. There are other mechanisms that are just as important. Similarly, the clocks all have their quirks. The original epigenetic clock is insensitive to exercise, for example. It does not distinguish between fit and sedentary twins, which makes little sense given what we know of the power of exercise to influence the course of long-term health and aging. Further, epigenetic aging doesn't correlate well with loss of telomere length.

The open access paper I'll point out today is a different example of the quirky nature of epigenetic clocks. Researchers have found that heart tissue consistently produces younger epigenetic ages than assessments carried out in white blood cells, using a clock based on a much smaller number of CpG sites than the original epigenetic clock. The question in all such studies is the degree to which it reflects a real phenomenon - i.e. that the heart ages more slowly than the immune system - versus being an artifact of the clock, resulting from tissue-specific interactions between processes of aging and the epigenetic regulation of cellular metabolism.

The biological age of the heart is consistently younger than chronological age

People do not age at the same rate, and some of us age much more dramatically than others. Genetic and environmental factors can contribute to biological aging, which means that people may be affected differently, appearing younger or older than their birth date may predict. Consequently, age, when measured chronologically, may not be a reliable indicator of the rate of physiological breakdown of the body or organs. Indeed, individual organ systems, cells, organelles, and molecules within individuals may age at significantly different rates. Therefore, it can be postulated that even the heart may have a different aging profile to the body.

The advent of epigenome-wide high-throughput sequencing analyses has led to a successful identification of a large number of genomic sites highly associated with age. Age-predicting models have been developed and validated for an accurate "biological age" estimation. An "epigenetic clock" has been created, with unprecedented accuracy for DNAmAge estimation with an average error of only 3.6 years. Such models were based on DNA mainly derived from blood circulating leucocytes as they represent an easily available source. In this study, we applied a well studied prediction model developed on data from five CpG sites, to increase the practicability of these tests.

We have determined the biological age of the heart, specifically of the right atrium (RA) and left atrium (LA), and of peripheral blood leucocytes, by measuring the mitotic telomere length (TL) and the non-mitotic epigenetic age (DNAmAge). We found that DNAmAge, of both atrial tissues (RA and LA), was younger in respect to the chronological age (-12 years). Furthermore, no significant difference existed between RA and LA, suggesting that, although anatomically diverse and exposed to different physiological conditions, different areas of the heart had the same epigenetic non-mitotic age. Furthermore, the epigenetic age of both RA and LA, was even younger than that of the blood (-10 years).

In the present study, we demonstrated that biological age of the heart did not reflect the donor's chronological age, while blood tracked these modifications. This would suggest that while blood is more susceptible to epigenetic changes induced by the interaction of advancing age and environmental factors, the heart is affected by these factors to a lower extent. It could be also postulated that the presence of stem cells in the cardiac muscle may explain why human heart tissue tends to have a lower DNAmAge. In fact, stem cells are found in relatively large numbers within myocardial tissue and show a DNAmAge close to zero. However, further investigation is required to elucidate the role of cardiac stem cells in determining epigenetic age of cardiac tissue and to fully understand its discrepancy with chronological age.

The heart regenerates poorly in mammals; functional tissue is replaced by scar tissue following injury, such as a the damaged caused in a heart attack. Researchers have recently found that type V collagen is an important determinant of the extent of this scarring, which varies considerably from individual to individual. Greater scarring leads to worse heart muscle function and a poor prognosis for the patient.

Genetic engineering of animals to remove the capacity to generate this type V collagen increases scar size following the induction of a heart attack. Researchers here show that this results because differences in the mechanical properties of scar tissue lacking type V collagen cause greater efforts on the part of cells to try to reinforce and expand the scar. This discovery may or may not point the way towards strategies to minimize scar formation in heart tissue; that remains to be seen.

Following acute myocardial infarction (MI), dead cardiac muscle is replaced by scar tissue. Clinical studies demonstrate that scar size in patients with prior MI is an independent predictor of mortality and outcomes, even when normalized with respect to cardiac function. Despite the immense pathophysiologic importance of scar burden, little is known about factors that regulate scar size after ischemic cardiac injury.

To identify factors determining scar size after MI, we subjected animals to ischemic cardiac injury and performed transcriptional profiling of heart scars isolated from 3 days to 6 weeks post injury. We observed that scars rapidly attained transcriptional maturity, and there were minimal transcriptional changes in the maturing scar tissue beyond 2 weeks of injury. We thus hypothesized that genes that regulate scar size are likely to be differentially expressed early after ischemic injury. Collagens were one of the most highly differentially upregulated genes in the injured heart early after ischemic cardiac injury.

In this report, we demonstrate that collagen V (Col V), a fibrillar collagen that is minimally expressed in the uninjured heart and a minor component of scar tissue, limits scar size after ischemic cardiac injury. Animals lacking Col V in scar tissue exhibit a significant and paradoxical increase in scar size after ischemic injury. In the absence of Col V, scars exhibit altered mechanical properties that drive integrin-dependent mechanosensitive feedback on fibroblasts, augmenting fibroblast activation, extracellular matrix (ECM) secretion, and increase in scar size.

A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.

Link: https://doi.org/10.1016/j.cell.2020.06.030

The maintenance of muscle tissue declines with age, leading to both loss of muscle mass and strength, as well as impaired regeneration following injury. One of the more important aspects of this aspect of aging appears to be loss of function in muscle stem cell populations, but a broad selection of other contributing mechanisms have been identified over the years. Here, researchers dig into the biochemistry of muscle regeneration in order to identify more specific areas of dysfunction. This sort of work tends to identify changed levels of protein expression, a proximate cause of the problem at hand, but in most cases it remains a struggle to link regulatory changes in important processes with specific deeper causes of aging.

Skeletal muscle constitutes approximately 40% of the total mass of the human body and plays a central role in health and well-being. Central to the maintenance of a healthy skeletal muscle mass is its regenerative capacity, enabling muscle to completely restore function within 7-10 days after severe damage. The regeneration process can be categorized into the following three sequential but widely overlapping stages: (1) inflammation and necrosis of damaged myofibres, (2) activation, proliferation, differentiation, and fusion of satellite cells, and (3) maturation and remodeling of the regenerated muscle. Each stage is essential to drive the following subsequent stage, thereby imparting coherence to the overall regeneration process.

The extracellular matrix (ECM) is critical in maintaining normal skeletal muscle function and driving skeletal muscle regeneration. Skeletal muscle ECM is composed of a plethora of structural, adhesion, and signal-stimulating proteins that are transiently degraded and reconstituted depending on the mode and severity of tissue injury. Aged skeletal muscle does not regenerate well in response to injury, and there is evidence of impairment at each stage of the regeneration process including accumulation of collagen (i.e., fibrosis). However, it is unclear if this age-related skeletal muscle fibrosis occurs as a result of impaired degradation in the first week following tissue damage.

We investigated ECM proteins and their regulators during early regeneration timepoints. The regeneration process was compared in young (three month old) and aged (18 month old) C56BL/6J mice at 3, 5, and 7 days following cardiotoxin-induced damage to the tibialis anterior muscle. The regeneration process was impaired in aged muscle. Greater intracellular and extramyocellular PAI-1 expression was found in aged muscle. Collagen I was found to accumulate in necrotic regions, while macrophage infiltration was delayed in regenerating regions of aged muscle. Young muscle expressed higher levels of MMP-9 early in the regeneration process that primarily colocalized with macrophages, but this expression was reduced in aged muscle. Our results indicate that ECM remodeling is impaired at early time points following muscle damage, likely a result of elevated expression of the major inhibitor of ECM breakdown, PAI-1, and consequent suppression of the macrophage, MMP-9, and myogenic responses.

Link: https://doi.org/10.3390/ijms21134575

The capacity for flight is frequently associated with greater species longevity, such as in bats, for example. The present consensus suggests that the cellular adaptations needed to support the greater metabolic capacity required for flight also resist some forms of molecular damage important in aging. This is particularly the case for adaptations in mitochondria, the power plants of cells, where damage and loss of function is known to be important in aging. The membrane pacemaker hypothesis is one way of looking at this; species that evolve cell membranes that are more resilient to oxidative damage will live longer as a result.

Today's open access paper reports on the interesting approach of using gain and loss of flight in evolutionary history as a way to look for genes and functions that might be important in aging. It is a good idea, but unfortunately didn't pan out in this particular study - commonalities between species were lacking. That a modest selection of species failed to produce shared genetic adaptations that appear relevant to aging and longevity may indicate the existence of broad a diversity of mechanisms relevant to metabolism and flight, rather than just a few important mechanisms, or perhaps a very complex, multifaceted relationship between metabolism and longevity. Other lines of work, such as the so far largely unsuccessful search for longevity-related genes with meaningful effect sizes in humans, support the latter conjecture.

Genetic factors for short life span associated with evolution of the loss of flight ability

Maximum life span (MLS) is a fundamental life-history trait related to the rate of aging and senescence in animals. It has been proposed that species with lower extrinsic mortalities have longer life spans because they can invest in long-term survival. Extrinsic mortality is generally determined by ecological factors, such as climate and predation risk, and may drive shortened or extended life spans through natural selection. However, MLS is influenced by complex molecular and metabolic processes such as mitochondrial homeostasis.

Mitochondria of aerobic animals produce reactive oxygen species (ROS), which can damage lipids, proteins, and nucleic acids. A low rate of mitochondrial ROS generation reportedly leads to long life spans in both long-lived and calorie-restricted animals because of low levels of both oxidative stress and accumulation of mutations in somatic mitochondrial DNA. Because animals with higher metabolic rates produce more ROS, a causal relationship between metabolic rate and life span can be expected. Additionally, a positive relationship between body mass and life span is pervasive in vertebrates. Because metabolic rates per mass are lower with increasing body mass, animals with smaller body masses could suffer more from ROS, and their life spans would be correspondingly shorter.

However, flight ability significantly affects MLS and aging rates in both mammals and birds regardless of body mass. Flight typically requires higher rates of energy consumption and generates more ROS than other types of locomotion, such as walking or swimming. However, a prolonged life span often evolved with the acquisition of flight ability, suggesting that there is no simple relationship between metabolism and life span.

Here, we examine the parallel evolution of flight in mammals and birds and investigate positively selected genes at branches where either the acquisition (in little brown bats and large flying foxes) or loss (in Adélie penguins, emperor penguins, common ostriches, emus, great spotted kiwis, little spotted kiwis, okarito brown kiwis, greater rheas, lesser rheas, and cassowaries) of flight abilities occurred. Although we found no shared genes under selection among all the branches of interest, 7 genes were found to be positively selected in 2 of the branches. Among the 7 genes, only IGF2BP2 is known to affect both life span and energy expenditure. The positively selected mutations detected in IGF2BP2 likely affected the functionality of the encoded protein. IGF2BP2, which has been reported to simultaneously prolong life span and increase energy expenditure, could be responsible for the evolution of shortened MLS associated with the loss of flying ability.

Greater immune activity implies greater inflammation, which has a negative impact on tissue function if maintained over time. In aging, a great deal of damage is done by the chronic inflammation of an overactive immune system. Researchers here provide evidence to indicate that the evolved state of immunity is a balancing act between a faster pace of aging on the one hand, resulting from an immune system that is more active, and vulnerability to infection on the other, resulting from an immune system that is less active.

As we age, the immune system gradually becomes impaired. One aspect of this impairment is chronic inflammation in the elderly, which means that the immune system is constantly active and sends out inflammatory substances. Such chronic inflammation is associated with multiple age-related diseases including arthritis and Alzheimer's disease, and impaired immune responses to infection. One of the questions in ageing research is whether chronic inflammation is a cause of ageing, or a consequence of the ageing process itself?

From their work in the tiny roundworm, Caenorhabditis elegans, the scientists discovered a change in an evolutionarily conserved gene called PUF60, which made the worms long lived but at the same time dampened the immune response. Worms with this change lived about 20% longer than normal worms, but when they were infected with certain bacteria, they succumbed more quickly to the infection. This means that an overactive immune system also has a price: it shortens life span. Conversely, a less active immune system pays off as longer life span - as long as the animal does not die from an infection.

PUF60 works as a splicing factor, and is involved in the removal (or "splicing out") of segments in the ribonucleic acid, RNA. This process is essential to generate functional proteins. The scientists found that the genetically changed PUF60 perturbs this process and alters the regulation of other genes that are involved in immune functions.

Link: https://www.mpg.de/15021569/a-balancing-act-between-immunity-and-longevity

Near everyone who dies from the SARS-Cov-2 virus responsible for the COVID-19 pandemic is old. The old are vulnerable firstly because their immune systems are much diminished in effectiveness, and secondly because the state of chronic inflammation characteristic of old age makes the cytokine storm that causes much of the SARS-Cov-2 mortality more likely and more severe.

Members of the medical research community focused on intervention in the aging process - a way to treat all age-related conditions by addressing their underlying causes - are attempting to use the attention given to COVID-19 to educate the public and policy makers. Any number of influenza seasons, in which the vast majority of the dead are elderly, seems to have failed to get the point across: that the age-related decline of the immune system causes great harm, and that harm might be significantly reduced in the future given a focus on research and development for immune rejuvenation. But perhaps this pandemic will cause people to listen. Hope springs eternal.

Understanding how drugs can delay aging and related diseases is part of a larger scientific endeavor supported by the National Institute on Aging and others called geroscience. This approach aims to understand and ultimately modify the basic biology of aging and in so doing, develop new paradigms to treat multiple age-related chronic diseases at the same time. Geroscientists have long hypothesized that by targeting the biology of aging, all diseases of aging can be delayed. Hallmarks of aging have been established and shown that they are all interconnected, thus targeting any single hallmark results in improvements in others. In animal preclinical studies, health span and life span have been dramatically increased by targeting those hallmarks, using genetic tools and drugs, demonstrating that aging is a modifiable condition.

Older people are at such risk in part because the vigor of our immune response flags as we age. Of particular importance are the hallmarks of immune dysfunction underlying the vulnerability of older adults to infections and the inflammation which accounts for the response to those infections. In addition to age, many of us are also weakened by coexisting age-related conditions that diminish our resilience further.

Interventions with existing drugs with established safety profiles that target the biology of aging, immune mechanisms and resiliency (i.e. "geroprotectors" or "gerotherapeutics"), should be explored. While many geroprotectors have been successfully tested in pre-clinical settings, to date none of them has been approved as geroprotectors for use in humans. Consequently, self-medication with any of these compounds is highly discouraged.

One such drug is metformin which has been shown to target multiple hallmarks of aging and increase health span and life span in animals. Metformin has already indicated protective capacity against COVID-19. In a retrospective analysis of 283 type 2 diabetes patients from Wuhan, China, with confirmed COVID-19, investigators found no difference in the length of stay in hospital, but persons taking metformin had significantly lower in-hospital mortality (3 of 104, 2.9%) than those not taking metformin (22 of 179, 12.3%).

A second line of drugs are mTOR inhibitors, which have been shown to increase healthspan and lifespan in almost all animals tested, from yeast to rodents. The mTOR inhibitor rapamycin reverses age-related declines in influenza vaccine response in mice and two Phase 2 clinical trials completed by resTORbio showed that the rapamycin derivative everolimus could enhance influenza vaccine response in healthy elderly people. A phase 3 clinical trial failed.

Given the current public health crisis that is disproportionately affecting our aging population, it is imperative that we start discussing pragmatic approaches to rapidly implement the testing of such drugs in the face of the COVID-19 pandemic and an aging global population. At this stage, broad clinical trials of potential geroprotective therapies are needed, to enable extensive data collection and analysis of their potential benefits and indications.

Link: http://www.aginganddisease.org/article/0000/2152-5250/ad-0-0-0-2007060732-1.shtml

The practice of calorie restriction involves reducing calorie intake by up to 40% while maintaining an optimal intake of micronutrients. It can meaningfully extend life span in short-lived species such as mice, but does not add more than a few years in humans. The effect on lifespan of this and other interventions known to slow aging via upregulation of stress response mechanisms scale down as species life span increases - though, interestingly, the short-term benefits to health look quite similar across mammalian species.

The most important mechanism of action in the calorie restriction response, as well as responses to heat and other stresses, appears to be an increased operation of autophagy. Autophagy is the name given to a collection of cellular maintenance processes that break down unwanted or damaged proteins and cell structures by conveying them to a lysosome, a membrane packed full of enzymes capable of breaking down most of the molecules a cell will encounter. It is noteworthy that disabling autophagy, or important related processes such as the formation of stress granules to protect vital proteins from increased autophagy, blocks the benefits the calorie restriction response. It is similarly noteworthy that the efficiency of autophagy becomes impaired with age, and this is thought to contribute to many manifestations of aging.

The present consensus on why calorie restriction extends life notably in mice but not in humans is that the calorie restriction response evolved to enhance reproductive fitness in the face of seasonal famine, extending life to allow individuals to survive and reproduce once food was again plentiful. A season is a large fraction of a mouse life span, but not a large fraction of a human life span, and therefore only the mouse evolves to experience sizable increases in life span when calorie intake is low. This is far from the only evolutionary explanation for the calorie restriction response, however. Today's open access paper is a review of the topic, providing an overview of present viewpoints.

Lifespan Extension Via Dietary Restriction: Time to Reconsider the Evolutionary Mechanisms?

Dietary restriction (DR), a moderate reduction in food intake whilst avoiding malnutrition, is the most consistent environmental manipulation to extend lifespan and delay ageing. First described in rats, DR has since been shown to extend lifespan in wide range of taxa: from model lab species such as Drosophila melanogaster and mice, to non-model species such as sticklebacks, crickets, and non-human primates. Owing to this taxonomic diversity, it is presumed that the underlying physiological mechanisms of DR are evolutionarily conserved and thus DR has been widely used to study the causes and consequences of variation in lifespan and ageing. Despite this attention, both the evolutionary and physiological mechanisms underpinning DR responses remain poorly understood.

Since its inception DR has become an all-encompassing description for multiple forms of dietary interventions. The most widely studied form of DR is calorie restriction (CR), a reduction in overall calorie intake whilst avoiding malnutrition. Common forms of CR include providing a restricted food portion, dilution of the diet, or restricting food availability temporally. Positive effects of CR on lifespan are well supported. Initial explorations of the role of specific dietary components, such as protein content, found that the effects were largely driven by caloric intake. Consequently, until recently DR and CR were largely interpreted as synonymous terms. Owing to this focus on CR, the predominant evolutionary explanations of the DR effect were developed to explain responses to CR and not macronutrient availability.

The Resource Reallocation Hypothesis

The most widely accepted evolutionary explanation of DR is a trade-off model based around the disposability theory of ageing. This theory suggests that a trade-off exists between reproduction and somatic maintenance (lifespan). The Resource Reallocation Hypothesis (RRH) proposes that during periods of famine (e.g., CR), natural selection should favor a switch in allocation, in which context organisms reallocate energy almost exclusively to somatic maintenance and not to reproduction. By investing heavily in somatic maintenance, organisms will improve their chances of surviving the period of famine, when it is likely that the cost of reproduction is high and offspring survival low, resulting in lower fitness returns. Once conditions improve, investment in reproduction can resume, and that should result in higher fitness. Critically, the reinvestment strategy described in the RRH will only lead to higher fitness if conditions improve. Owing to the trade-off, the RRH predicts that under DR conditions in the lab, there should be an increase in lifespan accompanied by a corresponding decrease in reproduction.

The Nutrient Recycling Hypothesis

Recently, the RRH has been critiqued, the argument against it being that adopting a pro-longevity investment strategy is unlikely to increase survival in the wild, where the main sources of mortality are extrinsic (i.e., predation, wounding, or infection). An alternative evolutionary explanation was proposed that we will term here the nutrient recycling hypothesis (NRH). As with the RRH, the NRH was proposed to explain an effect of CR, not the more recent suggestion of specific macronutrient effects. The NRH proposes that rather than sacrificing reproduction to increase longevity, organisms under DR attempt to maintain reproduction as much as possible in the face of reduced energy resources.

To achieve this, organisms upregulate the activity of cell recycling mechanisms such as autophagy and apoptosis. This allows better use, and even recycling, of the available energy, which can then be used to maintain reproductive function. The argument here is not that the level of reproduction achieved under DR is greater or even matched to that of a fully fed individual, rather that the loss of reproduction is minimized. An interesting suggestion of the NRH is that the pro-longevity effect of DR is an artefact of benign lab environments. The main sources of mortality in the laboratory are old age pathologies such as cancer, which are ameliorated by upregulation of autophagy and apoptosis. However, in the wild, cancer and other old-age pathologies are a relatively minor source of mortality, so the protective effect of the DR response may not be observed.

The Toxic Protein Hypothesis

A more recent hypothesis to be put forward is the toxic protein hypothesis (TPH), which is a constraint-based model rather than an evolutionary theory. Unlike the theories already discussed, the TPH was put forward in light of renewed focus on the role of macronutrients in DR responses. The TPH argues that protein is essential for reproductive function, where increasing protein intake leads to higher reproductive rates. However, it is proposed that high consumption of protein has direct negative effects on late-life health and lifespan, through increased production of both toxic nitrogenous compounds from protein metabolism and mitochondrial radical oxygen species.

Therefore, organisms face a constraint in the amount of protein they can consume, balancing high protein intake to maximize early life reproductive output whilst avoiding overconsumption, which may reduce lifespan and ultimately result in lower fitness. As with the other hypotheses, under the TPH there would be an optimal protein intake that maximizes lifetime reproductive success or fitness. However, the TPH argues that the DR response of increased lifespan is the result of protein restriction reducing the direct physiological costs of protein ingestion.

Researchers here note that mifepristone, an abortifacient drug, slows aging in flies. This is interesting, but the mechanisms of action so far have the look of being quite specific to circumstance and gender - it blocks a detrimental effect of mating in female flies that increases inflammation. So I'd wager that this will turn out to be of academic interest only at the end of the day. If reductions in inflammation are the primary downstream benefit, this class of drug probably compares poorly to senolytics in any case.

Studying one of the most common laboratory models used in genetic research - the fruit fly Drosophila - researchers found that the drug mifepristone extends the lives of female flies that have mated. Mifepristone, also known as RU-486, is used by clinicians to end early pregnancies as well as to treat cancer and Cushing disease. During mating, female fruit flies receive a molecule called sex peptide from the male. Previous research has shown that sex peptide causes inflammation and reduces the health and lifespan of female flies. Researchers found that feeding mifepristone to the fruit flies that have mated blocks the effects of sex peptide, reducing inflammation and keeping the female flies healthier, leading to longer lifespans than their counterparts who did not receive the drug.

The drug's effects in Drosophila appear similar to those seen in women who take it. "In the fly, mifepristone decreases reproduction, alters innate immune response and increases life span. In the human, we know that mifepristone decreases reproduction and alters innate immune response, so might it also increase life span?" Seeking a better understanding of how mifepristone works to increase lifespan, researchers looked at the genes, molecules, and metabolic processes that changed when flies consumed the drug. They found that a molecule called juvenile hormone plays a central role.

Juvenile hormone regulates the development of fruit flies throughout their life, from egg to larvae to adult. Sex peptide appears to escalate the effects of juvenile hormone, shifting the mated flies' metabolism from healthier processes to metabolic pathways that require more energy to maintain. Further, the metabolic shift promotes harmful inflammation, and it appears to make the flies more sensitive to toxic molecules produced by bacteria in their microbiome. Mifepristone changes all of that. When the mated flies ate the drug, their metabolism stuck with the healthier pathways, and they lived longer than their mated sisters who did not get mifepristone. Notably, these metabolic pathways are conserved in humans, and are associated with health and longevity.

Link: https://www.eurekalert.org/pub_releases/2020-07/uosc-smh070920.php

Senescent cells accumulate with age, and their inflammatory secretions disrupt tissue structure and function. In the heart, the presence of senescent cells contributes to fibrosis, hypertrophy, and other aspects of the progression towards heart failure. Since senescent cells actively maintain a disrupted state of cells and tissue, targeted removal can quickly and significant reverse aspects of aging and age-related disease. This has been demonstrated in numerous organs, including the heart, in animal studies. For example, even the structural changes of ventricular hypertrophy can be reversed via treatments that selectively destroy senescent cells.

Adult stem cells and progenitor cells are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease.

Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects.

Here we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.

Link: https://doi.org/10.3390/cells9061558