Fight Aging!

There are two activities in medical science in which both the academic research community and clinical development industry are truly terrible at achieving results, or indeed even at getting started at all. The first is transfer of programs from academia to industry. The renowned valley of death in the development of new medical biotechnologies is very real; so very many programs languish undeveloped simply because neither side can effectively coordinate with the other. The second is the testing of synergies between multiple therapies that are applied at the same time to the same patient for the treatment of the same condition. We live in a world in which age-related conditions are the result of multiple distinct contributing mechanisms, so why is it that the exploration and application of combined therapies targeting separate mechanisms is such a rare occurrence?

Firstly, different therapies tend to be owned by different groups (companies or universities) who have only limited incentives to collaborate with one another. Because the biotech field is governed in a very heavy-handed way by intellectual property and other forms of government regulation, setting up a collaboration is a costly matter. Thus in a world in which the expectation is that few efforts will be successful, as is the case for most initiatives in medical science, there is an unwillingness to explore. Secondly, the regulatory process for approval is very, very costly. Taking a candidate drug through to phase III trial success is at least a $150M proposition, and usually more. Companies do all they can to make clinical trials as simple as possible, and there is no incentive to roll the dice on a collaborative trial that depends on another drug outside the control of the company in question.

And yet, aging and all age-related diseases are the consequence of multiple underlying forms of molecular damage. They will require multiple very different therapies to achieve complete reversal or prevention. The perverse incentives in medical regulation and intellectual property are acting to close off the most promising strategy for the treatment of aging, which is to tackle all of its varied causes concurrently. Something must change here. As Aubrey de Grey points out in the short interview below, this is the next frontier for patient advocacy. Now that the first rejuvenation therapies are being actively developed, using them together is a logical next step.

Aubrey de Grey: "Damage repair is the future of longevity medicine"

Aubrey is a plain-speaking biomedical gerontologist who is committed to combating the aging process. We started by asking him about what he was up to at the moment.

SENS Research Foundation suffered a fair amount of slowdown as a result of the pandemic, but we're picking up now. I think the most exciting thing we're doing is continuing to strengthen the pipeline between the really early-stage translational work we do at SENS and the "just investable" stage work pursued by startups in our space, including our own spinouts. Basically, the appetite of some investors is increasingly emphasising projects that are so early that they would historically be viewed as pre-competitive; that boundary is now becoming very blurred.

What isn't getting sufficient exposure?

I would say that the single biggest elephant in the room is the simultaneous administration of multiple therapies. It is subliminally understood that damage repair is the future of longevity medicine, and also that the damage repair paradigm is inescapably a divide-and-conquer one that will entail combination therapies, but the medical industry is really not set up to develop and promote that way of working. At some point that has to change, and I'm hopeful that investors at the more courageous end of the spectrum will soon find ways to start that process in earnest.

Our survey found that most investors appear to prefer seed-to-early-stage investing, have you found this to be case in your networks?

Absolutely. At this point I don't see how things could be otherwise, actually, because the investment opportunities consist almost entirely of startups, which in turn is because the underlying technologies are so new.

We also saw that senolytics are a very popular category for investors - are you seeing an increased appetite from investors?

I do see that tendency too, and it's not surprising to me, because senolytics have two huge things going for them: they are bona fide rejuvenators (i.e. they repair a type of aging damage rather than just slowing down its accumulation), which is much more exciting to people old enough to have money to invest, and they are only just now going into clinical trials and showing impressive results, so they are opportunities for first movers.

The present understanding of Alzheimer's disease is illustrative of a broader issue with aging in general, in that while there is considerable evidence to pin down specific pathological mechanisms in cells and tissues, it is hard to prove exactly how these mechanisms interact. What is cause, what is consequence. What is important, what is merely a side-effect of other, important processes. At present there is some upheaval in the Alzheimer's research community based on the failure of amyloid-β clearance to produce meaningful benefits in patients. This may or may not disrupt the present thinking on the condition, that early amyloid-β aggregation sets the stage for later neuroinflammation and tau aggregation. Amyloid-β may be a good early target, or it may turn out to be a side-effect of rising levels of chronic inflammation or persistent infection, and thus not a useful target at all.

Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis.

AD pathogenesis involves pathogenic contributions from multiple components and alterations in behavior of various cell types within the central nervous system. Aβ is generated in neurons and then released to the extracellular space, where it can be degraded or cleared by microglia and astrocytes. Increased Aβ production or impaired Aβ degradation/clearance leads to Aβ accumulation. Tau is mainly expressed in neurons, and highly modulated through various post-translational modifications. Abnormal PTMs, liquid-liquid phase separation, and pathogenic tau seeds can cause tau aggregation and accumulation through different mechanisms. Tau pathology may be propagated during disease progression, and glial cells play an important role in the process of seeding and dispersion. Forms of Aβ aggregates, together with tau accumulation, can cause neuronal dysfunction and glial activation and the subsequent neuroinflammation; these events are regulated by various receptors expressed in neurons, microglia and astrocytes.

Genetic factors can cause or affect AD pathogenesis. Early-onset AD is mainly due to mutations in APP and PS1/PS2, which are involved in Aβ generation, while late-onset AD is largely associated with a group of genes enriched in glial cells, such as APOE and TREM2, which are important for Aβ clearance and glial function. Therefore, differential mechanisms may be involved in different forms of AD. In addition, other factors such as aging, metal ion, virus, and microbiota may also contribute to AD pathogenesis via various mechanisms. Mechanisms for late-onset AD are complex and subtypes of late-onset AD may exist. However, most of the available AD animal models carrying early-onset AD-associated mutations can only mimic early-onset AD. Development of animal models to recapitulate pathogenesis of late-onset AD may be beneficial to compare early and late stage forms of AD. This may uncover mechanisms specific to late-onset AD which represents over 90% of AD cases, and potentially provide new insights to therapeutic targets for treatment.

Link: https://doi.org/10.1186/s13024-020-00391-7

Fitness produced by training is here shown to correlate with reduced inflammatory signaling, but has no effect on the burden of senescent cells in old muscle tissue. This is interesting, as the accumulation of senescent cells with age is responsible for a sizable fraction of inflammatory signaling in tissues. Senescent cells secrete a potent mix of signals that cause chronic inflammation and tissue dysfunction, and are an important contributing cause of aging. The likely explanation here is that the cellular adaptations to exercise act to reduce harmful aspects of persistent senescent cell signaling. There is a good deal of research to show that senescent cell signaling can be muted to various degrees. This is probably not as a good a strategy for the development of new therapies as is the targeted destruction of senescent cells, but exercise is free.

The aim of the present study was to determine if the training status decreases inflammation, slows down senescence and preserves telomeres health in skeletal muscle in older compared to younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies (n=34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS) and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence associated b-gal (SA-b-Gal) staining and qRT-PCR.

Independently of the endurance training status, TIF levels (+35%) and the percentage of SA-b-Gal positive cells (+30%) were higher in cultured satellite cells of older compared to younger subjects. p16 (4-5 fold) and p21 (2-fold) mRNA levels in skeletal muscle were higher with age but unchanged by the training status. Aging induced higher CD68 mRNA levels in human skeletal muscle (+102%). Independently of age, both trained groups had lower IL-8 mRNA levels (-70%) and tended to have lower TNF-alpha mRNA levels (-40%) compared with the sedentary subjects.

All together, we found that the endurance training status did not slow down senescence in skeletal muscle and satellite cells in older compared to younger subjects despite reduced inflammation in skeletal muscle. These findings highlight that the link between senescence and inflammation can be disrupted in skeletal muscle.

Link: https://doi.org/10.1152/ajpendo.00149.2020

Investigation of the comparative biology of aging is one of many notable communities within the broader research community focused on aging and age-related disease. Scientists use comparisons between different species with very different life spans as a way to try to pin down the mechanisms that are most important in aging. Thus there is work on naked mole-rats versus mice, both similarly sized rodents. Whales capable of living for centuries are compared to smaller mammals that are not. Humans are compared to our nearest primate relatives, all of whom are less long-lived than we are. And so forth.

One of the more interesting comparisons to be made is between bats and other mammals. It is quite clear that flight requires considerable metabolic adaptation, and it seems plausible that these adaptations make individuals more resistant to some of the processes of aging. Both birds and bats tend to be long-lived for their size. Not all bats are long-lived, however, which means that perhaps there are things to be learned from a comparison of long-lived and short-lived bat species. That is the subject of today's open access paper.

It remains a question as to whether work on the comparative biology of aging will produce practical outcomes. It is one thing to identify a mechanism, or a different arrangement of cellular biochemistry, as likely important in aging. It is entirely another thing to try to build a therapy based on the way that bat, whale, or naked mole-rat cells function. There is no guarantee that any particular species difference is a practical basis for medical applications. Engineering a better human that ages more slowly by changing cellular metabolism into something that looks more like that of another species is more likely a product for later in the century, not now. Also, aging more slowly is of little use to people already old - we want rejuvenation and repair of damage, not ways to make damage accumulate more slowly.

Genetic variation between long-lived versus short-lived bats illuminates the molecular signatures of longevity

Natural selection has shaped a large variation of lifespan across mammals, with maximum lifespan ranging from a few months (e.g. short-lived shrews) to 211 years (e.g. bowhead whale). Although the bowhead whale is exceptionally long-lived, its lifespan is arguably not as extreme as that of a 30 years old naked mole-rat given their body sizes, as maximum lifespan (MLS) exhibits a positive correlation with body size within mammals. Thus, lifespan comparison across mammals requires body size correction. To resolve this, the longevity quotient (LQ) was introduced, which is defined as the ratio of observed lifespan to predicted lifespan for a non-flying mammal of the same body size. Using this approach bats are the longevity extremists, with some species living up to ten times longer than expected given their body size. The Brandt's bat (Myotis brandtii) holds the record for longevity, with a maximum lifespan of more than 40 years, living 8-10 times longer than expected given a body weight of ~7 grams. This renders bats as one of the most ideal taxa to explore the molecular basis of extraordinary longevity in mammals.

Although the majority of bat species are long-lived, especially within the Myotis genus, there are a few short-lived exceptions, such as the velvety free-tailed bat (Molossus molossus) and the evening bat (Nycticeius humeralis), living as long as would be expected given their body size. A recent study has suggested that the ancestral bat lived up to 2.6 times longer than expected given body size, indicating that the extreme longevity observed in the longest-lived bat genera may have evolved multiple times. This also suggests that short-lived bat species may have lost their longevity adaptations. Therefore, this wide range of lifespans observed in bats enables us to utilize comparative evolutionary approaches to search for genetic differences within closely-related long- and short-lived bat species.

In this study we performed a comparative genomic and transcriptomic analysis between long-lived Myotis myotis (MLS = 37.1 years; LQ = 5.71) and short-lived Molossus molossus (MLS = 5.6 years; LQ = 0.99) to ascertain the molecular signatures associated with longevity in bats. Based on the genome-wide alignments of single-copy orthologous genes between these two species, we detected and further investigated the genes that were fast-evolving and showed significant positive selection. We also deep sequenced blood transcriptomes from eight adult individuals for each species, and explored the genes and pathways that were differentially expressed. To ascertain if long-lived bats have evolved a transcriptomic signature of longevity, we further investigated the expression of 'pro'- and 'anti'-longevity genes in the blood transcriptomes of M. myotis and M. molossus. Although the majority of genes underwent purifying selection, we observed a significant transcriptional alteration between these two species.

Among 2,086 genes that exhibited large interspecific expression variation, the genes that showed higher expression in long-lived M. myotis were mainly enriched in DNA repair and autophagy. Further pathway analysis suggested that six biological processes, including autophagy, were differentially expressed between M. myotis and M. molossus. We also show that M. myotis had significantly lower expression levels of anti-longevity genes, suggestive of a transcriptomic signature of longevity naturally evolved in long-lived bats. Together with the previous findings in other long-lived mammals, our study implies that enhanced DNA repair and autophagy activity may represent a universal mechanism to achieve longevity in long-lived mammals.

Researchers here provide evidence to indicate that increased expression of CD47 in aged blood vessels impairs a range of functions, from maintenance of these tissues to the generation of new blood vessels. The latter point is interesting given that capillary networks become less dense with age. This is thought to impair blood flow to tissues and thus contribute to age-related loss of function. The animal evidence here suggests that inhibition of CD47 may be a viable strategy to reduce the impact of aging on the vasculature, and thus also many of the consequences of vascular aging throughout the body.

The aged population is currently at its highest level in human history and is expected to increase further in the coming years. In humans, aging is accompanied by impaired angiogenesis, diminished blood flow, and altered metabolism, among others. A cellular mechanism that impinges upon these manifestations of aging can be a suitable target for therapeutic intervention. Here we identify cell surface receptor CD47 as a novel age-sensitive driver of vascular and metabolic dysfunction. With the natural aging process, CD47 and its ligand thrombospondin-1 were increased, concurrent with a reduction of self-renewal transcription factors OCT4, SOX2, KLF4, and cMYC in arteries from aged wild-type mice and older human subjects compared to younger controls.

These perturbations were prevented in arteries from aged CD47 knockout mice. Arterial endothelial cells isolated from aged wild-type mice displayed cellular exhaustion with decreased proliferation, migration, and tube formation compared to cells from aged CD47 knockout mice. CD47 suppressed ex vivo sprouting, in vivo angiogenesis and skeletal muscle blood flow in aged wild-type mice. Treatment of arteries from older humans with a CD47 blocking antibody mitigated the age-related deterioration in angiogenesis. Finally, aged CD47 knockout mice were resistant to age- and diet-associated weight gain, glucose intolerance, and insulin desensitization.

These results indicate that the CD47-mediated signaling maladapts during aging to broadly impair endothelial self-renewal, angiogenesis, perfusion, and glucose homeostasis. Our findings provide a strong rationale for therapeutically targeting CD47 to minimize these dysfunctions during aging.

Link: https://doi.org/10.3390/cells9071695

We humans have not evolved for optimal function given a continually high calorie intake. We, and all other species, evolved in an environment characterized by periods of feast and famine: we desire food constantly, but nonetheless need some amount of hunger in order to be healthy. Periods of low calorie intake spur increased activity of tissue maintenance mechanisms throughout the body. A lower overall calorie intake minimizes excess visceral fat tissue that causes chronic inflammation and metabolic disease. In this modern society of comfort and cheap calories, all too many people are eating themselves into shorter, less healthy lives. This will continue until the advent of rejuvenation therapies that can meaningfully target the causes of aging, to a degree sufficient to outweight environmental influences on the pace of aging.

The global increase in food security due to modern long-term food storage coupled with the increase in worldwide global food transportation, and international marketing has reduced the cost of food, increasing its availability in the developed world. However, food commercialization and the shift toward production of processed and ultra-processed foods have revealed clear adverse effects, such as the identification of processed food as a major cause for over-eating and the increase in the risk of metabolic syndrome, obesity, and diabetes. As the brain is one of the primary energy-demanding organs in the human body, it comes with no surprise that the brain is highly affected by such metabolic disorders.

Worldwide, the life expectancy of males rose from 59.6 years in the 1980's to 69.0 years in 2015, whereas the life expectancy of females increased from 63.7 to 74.8 years, respectively. This increase in lifespan is correlated with multiple age-dependent pathologies which have also increased in prevalence, such as neurodegenerative disorders. It is plausible to argue that the combined effect of the continued increase in lifespan and life-long continuous food consumption leads to a dramatic increase in the prevalence of neurodegenerative disorders in the elderly population.

Studies in laboratory animals show that caloric restriction (decreased food intake or intermittent fasting) can extend lifespan in rodents and primates and delay the onset of age-related diseases such as hypertension and diabetes. Moreover, caloric restriction may protect neurons from degeneration and enhance adult neurogenesis and neuronal plasticity, which may protect the brain from a cognitive decline during aging and neurodegenerative diseases. One of the crucial processes that are adversely affected during aging is cellular autophagy, which is tasked with eliminating aggregated proteins, unhealthy organelles, and multiple intracellular components. Multiple mechanisms can explain the roles of fasting and caloric restriction in ameliorating neurodegeneration. One of the most studied mechanisms is the upregulation of autophagy via inhibiting mTOR activity.

The sobering statistics of one in three elderly people suffering from a type of age-related dementia call to devise a multi-pronged approach to targeting age-related neurodegenerative diseases. Synthesis of the current data indicates that not only age but also dietary lifestyles that changed dramatically during the twentieth century are at play. Many factors that are at play during aging have a role in promoting neurodegeneration, such as oxidative stress, accumulation of DNA damage, cell senescence, neuroinflammation, and decreased autophagic flux. Aging is also characterized by elevated levels of neuroinflammation that are transcriptionally regulated. Autophagy, however, is a cellular pathway that throughout life is predominantly regulated extrinsically in a nutrient-consumption mediated manner. This places food consumption as a major factor, along with aging itself, in promoting neurodegenerative disorders.

Link: https://doi.org/10.3389/fnagi.2020.00182

As of the past few years, the long-standing debate over whether moderate alcohol intake has a protective effect on health had appeared to resolve to the conclusion that the observed epidemiology is explained by socioeconomic factors, not by the metabolic effects of molecules such as polyphenols present in wine or other alcoholic drinks. People who engage in more modest alcohol consumption tend to be in the wealthier sections of society, and thus are more health conscious, undertake lifestyle choices, and make better use of available medical technologies.

In that context, today's open access paper is quite interesting. The authors report on a study in which a 4.4% extension of mean lifespan and various improvements in metabolism take place in mice that are given drinking water that is 3.5% ethanol, that intervention starting at 8 weeks of age. The researchers suggest that this might be mediated by pathways involving AMPK and mitochondrial function, and note that there is a comparatively lack of research into alcohol intake at this low, sustained level. It will be interesting to see how this line of inquiry develops in the years ahead, although I'd be the first to say that the effect size here is far too small to be of more than academic interest.

Long-term low-dose ethanol intake improves healthspan and resists high-fat diet-induced obesity in mice

Previous studies on the protection of alcoholic beverages have been primarily focused on the polyphenols such as resveratrol, procyanidins and other substances like catechin and tannin. Ironically, the most important common component of all alcoholic beverages, alcohol or ethanol, has received much less attention. In this study, we use ethanol, the common substance in all kinds of alcoholic beverages, as a single variable to explore its effects in vivo. Our data showed that the long-term 3.5% ethanol substitution for drinking water had beneficial effects in mice, the daily performance of ethanol-fed mice was enhanced, the athletic ability and healthspan of ethanol-fed mice drastically improved. Furthermore, the ethanol-fed mice showed the resistance to high-fat diet (HFD). When supplemented with 3.5% ethanol, the HFD mice showed reduced multiple organ pathogenicity, increased insulin sensitivity, and decreased NF-kB activation and inflammatory cytokines. These changes caused by ethanol are astonishing and impressive.

It has been well accepted that acute and chronic excessive alcohol exposure is conducive to tissue injury. However, one should be mindful that the injuries caused by the excessive use of alcohol are dose-dependent. In our study, the long term 3.5% ethanol-fed mice did not show the common negative effects of alcohol. At this dose, we did not observe any pathological structural changes in the liver, the heart, or the kidneys; neither did we detect any impairments of learning, memory, and cognition by the water maze.

One of the pathophysiological mechanisms induced by alcohol abuse has been identified as mitochondrial dysfunction. On the other hand, the mitochondrial volume was associated with high levels of physical activity. The improved mitochondrial function of long-term low-dose ethanol-intake (LLE) mice may be due to their high level of daily physical activity and enhancement of athletic ability of LLE mice. In our experiments, we observed that the mitochondrial density in the liver and the skeletal muscles of the ethanol-fed group increased, and the morphology became stronger with more cristae, indicating improved mitochondrial function under the moderate ethanol feeding.

AMPK induces mitochondrial biogenesis and has emerging roles in the regulation of both mitochondrial metabolism and dynamics. Phosphorylation activity of AMPK, necessary for mitochondrial biogenesis via SIRT1 and PGC1a, was increased in the liver of the LLE mice. Considering the activation of AMPK by moderate ethanol intake, it seems reasonable to entertain the hypothesis that the rapid acetate metabolism following the ingestion of ethanol generates sufficient AMP to transiently activate AMPK, which in turn induces the synthesis of certain long-lived proteins that act to boost insulin sensitivity and possibly aid the efficiency of fat oxidation as well.

The raised blood pressure of hypertension can be minimized with age by staying thin and active, type 2 diabetes is near entirely avoidable via much the same strategy, and smoking is just a bad idea. There is a mountain of evidence in each case for these outcomes to negatively impact health and lead to an earlier death. The work here is a reminder that if you want your mind to corrode somewhat more rapidly than would otherwise be the case, there exists a range of bad lifestyle choices that can achieve that goal.

A recent study involved 2,675 people with an average age of 50 who did not have dementia. Researchers measured their cardiovascular risk factors at the start of the study: 43% were considered obese, 31% had high blood pressure, 15% were smokers, 11% had diabetes, and 9% had high cholesterol. Participants were given thinking and memory tests at the beginning of the study and five years later. Then researchers estimated the association of the five cardiovascular risk factors with decline in their performance on the thinking and memory tests that was not defined as dementia, but was faster than what was seen in a group of adults of similar ages.

Five percent of the participants had accelerated cognitive decline over five years. A total of 7.5% of those with high blood pressure had faster decline, compared to 4.3% of those who did not have high blood pressure. And 10.3% of those with diabetes had faster decline, compared to 4.7% of those who did not have diabetes. A total of 7.7% of current smokers had faster decline, compared to 4.3% of those who never smoked.

After adjusting for age, race, education, and other factors that could affect the risk of cognitive decline, researchers found that people who smoked were 65% more likely to have accelerated cognitive decline, those with high blood pressure were 87% more likely and those with diabetes had a nearly three times as likely to have accelerated cognitive decline. People who had one or two of the risk factors were nearly twice as likely to have accelerated decline than people with no risk factors. People with three or more of the risk factors were nearly three times as likely to have faster decline than those with no risk factors.

Link: https://www.aan.com/PressRoom/Home/PressRelease/3806

This open access paper expands on earlier work on cellular senescence in long-lived naked mole-rats. Individuals of this species can live as much as nine times longer than equivalently sized rodents, and are near immune to cancer. In other mammals, senescent cells accumulate with age and disrupt tissue function via their inflammatory signaling. Evidence suggests that this is an important cause of degenerative aging, given that selective destruction of these errant cells produces rejuvenation and extended life span in mice.

In naked mole-rats, senescent cells exhibit very little of the harmful signaling that occurs in other mammals. These cells also also self-destruct more readily when stressed. That naked mole-rat senescent cells are more prone to self-destruction following oxidative stress is not just a benefit when it comes to getting rid of these harmful cells, but it also prevents damage to molecules caused by oxidative reactions - another important mechanism of aging - from causing further harm to tissues.

Naked mole-rats (NMRs) are the longest-lived rodents, showing minimal aging phenotypes. An unsolved paradox is that NMRs exhibit low intracellular anti-oxidant defence despite minimal aging. Here, we explained a link between these "contradicting" features by a phenomenon termed "senescent cell death" - senescence induced cell death in NMR cells due to their inherent vulnerability to reactive oxygen species and unique metabolic system.

Generally, the "free radical theory of aging", later modified to "mitochondrial free radical theory", is the well-known theory of aging mechanism. Intracellular reactive oxygen species (ROS), deriving especially from mitochondria, damages macromolecules such as lipids, DNA, and proteins, and the accumulated damages in tissues are assumed to contribute aging process. Indeed, the mitochondrial ROS production rate is negatively correlated with the maximal lifespan of animal species.

However, previous insights on responses of long-lived NMRs to ROS are puzzling: 1) Several reports suggested that NMRs have stronger anti-oxidant mechanisms. 2) However, many other reports suggested that NMRs exhibit low anti-oxidant defence. From young ages, NMR suffers greater oxidative damages in tissue DNA, protein, and lipids than mice. Nevertheless, the level of oxidative damage does not increase further and remains constant for more than 20 years. Thus, at least in part, NMR exhibits low intracellular anti-oxidant defence despite their delayed aging. These complex but interesting observations raise a possibility that NMR may have developed a unique system to remove damaged cellular components or the cells that suffered the oxidative damage during aging.

In mammalian cells, one of the typical "damaged" cellular status along with elevated oxidative damage is cellular senescence. Cellular senescence is an irreversible cell proliferation arrest induced in response to stresses such as DNA damage, oncogene activation, and telomere shortening. Cellular senescence contributes to avoidance of cancer formation by stopping proliferation of damaged cells. In addition, cellular senescence has important roles in tissue homeostasis, embryonic development, and wound healing. On the other hand, accumulation of senescent cells promotes age-related physiological deterioration and disorders, by secreting a bioactive "secretome" called senescence-associated secretory phenotype (SASP).

In NMR skin, we observed few senescent cells during aging or after ultraviolet irradiation, suggesting suppression of senescent cell accumulation in NMR tissue. We discovered that senescent NMR fibroblasts induce senescent cell death through retinoblastoma protein activation accompanied by autophagy dysregulation, increased oxidative damage, and accelerated H2O2-releasing metabolic pathways.

Link: https://doi.org/10.1101/2020.07.02.155903

Today's research materials report on recently presented preliminary evidence, based on work in tissue slices from mouse brains, for oxytocin to dampen the harms done to the function of neurons by amyloid-β. Amyloid-β is one of the few proteins in the body capable of becoming altered in ways that encourage other molecules of amyloid-β to alter in the same way, aggregating into solid deposits in and around cells. This is disruptive to cell function when it occurs in the brain, and rising amyloid-β aggregation is widely thought to be the early, formative stage of Alzheimer's disease.

Oxytocin is one of the factors that diminishes with age in blood, identified as potentially interesting in parabiosis studies of recent years. This work was largely focused on the role of oxytocin in muscle regeneration via its influence on stem cell function, however. More recently, increasing oxytocin and lowering TGF-β in combination was shown to reverse measures of aging in numerous tissues in mice. That, again, seems to be a matter of effects on inflammation and stem cell function rather than something more specific such as an influence on cell mechanisms relevant to amyloid-β.

Oxytocin Could Be Used to Treat Cognitive Disorders Like Alzheimer's

Alzheimer's disease is a progressive disorder in which the nerve cells (neurons) in a person's brain and the connections among them degenerate slowly, causing severe memory loss, intellectual deficiencies, and deterioration in motor skills and communication. One of the main causes of Alzheimer's is the accumulation of a protein called amyloid β (Aβ) in clusters around neurons in the brain, which hampers their activity and triggers their degeneration.

Studies in animal models have found that increasing the aggregation of Aβ in the hippocampus - the brain's main learning and memory center - causes a decline in the signal transmission potential of the neurons therein. This degeneration affects a specific trait of the neurons, called synaptic plasticity, which is the ability of synapses (the site of signal exchange between neurons) to adapt to an increase or decrease in signaling activity over time. Synaptic plasticity is crucial to the development of learning and cognitive functions in the hippocampus. Thus, Aβ and its role in causing cognitive memory and deficits have been the focus of most research aimed at finding treatments for Alzheimer's.

Researchers first perfused slices of the mouse hippocampus with Aβ to confirm that Aβ causes the signaling abilities of neurons in the slices to decline, impairing synaptic plasticity. Upon additional perfusion with oxytocin, however, the signaling abilities increased, suggesting that oxytocin can reverse the impairment of synaptic plasticity that Aβ causes. In a normal brain, oxytocin acts by binding with special structures in the membranes of brain cells, called oxytocin receptors. Expectedly, when the receptors were blocked, oxytocin could not reverse the effect of Aβ, which shows that these receptors are essential for oxytocin to act.

Oxytocin is known to facilitate certain cellular chemical activities that are important in strengthening neuronal signaling potential and formation of memories, such as influx of calcium ions. Previous studies have suspected that Aβ suppresses some of these chemical activities. When the scientists artificially blocked these chemical activities, they found that addition of oxytocin addition to the hippocampal slices did not reverse the damage to synaptic plasticity caused by Aβ. Additionally, they found that oxytocin itself does not have any effect on synaptic plasticity in the hippocampus, but it is somehow able to reverse the ill-effects of Aβ.

Oxytocin reverses Aβ-induced impairment of hippocampal synaptic plasticity in mice

Oxytocin, a peptide hormone synthesized in the hypothalamic paraventricular nucleus, has been reported to participate in the regulation of learning and memory performance. However, no report has demonstrated the effect of oxytocin on the amyloid-beta (Aβ)-induced impairment of synaptic plasticity. In this study, we examined the effects of oxytocin on the Aβ-induced impairment of synaptic plasticity in mice.

To investigate the effect of oxytocin on synaptic plasticity, we prepared acute hippocampal slices for extracellular recording and assessed long-term potentiation (LTP) with perfusion of the Aβ active fragment (Aβ25-35) in the absence and presence of oxytocin. We found that oxytocin reversed the impairment of LTP induced by Aβ25-35 perfusion in the mouse hippocampus. These effects were blocked by pretreatment with the selective oxytocin receptor antagonist L-368,899. Furthermore, the treatment with the ERK inhibitor U0126 and selective Ca2+-permeable AMPA receptor antagonist NASPM completely antagonized the effects of oxytocin.

An analysis of a large study population here shows that glucosamine supplementation results in about a 15% reduction in mortality, a sizable effect size in the context of what is known of the effects of lifestyle choices and supplementation on aging. Glucosamine is used as an anti-inflammatory intervention, but there is at best only mixed evidence for it to actually do much good as a treatment for specific inflammatory conditions such as arthritis. It is nonetheless widely used, hence the ability to see outcomes in sizable group of people. The effect on mortality is certainly an interesting outcome, given the lack of robust and compelling evidence for specific benefits.

Glucosamine is a non-vitamin, non-mineral specialty supplement commonly used to manage osteoarthritis and joint pain. Although the effectiveness of glucosamine supplementation for osteoarthritis and joint pain remains controversial, several human, animal, and laboratory studies have suggested that glucosamine may have anti-inflammatory properties, which could decrease the risk of multiple diseases. In this large-scale prospective cohort study of nearly half a million UK adults, we evaluated the association between regular glucosamine supplement use and mortality from all causes, cardiovascular disease (CVD), cancer, respiratory disease, and digestive disease.

At baseline, 19.1% of the participants reported regular use of glucosamine supplements. During a median follow-up of 8.9 years, 19,882 all-cause deaths were recorded, including 3,802 CVD deaths, 8,090 cancer deaths, 3,380 respiratory disease deaths and 1,061 digestive disease deaths. The hazard ratios associated with glucosamine use were 0.85 for all-cause mortality, 0.82 for CVD mortality, 0.94 for cancer mortality, 0.73 for respiratory mortality and 0.74 for digestive mortality. The inverse associations of glucosamine use with all-cause mortality seemed to be somewhat stronger among current than non-current smokers.

Glucosamine and chondroitin supplements are often taken together in a single daily supplements, and it is therefore possible that our observed associations are driven by either of these supplements. To address this issue, we performed sensitivity analyses examining the associations of glucosamine use alone (excluding participants who took chondroitin) with all-cause and cause-specific mortality. We found that the estimates did not change substantially. Therefore, it is likely that glucosamine use may reduce the risk of mortality, regardless of the co-administration of chondroitin.

Several potential mechanisms could explain the inverse association between glucosamine use and mortality. First, nuclear factor-κB (NF-κB) has been implicated in several diseases, such as inflammation-related CVD and cancers. Glucosamine use may affect inflammation by inhibiting the transcription factor NF-κB from translocating to the nucleus, reducing inflammation and thus lowering related mortality. Aside from reducing inflammation, an animal study reported that glucosamine use could trigger a mimic response of a low carbohydrate diet, via reducing glycolysis and increasing amino acid catabolism in mice. This could explain the linkage between glucosamine use and its protective effect, as population-based studies found that low carbohydrate diets are indeed related to a reduced risk of mortality.

Link: http://dx.doi.org/10.1136/annrheumdis-2020-217176

Researchers here analyze amounts and types of glycans in stem cells isolated from the skin of old and young mice. The differences observed might serve as a biomarker of aging, but also may be a contributing proximate cause of the age-related decline in skin stem cell function. As is usually the case, connecting downstream changes of this nature to the deeper causes of aging is a project yet to make any meaningful progress. It is also unclear as to whether glycan profile changes are a sizable cause of dysfunction versus all of the other possible proximate causes of stem cell functional decline.

Aging in the epidermis is marked by a gradual decline in barrier function, impaired wound healing, hair loss, and an increased risk of cancer. This could be due to age-related changes in the properties of epidermal stem cells and defective interactions with their microenvironment. Currently, no biochemical tools are available to detect and evaluate the aging of epidermal stem cells.

Cellular glycosylation is involved in cell-cell communications and cell-matrix adhesions in various physiological and pathological conditions. Here, we explored the changes of glycans in epidermal stem cells as a potential biomarker of aging. Using lectin microarray, we performed a comprehensive glycan profiling of freshly isolated epidermal stem cells from young and old mouse skin. Epidermal stem cells exhibited a significant difference in glycan profiles between young and old mice. In particular, the binding of a mannose-binder rHeltuba was decreased in old epidermal stem cells, whereas that of an α2-3Sia-binder rGal8N increased.

These glycan changes were accompanied by upregulation of sialyltransferase, St3gal2, and St6gal1 and mannosidase Man1a genes in old epidermal stem cells. The modification of cell surface glycans by overexpressing these glycogenes leads to a defect in the regenerative ability of epidermal stem cells in culture. Hence, our study suggests the age-related global alterations in cellular glycosylation patterns and its potential contribution to the stem cell function. These glycan modifications may serve as molecular markers for aging, and further functional studies will lead us to a better understanding of the process of skin aging.

Link: https://doi.org/10.1111/acel.13190

As a general rule, one should be skeptical about any and all single studies that identify longevity-associated genes from human data. Typically the results cannot be replicated in different study populations, and the effect sizes are in any case small. Identified gene variants confer only small changes in the odds of reaching a given age. Only a handful of gene variants show up reliably in multiple studies carried out in different human populations. So, unfortunately, however interesting or novel the data in a new study, such as the association of longevity with maintenance of normal iron levels noted in today's open access research paper, there is a good chance that it will remain unconfirmed.

Other approaches to determining the genetic contribution to longevity tend to indicate that genetic variants are much less important than lifestyle choices for near every individual. This all suggests that there exist a very large number of tiny, interacting, situational gene variants that influence longevity, but most likely nothing more promising than that. This isn't the road to greatly extended healthy human life spans; it is a road to better understanding the fine details of aging as it occurs today, very little influenced by medicine.

Multivariate genomic scan implicates novel loci and haem metabolism in human ageing

Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan, parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes.

The effects of loci of interest on male and female lifespan are largely the same, although their effect on survival may be slightly stronger in middle age (40-60 years) compared to old age (older than 80 years). We find these loci of interest colocalise with the expression of 28 cis-genes and 50 trans-genes, some of which are known to become differentially expressed with increasing age. Lastly, we find these genes are enriched for seven hallmark gene sets (particularly haem metabolism) and 32 largely overlapping biological pathways (including apoptosis and homeostasis), and in line with the highlighted pathways, we find a causal role for iron levels in healthy life.

Haem synthesis declines with age and its deficiency leads to iron accumulation, oxidative stress, and mitochondrial dysfunction. In turn, iron accumulation helps pathogens to sustain an infection, which is in line with the known increase in infection susceptibility with age. In the brain, abnormal iron homeostasis is commonly seen in neurodegenerative diseases such as Alzheimer's and Parkinson's disease and multiple sclerosis. Plasma ferritin concentration, a proxy for iron accumulation when unadjusted for plasma iron levels, has been associated with premature mortality in observational studies, and has been linked to liver disease, osteoarthritis, and systemic inflammation.

The intestinal lining is an important tissue. Among its other functions, it protects the body from inflammation that can be generated by the actions of gut microbes. This barrier declines with age, and this is thought to be influential in the increased chronic inflammation observed in older people. Ways to spur greater maintenance and repair on the part of cell populations making up intestinal tissue would likely be of great benefit, given the importance of chronic inflammation as a driver of age-related disease.

A strong cellular lining is essential for a healthy gut as it provides a barrier to the billions of microbes and harmful toxins present in our intestinal tract. This barrier is often damaged by infection and inflammation, which causes many painful symptoms. Researchers investigated the environment that surrounds gut stem cells and used "mini gut" organoid methodology where tiny replicas of gut tissue were grown in a dish. The study defined key cells that reside in close proximity to stem cells in the gut that produce the biomolecule Neuregulin-1 (NRG1) that acts directly on stem cells to kick-start the repair process.

"Our really important discovery is that supplementation with additional Neuregulin-1 accelerates repair of the gut lining by activation of key growth pathways. Our findings open new avenues for the development of Neuregulin 1-based therapies for enhancing intestinal repair and supporting rapid restoration of the critical gut function."

Gastrointestinal disease, such as Crohn's disease and ulcerative colitis, is a major health issue worldwide and results in severe damage to the epithelial cell layer lining the gut. Under these conditions, the intestine has a limited capacity to repair efficiently to restore its main absorptive function and is associated with symptoms including diarrhoea, dehydration, loss of weight and malnutrition. Developing ways to support intestinal tissue repair will dramatically improve patient recovery.

Link: https://www.eurekalert.org/pub_releases/2020-07/mu-htr072020.php

Researchers here provide evidence for age-related deafness to be caused by the loss of viable hair cells in the inner ear, rather than other possible mechanisms. As pointed out, this is perhaps the best outcome for such a study, given the numerous approaches to hair cell regeneration or hair cell replacement that are underway in the scientific community. While it is interesting to compare this result with earlier data suggesting that hair cells survive in old individuals, but are disconnected from the brain, it nonetheless boosts the prospects for near term reversal of age-related hearing loss.

Scientists have demonstrated that age-related hearing loss, also called presbycusis, is mainly caused by damage to hair cells, the sensory cells in the inner ear that transform sound-induced vibrations into the electrical signals that are relayed to the brain by the auditory nerve. Their research challenges the prevailing view of the last 60 years that age-related hearing loss is mainly driven by damage to the stria vascularis, the cellular "battery" that powers the hair cell's mechanical-to-electrical signal conversion.

Researchers examined 120 inner ears collected at autopsy. They compared data on the survival of hair cells, nerve fibers, and the stria vascularis with the patients' audiograms to uncover the main predictor of the hearing loss in this aging population. They found that the degree and location of hair cell death predicted the severity and pattern of the hearing loss, while stria vascularis damage did not. Previous studies examined fewer ears, rarely attempted to combine data across cases and typically applied less quantitative approaches. Most importantly, prior studies greatly underestimated the loss of hair cells, because they didn't use the state-of-the art microscopy techniques.

Previous animal studies suggested that presbycusis is caused by atrophy of the stria vascularis, a highly vascularized cluster of ion-pumping cells, located in the inner ear adjacent to the hair cells. The stria serves as a "battery" that powers the hair cells as they transform sound-evoked mechanical motions into electrical signals. In aging laboratory animals, such as gerbil, there is very little loss of hair cells, compared to humans, even at the end of life. However, there is prominent damage to the stria vascularis, and damage to the stria will, indeed, cause hearing loss. Prior to this new study, most scientists have assumed that the aging gerbil data also apply to human presbycusis.

The researchers say the new findings are good news given recent progress in the development of therapies to regenerate missing hair cells. If presbycusis were due primarily to strial damage, hair cell regeneration therapy would not be effective. This new study turns the tables, suggesting, that vast numbers of hearing impaired elderly patients could likely benefit from these new therapies as they come to the clinics, hopefully within the next decade.

Link: https://www.eurekalert.org/pub_releases/2020-07/meae-suh071520.php

Cells are liquid bags of molecules, constantly interacting and reacting with one another. Many of those reactions are unwanted and damaging to the molecular machinery of the cell, but repair of structures and replacement of damaged molecules is also a constant and ongoing process. The most efficient repair processes are those that attend the DNA that is folded away in the cell nucleus. Despite these processes, mutational damage to nuclear DNA slips though the layered schemes of protection and repair. It has to: without that damage, evolution would not occur.

There is some debate over the degree to which nuclear DNA damage contributes to the aging process. Evidently, and well proven, it is an important reason as to why cancer is an age-related disease - due to the occurrence of mutations in cancer suppression genes, for example. Nonetheless, looking beyond the matter of cancer risk, most mutational damage occurs in places where it will do little to no harm, in unused genes in the nuclear DNA of somatic cells with few divisions remaining before they self-destruct. Still, the consensus in the research community is that sufficient disarray can be caused by random mutational damage to negatively affect the operation of metabolism and tissue function.

The primary mechanism by which random mutational damage is thought to lead to metabolic disarray is known as somatic mosaicism. When a mutation occurs in a stem cell or progenitor cell, it can spread throughout a tissue over time via the daughter somatic cells generated to support that tissue. It remains to be determined as to just how much harm is caused by somatic mosaicism, in comparison to other mechanisms of aging that are known to be important. A meaningful assessment would likely require some way to remove or reduce mosaicism, meaning identification and repair of large numbers of mutations in large numbers of cells in disparate parts of the body, which is a little beyond the capabilities of medical science at the present time.

Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging

The main argument against a causal role of random somatic mutations in aging and aging-associated disease has been that the spontaneous mutation frequency, even at an old age, is too low to impair cellular function. The exception is cancer, where particular driver mutations are selected for a growth advantage. Mutation frequencies in somatic cells have been considered to be low because estimates were based on the mutation frequencies observed in the germline of various species, including humans, as deduced from heritable changes in proteins.

However, new single-cell sequencing methods found many more mutations per cell; i.e., up to several thousands of single nucleotide variants (SNVs), depending on the age of the subject and the cell type. This suggests that the somatic mutation rate is higher than the germline mutation rate. Indeed, in a direct comparison of germline and somatic mutation rates in humans and mice, the somatic mutation rate was found to be almost 2 orders of magnitude more frequent than the germline mutation rate. To some extent, this can be explained by selection against deleterious mutations in the germline. However, most random mutations have no effect. So far there is very little insight into the mechanism through which random somatic mutations could be pathogenic in aging mammals. Here we propose that there are essentially three such mechanisms.

Clonal Expansion of Mutations in Human Disease Genes

It has been known for some time that many Mendelian genetic diseases have a somatic mutational counterpart. Somewhat surprisingly, the fraction of cells in a tissue harboring the disease-causing mutation can be as low as 1% and still show disease. In many cases, the somatic mutation confers a growth advantage to mutant cells, but often the mutation is simply clonally amplified by chance. The most dramatic example of clonal amplification of a human disease gene is an individual with sporadic early-onset Alzheimer's disease who showed somatic mosaicism for a presenilin 1 gene mutation. The degree of mosaicism in this individual at the age of presentation was 8% in peripheral lymphocytes and 14% in the cerebral cortex.

Of course, human development and aging cannot be explained by a simple series of cell divisions, like a cell line in culture, but is subject to complex and hierarchically dictated schemes, with some cells dividing much more frequently than others and others becoming subject to apoptosis. Nevertheless, accidental somatic mutation early in development could be a significant mechanism in the etiology of human disease, alone or in combination with a germline variant. In such cases, the phenotypic effects are straightforward and associated with the known role of the target gene(s) as a germline defect. However, combinations of low-frequency disease gene mosaics could occur, in which case the phenotypic effects in terms of aging phenotypes in organs and tissues are difficult to predict.

Somatic Evolution

Evolution does not only occur in populations of organisms but also in populations of cells which are genetically heterogeneous because of de novo mutations. Most attention has been focused on evolution of somatic cells in relation to the well-documented, age-related increase in cancer incidence and mortality. However, there is evidence that somatic evolution also causally contributes to age-related diseases other than cancer. Somatic evolution has also been considered a potential mechanism for cardiovascular disease, which, like cancer, is a major age-related disorder. Evidence of genomic instability in atherosclerotic cells has been reported, leading to the hypothesis that expansion of mutant cells could be a major causal factor in cardiovascular disease.

In summary, in tissues of mammals, the adaptive landscape of somatic evolution during aging is similar to the adaptive landscape of evolution but from a different perspective. Indeed, in the aging tissue, selection for fitness among individual cells tends to move them away from their optimal peak of functioning, in concert with other cells in their host, to a more selfish pattern of genetic variation. This pushes the aging process toward loss of functionality and increased risk of disease, most notably loss of proliferative homeostasis; e.g., neoplasia, fibrosis, and inflammation, long recognized as a major aging-related phenomenon.

Mutational Networking

Certain acquired gene mutations that are not by themselves disease causing can confer a selective advantage to the cell, which expands and gradually erodes organ and tissue functioning because of increasingly selfish behavior. Although the magnitude of the adverse effects of these events in aging still await more extensive studies, there is a third possible mechanism by which randomly accumulating mutations eventually affect cell fitness. This does not require clonal outgrowth and depends on the penetration of such mutations in the DNA sequence components of the gene-regulatory networks (GRNs) that provide function to a mammalian organism throughout its life. Virtually all mutations would accumulate not in the about 1% protein-coding part of the genome but in the gene-regulatory regions that make up approximately 11% of all genome sequences.

Accumulated mutations in GRNs could explain the defects in cell signaling that have been observed with age. Cells respond to environmental challenges such as temperature changes, infections, and a variety of other stressors through GRNs and their networks of regulatory interactions. Although the dynamics of these complex networks in humans are far from understood, their actions are ultimately based on genes and the regulatory sequences that control their expression.

In the study noted here, researchers provide evidence for a few months of hyperbaric oxygen treatment to increase blood flow to the brain, perhaps in large part by spurring greater growth of small blood vessels in brain tissue. In older patients this produced improvements in measures of cognitive function. There is a good deal of evidence in the literature to suggests that changes in blood flow to the brain cause altered cognitive function. Consider that exercise improves memory function, for example, both immediately following exercise, and then over the long term. Further, it is the case that capillary networks decline in density throughout the body with age, and this is thought to contribute to degenerative aging by lowering the flow of blood to energy-hungry tissues such as the brain and muscles.

Besides common pathological declines such as in Alzheimer's disease and mild cognitive impairments, normal cognitive aging is part of the normal aging process. Processing speed, conceptual reasoning, memory, and problem-solving activities are the main domains which decline gradually over time. Cerebrovascular dysfunction is an additional distinctive feature of aging that includes endothelial-dependent vasodilatation and regional decreases in cerebral blood flow (CBF). Although not associated with a specific pathology, reduced regional CBF is associated with impaired cognitive functions.

Hyperbaric oxygen therapy (HBOT) utilizes 100% oxygen in an environmental pressure higher than one absolute atmospheres (ATA) to enhance the amount of oxygen dissolved in body's tissues. Repeated intermittent hyperoxic exposures has been shown to induce physiological effects which normally occur during hypoxia in a hyperoxic environment, including stem cells proliferation and generation of new blood vessels (angiogenesis). Angiogenesis is induced mainly in brain regions signaling ischemia or metabolic dysfunction. In turn, neovascularization can enhance cerebral blood flow and consequently improve the metabolic activity.

A randomized controlled clinical trial randomized 63 healthy adults (older than 64) either to HBOT or control arms for three months. Primary endpoint included the general cognitive function measured post intervention/control. Cerebral blood flow (CBF) was evaluated by perfusion magnetic resonance imaging. There was a significant group-by-time interaction in global cognitive function post-HBOT compared to control. The most striking improvements were in attention and information processing speed. Analysis showed significant cerebral blood flow increases in the HBOT group compared to the control group.

Link: https://doi.org/10.18632/aging.103571

Mitochondria, the power plants of the cell, are the distant descendants of ancient symbiotic bacteria. They contain their own remnant mitochondrial DNA, a small genome distinct from that in the nucleus. This DNA is, unfortunately, less well protected and repaired than is the case for nuclear DNA. It can suffer forms of mutation that cause a mitochondrion to be both dysfunctional and able to resist the quality control mechanism of mitophagy that is responsible for removing damaged mitochondria. Since mitochondria reproduce by replication, this can lead to cells quickly overtaken by broken mitochondria, which in turn pollute the surrounding tissue with damaging oxidative waste products.

As is true for most low level causative mechanisms of aging, it is an open question as to the relative importance mitochondrial DNA damage in the progression of aging, when compared with other known forms of molecular damage. Mitochondrial dysfunction is implicated in many age-related conditions, and in differences in species life span. The ability to measure mutational rates in specific tissues is a necessary step on the way to a better understanding the importance of this process in age-related disease and loss of function.

Researchers used an extremely accurate DNA sequencing method to sequence the entire genome of mitochondria - organelles that are the powerhouse of the cell - in both reproductive cells and other cells in the body and showed that, depending on the cell type, ten-month-old mother mice had approximately two-to-three times more new mutations than their nearly one-month-old pups.

The study is the first to directly measure new mutations across the whole mitochondrial genome in reproductive cells. "Previous studies identified new mutations by comparing DNA sequence between parents and offspring, rather than looking directly at the reproductive cells. This could provide a biased picture of the rate and pattern of new mutations, because selection could prevent some mutations, for example those that are incompatible with life, from ever being seen."

When the team compared the mitochondrial genome sequences of the mother mice and their pups, they found an increase in the number of mutations in the older mice for all of the tissues that they tested. This suggests that as the mice age, their mitochondrial genomes accumulate mutations, so the team wanted to know if they could identify the source of these mutations. Mutations can occur because of errors in DNA replication when a cell divides and makes copies of its genetic material for each of the resulting daughter cells. They can also be caused by environmental factors like UV light or radiation, for example, or if there are errors during DNA repair.

"When we looked at the pattern of mutations in the mitochondrial genomes it fit with what we would expect for most of them occurring through replication errors. But we also observed some differences in the mutation patterns between oocytes and body cells. This suggested that the contribution of different molecular mechanisms to mitochondrial mutations varies among these cells. Given that they undergo different numbers of cell divisions, it makes sense that the contribution of various mechanisms to the mutation process might be different between the tissues. However, because we see some evidence of replication error mutations in the mitochondrial genomes of oocytes as well, it's possible that there is turnover of mitochondrial genomes in oocytes even though the cells are not dividing themselves."

Link: https://news.psu.edu/story/621812/2020/07/15/research/new-mutations-accumulate-reproductive-cells-older-mice

Most somatic cells in the body replicate, but sizable populations do not, known as post-mitotic cells, such as varieties of neuron in the central nervous system. Cellular senescence is fundamentally a process by which cell division is halted, a reaction to DNA damage, short telomeres, or a toxic signaling environment. Cells that become senescent swell in size, as though about to divide, but instead remain large. While in that state, they secrete a potent mix of inflammatory molecules that rouse the immune system, degrade surrounding tissue structure, and alter the behavior of nearby cells. In the short term this can be useful, as a way to suppress cancer or aid in wound healing. When sustained for the long term, it is very harmful.

Senescent cells are normally quickly destroyed, but they accumulate in tissues with age, the result of a slowing of clearance processes. This is an important contributing cause of aging, and thus considerable effort is presently devoted to the development of senolytic therapies capable of selectively destroying senescent cells. In this context, one interesting question is whether or not non-replicating cells - particularly those in the brain - are capable of becoming senescent, or something like senescent. They do undergo damage, but is cell division required for cells to become harmful in this way? What does senescence look like in post-mitotic cells? Will they be destroyed by senolytic therapies? Answering this question is more complex than one might think.

Senescence-like phenotype in post-mitotic cells of mice entering middle age

There is currently no single marker with absolute specificity for senescent cells. Some markers have more universal validity while others are related to specific senescent cell types. One of the most frequently used marker of cell senescence is the activity of senescence-associated beta-galactosidase (SA-β-gal). Since 1995, the wide use of SA-β-gal to study senescence in human or mice tissues in situ has been accompanied by controversies and technical challenges. In this respect, while senescent features have been found to be activated in a range of post-mitotic cells, independent multi-marker integration and confirmation of these results is still lacking for most of them.

Here, we attempted to independently deepen this knowledge using multiple senescence markers within the same cells of wild type mice entering middle age (9 months of age). A histochemistry protocol for the pH-dependent detection of β-galactosidase activity in several tissues was used. At pH 6, routinely utilized to detect senescence-associated β-galactosidase activity, only specific cellular populations in the mouse body (including Purkinje cells and choroid plexus in the central nervous system) were detected as strongly positive for β-galactosidase activity. These post-mitotic cells were also positive for other established markers of senescence (p16, p21, and DPP4), detected by immunofluorescence, confirming a potential senescent phenotype.

Choroid plexus produces cerebrospinal fluid (CSF) and participate in brain immunosurveillance. During ageing, CSF secretion decreases as much as 50%. These modifications are concurrent with subnormal brain activity, reduced beta-amyloid clearance, and increased glycation phenomena as well as oxidative stress. The potential interplay between senescent phenotype of the choroid plexus at young/mid age and its functional decline at older age is unknown. Senescence markers have been observed in neurons in the CNS also in a pathological context, during ischemia or Alzheimer's disease.

Future research on senescent post-mitotic cells should encompass also the crucial role of mammalian target of rapamycin (mTOR) pathway. During cell cycle arrest caused by contact inhibition cells do not undergo a fully senescent phenotype. It was demonstrated that the conversion from cell cycle arrest to senescence, a phenomenon called geroconversion, requires stimulation of mTOR and downstream effectors, such as pS6K, concomitantly to p16/p21 activation. Therefore, our study thus encourages exploring the function of post-mitotic cells positive for SA-β-gal activity and other senescence markers in healthy adult or middle age organisms, by simultaneous assessment of related phenomena, to understand whether post-mitotic senescence plays a significant role as driver of ageing phenotypes.

Neurodegenerative conditions are largely marked by the accumulation of a few different types of toxic protein aggregate, both amyloid-β and tau in the case of Alzheimer's disease. These few types of protein are capable of alteration in ways that seed other molecules of the same protein to also alter in the same way, linking to form solid deposits in and around cells. These deposits are clearly toxic - but, equally, it is becoming clear that removing amyloid-β doesn't appear to do much good in Alzheimer's patients, for reasons that continue to be debated. Perhaps because amyloid-β aggregation is an early phase of the condition, and the real damage is done by later mechanisms triggered by amyloid, such as tau aggregation. Perhaps because amyloid-β aggregation is a side-effect of more important mechanisms such as chronic viral infection and consequent neuroinflammation.

Super-agers, or individuals whose cognitive skills are above the norm even at an advanced age, have been found to have increased resistance to tau and amyloid proteins, according to new research. An analysis of positron emission tomography (PET) scans has shown that compared to normal-agers and those with mild cognitive impairment, super-agers have a lower burden of tau and amyloid pathology associated with neurodegeneration, which probably allows them to maintain their cognitive performance.

Data from the Alzheimer's Disease Neuroimaging Initiative was utilized to create three age- and education-matched groups of 25 super-agers, 25 normal-agers and 25 patients with mild cognitive impairment, all above 80 years old. In addition, 18 younger, cognitively normal, amyloid-negative controls were included in the comparison as a reference group. PET images obtained for all individuals and researchers compared the tau and amyloid burden between the four groups. A logistic regression was performed to identify genetic and pathophysiological factors best predicting aging processes.

No significant differences between super-agers and the younger control group were observed in terms of in vivo tau and amyloid burden. The normal-ager group exhibited tau burden in inferior temporal and precuneal areas and no significant differences in amyloid burden, when compared to the younger control group. Patients with mild cognitive impairment showed both high amyloid and high tau pathology burden. Differences in amyloid burden dissociated the normal-agers from those with mild cognitive impairment, whereas lower tau burden and lower polygenic risk predicted super-agers from mild cognitive impairment patients.

Link: https://www.snmmi.org/NewsPublications/NewsDetail.aspx?ItemNumber=34196

The evidence strongly suggests that chronic inflammation in brain tissue is of great importance in the onset and progression of age-related neurodegenerative conditions. Overactivation of the immune system, resulting in chronic inflammation, is a feature of aging. It arises in part due to the accumulation of senescent cells and their inflammatory secretions, but persistent viral infection and a range of other mechanisms are also implicated.

Inflammaging represents a persistent low-grade systemic inflammation with inapparent clinical symptoms. In fact, it operates as a seesaw with a progressive pro-inflammatory "overload". Cytokines, such as interleukins and tumor necrosis factor α (TNFα), as well as a gamut of self-debris originated from dysfunctional cells fuel the constant activated state of the immune system. With aging, accumulation of these endogenous signals is less compensated by the autophagic machinery. These stressors function as damage-associated molecular patterns (DAMPs), activating the pattern recognition receptors (PRRs) of the innate immune system.

In the brain, the neurovascular unit (NVU) establishes an intimate structural and functional connection among microvascular endothelial cells, pericytes, glial cells, neurons, and extracellular matrix components. Primary functions of the NVU are the development and maintenance of the blood-brain barrier (BBB) and neurovascular coupling. Cells of the NVU are also recognized for the role in the regulation of inflammation in the central nervous system (CNS). Inflammasome receptors appear to have a defined expression in cell types of the NVU with predominant expression of NLRP3 in endothelial cells. Experimental data strongly indicate that brain vasculature is as much affected by inflammation as neural tissue. A growing body of literature supports the idea that the NVU takes center stage in age-related neurological diseases, and of this, inflammasomes are undoubtedly crucial mediators.

Link: https://doi.org/10.3390/cells9071614

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

Senescent cells are created constantly throughout life, largely as a result of somatic cells reaching the Hayflick limit on replication, but the pace at which they are cleared by programmed cell death or the immune system slows with age. Senescent cells thus accumulate in old tissues, and this accumulation directly contributes to the progression of age-related disease and dysfunction. Senescence cells secrete a mix of molecules that cause chronic inflammation, disrupt tissue structure, and alter surrounding cell behavior. The more senescent cells there are in an organ, the worse the outcome.

Fortunately, this contributing cause of aging now has potential solutions. Senolytic treatments are those that selectively destroy some fraction of senescent cells, as much as half in some tissues for first generation senolytic drugs. Given that senescent cells work to actively maintain an aged, damaged state of tissue, removing them is a form of rejuvenation. This rejuvenating effect been demonstrated in numerous animal studies, showing that senolytics can reverse many specific age-related diseases, as well as extend healthy life span.

Today's open access paper reports on a representative example of such animal studies of senolytic drugs. The authors used perhaps the worst of the early senolytics, navitoclax, a drug that certainly kills senescent cells, but also kills or disrupts the function of enough normal cells to have significant side-effects that prevent easy clinical use in humans. Nonetheless, one can use this proven senolytic in animal studies to demonstrate the quite rapid reversal of age-related disease produced by the destruction of senescent cells - as is the case here.

Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis

Cell senescence is characterized by arrest of cell cycle, changes in metabolism, and loss of proliferative ability. Various markers have been used to identify senescent cells (SnCs), including gene expression of p21, p16, and p53, elevated levels of reactive oxygen species (ROS), and activation of senescence-associated β-galactosidase (SA-β-Gal). In aging articular cartilage, the senescent-related alterations in chondrocytes and mesenchymal stem cells (MSCs) during osteoarthritis, such as hypertrophy and loss of cell proliferative and differentiation capacity, may affect chondrogenic differentiation of MSCs and bring obstruction to cartilage regeneration.

In this regard, the term "chondrosenescence" was proposed to describe the age-dependent destruction of chondrocytes and highlight its hallmarks, and explain how they affect the phenotype of these cells and their specialized functions. Furthermore, SnCs have been shown accumulation in OA cartilage tissues with aging. These SnCs exhibit positive staining of SA-β-Gal, increased level of the senescence-related gene p16INK4a, senescence-associated secretory phenotype (SASP), increased production of pro-inflammatory mediators, and increased secretion of cytokines and chemokines.

Selective removal of these SnCs through a senolytic molecule (UBX0101) from osteoarthritic chondrocytes has been shown to reduce the expression of inflammation- and age-related molecules, and simultaneously delay the progression of post-traumatic osteoarthritis in p16-3MR mice. This finding supports a promising therapeutic strategy by targeting SnCs for osteoarthritis treatment. Another senolytic pharmacological agent navitoclax (also named ABT263), a specific inhibitor of the BCL-2 and BCL-xL proteins, has been reported to selectively clear SnCs in the hematopoietic system from premature aging mice after total-body irradiation by inducing cell apoptosis, and thus, rejuvenating aged tissue stem cells in normally aged mice.

In this study, we examined the ability of the senolytic drug ABT263 to clear SnCs and further evaluated the therapeutic effect of ABT263 on post-traumatic osteoarthritis. A destabilization of the medial meniscus (DMM) rat model was established for in vivo experiments. We found that ABT263 reduced the expression of inflammatory cytokines and promoted cartilage matrix aggregation by inducing SnC apoptosis. Moreover, osteoarthritis pathological changes in the cartilage and subchondral bone in post-traumatic osteoarthritis rat were alleviated by ABT263 intra-articular injection. These results demonstrated that ABT263 not only improves inflammatory microenvironment but also promotes cartilage phenotype maintenance]. Furthermore, ABT263 might play a protective role against post-traumatic osteoarthritis development. Therefore, strategies targeting SnC elimination might be promising for the clinical therapy of osteoarthritis.

Researchers here note a process by which the hardening of heart valves, known as aortic valve stenosis, accelerates in its later stages. The condition causes greater shear stress in blood flow, which in turn causes immune cells in the bloodstream to become more inflammatory. The resulting greater chronic inflammation in heart tissue accelerates the mechanisms that cause stenosis. This hardening of tissue is due to calcification; a growing fraction of cells in the valves adopt behaviors more appropriate to bone tissue, creating calcium structures. Inflammatory signaling, such as that produced by the presence of senescent cells in aged tissues, is known to contribute to this inappropriate cellular activity.

Aortic valve stenosis is the most common type of heart valve disease in the elderly and affects more than one in eight people aged over 75. The condition is typically caused by degeneration and thickening of the aortic valve, which narrows the valve opening and reduces blood flow. Blood cells that have to squeeze through the narrow valve come under intense frictional force, known as shear stress. A team of researchers and clinicians set out to investigate the effect of this shear stress on white blood cells - key players in our immune system's first line of defense. They found the constant stress of squeezing through the narrow aortic valve activates these cells, leading to harmful inflammation that accelerates the progression of aortic stenosis.

The team have identified a potential drug target by pinpointing the receptor that controls this white blood cell overactivity. The research combined clinical work, such as blood samples and valve measurements, with lab experiments using organ-on-a-chip technology that replicated the pathological conditions inside the aortic valve. "In someone with severe aortic valve stenosis, circulating blood cells come under heavy shear stress about 1500 times a day. We now know this constant frictional force makes the white blood cells hyperactive. If we can stop that inflammatory response, we can hope to slow down the disease. The same organ-on-a-chip technology that helped us make these discoveries will also enable us to easily test potential drugs to treat this harmful immune response."

Link: https://www.rmit.edu.au/news/all-news/2020/jul/heart-valve-disease

An increasing interest in intervening in the aging process, in treating aging as a medical condition, inevitably produces a greater interest in measuring aging. When is an individual old? Even in the absence of new biotechnologies of rejuvenation, people clearly age at different rates, the result of lifestyle choices such as exercise and weight, exposure to persistent pathogens, and related factors. One sixty year old can be more aged or less aged than another. It might seem a little academic to be debating today how to determine whether or not someone is old, but given the ability to actually produce rejuvenation - such as via senolytic drugs that clear senescent cells from old tissues - this becomes a much more practical concern.

One widely used measure of population aging is the potential support ratio, the inverse of the old age dependency ratio. The potential support ratio divides the population 20 years of age and older into two disjoint age groups. Conceptually, the ratio is meant to reflect the stages of the human life cycle, distinguishing between adults who are elderly and those who are not. To compute the ratio two sorts of information are needed, the number of people at each age starting from 20 and a threshold age that divides the adult population into a group who are elderly and a group who are not.

On its website Profiles of Ageing 2019 the UN now publishes a conventional potential support ratio (PSR) and a prospective potential support ratio (PPSR). The difference between the two variants is based solely on different threshold ages at which people first become categorized as"old" [1]. In the PSR that threshold age is age 65 and is fixed independent of time or place. In the PPSR the threshold age is the age where remaining life expectancy is 15 years. We call the first, the conventional old age threshold (COAT) and the second the prospective old age threshold (POAT). The COAT is the most commonly used old age threshold, but it has the disadvantage that it does not change over time and is the same for all countries regardless of their trajectories of aging.

The choice of whether to use the COAT or the POAT in assessing the extent of population aging is not arbitrary. It is not like choosing between Celsius and Fahrenheit in the measurement of temperature. Having measures of population aging based on the COAT and the POAT is like having two kinds of thermometers, where sometimes both indicate that the temperature is increasing and sometimes one indicates it is getting warmer while the other indicates it is getting cooler. Indeed, sometimes measures of population aging based on the two old age thresholds change in the same direction and sometimes they do not.

We propose that the old age threshold should be determined using an equivalency criterion - in other words, people at the old age threshold should be roughly similar to one another in terms of relevant characteristics regardless of when and where they lived. Using historical data on five-year death rates at the old age threshold as an indicator of one aspect of health, we assessed the extent to which the two approaches used by the UN are consistent with the equivalency criterion. The results indicate that the old age threshold based on a fixed remaining life expectancy is consistent with the equivalency criterion, while the old age threshold based on a fixed chronological age is not.

Link: https://doi.org/10.1371/journal.pone.0233602

Today's open access paper is a companion piece to a recent discussion of repetitive element activity as a potential biomarker of biological aging. In today's paper, the authors note that a number of interventions that modestly slow aging in mice also reduce the activity of repetitive elements in the genome. Many forms of repetitive element are the remnants of ancient viruses, sequences that are capable of copying themselves into new locations in the genome, but are normally suppressed. A fair amount of attention has been given to retrotransposons, one category of repetitive elements, in the context of aging in recent years, but all repetitive elements appear to become more active with age. The systems responsible for repressing their activity begin to run awry, for reasons that are incompletely understood.

Haphazard copying of repetitive elements is a form of stochastic mutational DNA damage, capable of randomly disrupting the blueprint of specific genes. This can result in the manufacture of broken proteins or the loss of expression of functional proteins. A higher pace of mutational damage raises the risk of cancer through an unlucky combination of mutations, but is thought to also lead to the disruption of tissue function more generally. In most cases mutational damage to the nuclear genome will occur in unused genes, or to genes that have little importance. Where it does disrupt important genes, it usually occurs in somatic cells that do not replicate widely and have a limited life span. In order for this sort of damage to cause significant downstream effects, it must occur in stem cells or progenitor cells that can spread it widely throughout tissue. This is known as somatic mosaicism, and certainly does occur, but it is still unclear as to how large a detrimental effect it produces, in comparison to other issues in aging.

Healthy aging interventions reduce non-coding repetitive element transcripts

Advances in transcriptomics (e.g., RNA-seq) have led to important insight on many genes and pathways linked with 'the hallmarks of aging' and broader health outcomes. However, most of these studies have focused on coding sequences - a small fraction of the genome. Non-coding, repetitive elements (RE, more than 60% of the genome) have been particularly neglected as 'junk DNA', despite growing evidence that they have many important biological functions. RE include DNA transposons, retrotransposons, tandem repeats, satellites and terminal repeats. A major fraction of RE, mainly DNA transposons and retrotransposons, are transposable elements (TE) with the ability to propagate, multiply, and change genomic position.

Most RE/TE are in genomic regions that are chromatinized and suppressed (inactive), but recent reports show that certain TE become active during aging, perhaps due to reduced chromatin architecture/stability (e.g., histone dysregulation). Activation of these specific TE may contribute to aging by causing genomic and/or cellular damage/stress (e.g., inflammation). However, we recently reported that aging is associated with a progressive, global increase in transcripts from most RE (not only TE) in model organisms and humans. This global dysregulation of RE may have an important, more general role in aging, as RE transcripts have been linked with other key hallmarks of aging including oxidative stress and cellular senescence. In fact, it has been suggested that RE dysregulation itself may be an important hallmark of aging. If so, a logical prediction would be that interventions that increase health/lifespan and reduce hallmarks of aging (e.g., calorie restriction [CR], select pharmacological agents and exercise) should also suppress RE/TE.

Here, we analyze RE in RNA-seq datasets from mice subjected to robust healthspan- and lifespan-increasing interventions including calorie restriction, rapamycin, acarbose, 17-α-estradiol, and Protandim. We also examine RE transcripts in long-lived transgenic mice, and in mice subjected to high-fat diet, and we use RNA-seq to investigate the influence of aerobic exercise on RE transcripts with aging in humans. We find that: 1) healthy aging interventions/behaviors globally reduce RE transcripts, whereas aging and age-accelerating treatments increase RE expression; and 2) reduced RE expression with healthy aging interventions is associated with biological/physiological processes mechanistically linked with aging. Thus, RE transcript dysregulation and suppression are likely novel mechanisms underlying aging and healthy aging interventions, respectively.

The old are more vulnerable to all stresses, and heat is no exception. Older people make up a majority of the fatalities in heatwaves. This topic isn't frequently discussed in comparison to other aspects of aging, however. Impairment of the physiological response to heat is a dysfunction of high level processes in numerous organs, not just the skin, and results from a long chain of cause and consequence under the hood. That chain linking low-level molecular damage to high level outcomes is poorly explored, to say the least. This is one of the reasons why targeting the repair of that low-level damage of aging is a more effective strategy for the treatment of aging as a medical condition.

Tens of thousands of deaths have been caused by heat waves across Europe since 2000. There are an estimated 1,500 heat-related deaths every year in the United States. A health center in Paris recorded 2,814 deaths during the 2003 heat wave, 81% of these were in people older than 75 years. Exposure to hotter than usual temperatures poses a thermoregulatory challenge to the human body, particularly when this occurs suddenly, precluding opportunities for acclimatization. Nevertheless, heat illness can be managed through simple behavior changes such as drinking more water and seeking shelter in air-conditioned buildings. Such behavioral strategies rely on effective efferent-afferent physiological responses, but these have been shown to decrease with aging.

Aging impacts thermoregulation in several ways. Older adults (≥ 50 years) store 1.3 to 1.8 times more body heat when exposed to the same heat load than younger adults (19-30 years) during both exercising and passive heat exposure in both humid and dry conditions. The higher heat storage in the older individuals is due to a reduction in heat loss caused by an attenuated sweat response and increased dry heat gain.

Sweating is a critical mechanism for heat loss in humans, particularly when ambient temperature is above skin temperature as dry heat exchange results in heat gain in these situations. Sweating function declines with age at differing rates. Sudomotor function declines first in the legs, followed by progressive decrements in the upper body. Loss of sweating capacity comes from reduced function of each sweat gland rather than a reduction in the number of sweat glands, and is thought to be caused by local rather than central factors. Older adults have a higher core temperature threshold for the onset of sweating. The delayed onset of sweating coupled with the inability to increase and maintain a high sweat rate will delay the effect of cooling from sweat reducing its effectiveness, resulting in a higher core temperature and greater heat strain in the elderly.

With aging, the cardiovascular system experiences functional and structural changes. Total blood volume decreases, reactive oxygen species increase, and nitric oxide availability reduces, yielding a decrease in endothelial-dependent dilation and a reduced blood flow. Older adults increase their skin blood flow (SkBF) ~2-3 times less than their younger counterparts during passive and active heat exposure. Attenuated SkBF will reduce dry heat loss, and therefore increase heat strain on the body. The elderly will struggle to dissipate heat effectively compared with their younger counterparts, resulting in increased thermal and physiological strain.

Link: https://doi.org/10.1177/2333721420932432

Obesity and its immediate consequences, such as non-alcoholic fatty liver disease and type 2 diabetes, are associated with greater neuroinflammation and risk of dementia. Excess visceral fat tissue does its part to produce chronic inflammation throughout the body, but here researchers focus on a specific metabolic dysregulation in the liver that produces inflammation in the brain. That inflammation in turn drives a faster progression towards neurodegenerative conditions. The lesson here, as in so much of this research: don't get fat, don't stay fat. You won't like the consequences.

Researchers have revealed the cause behind the previously established link between non-alcoholic fatty liver disease (i.e., NAFLD, recently reclassified as metabolic associated fatty liver disease or MAFLD) and neurological problems. The link they discovered, the unique role of an adipokine (Lipocalin-2) in causing neuroinflammation, may explain the prevalence of neurological Alzheimer's disease-like and Parkinson's disease-like phenotypes among individuals with MAFLD.

"Lipocalin 2 is one of the important mediators exclusively produced in the liver and circulated throughout the body among those who have nonalcoholic steatohepatitis - or NASH - which is a more advanced form of MAFLD. The research is immensely significant because MAFLD patients have been shown to develop Alzheimer's and Parkinson's-like symptoms as older adults. Scientists can use these results to advance our knowledge in neuroinflammatory complications in MAFLD and develop appropriate treatments."

Ninety percent of the obese population and 40-70 percent of those with type 2 diabetes appear to have MAFLD, according to the Centers for Disease Control and Prevention. In addition to overweight/obese status and diabetes, other risk factors include high cholesterol and/or triglycerides, high blood pressure and metabolic syndrome. These individuals have a higher risk for having diseased livers, which are associated with increased lipocalin 2 - as found in the present study. The lipocalin 2 circulates throughout the body at higher levels, possibly inducing inflammation in the brain.

Link: https://www.sc.edu/study/colleges_schools/public_health/about/news/2020/mafld_neuro_chatterjee.php

It is well known that visceral fat tissue is an important source of the chronic inflammation that drives the onset and progress of all of the common age-related diseases. This is normally discussed in the context of excess visceral fat, given the high prevalence of overweight individuals in our modern society of cheap calories and too little exercise. Visceral fat encourages the creation of senescent cells and their inflammatory secretions, but also rouses the immune system to inflammation via a range of other mechanisms. Overweight individuals have a shorter, less healthy life with higher lifetime medical expenses as a result.

These mechanisms are not only an issue in overweight individuals. As noted in today's research materials, even without excess visceral fat, there is a growing imbalance between the pro-inflammatory (macrophage) and anti-inflammatory (eosinophil) immune cell populations resident in visceral fat tissue. This contributes to age-related chronic inflammation, and thus disease and mortality. Having more visceral fat certainly makes the situation worse, but thin people do not remain immune to the harms.

Interestingly, researchers here demonstrate that an eosinophil cell therapy can reverse this process, and bring inflammatory fat tissue back under control. It remains to be seen as to how long this benefit lasts. Is it akin to first generation stem cell therapies in which the transplanted cells reduce inflammation via signaling that influences native cell behavior, but do not survive for long, or do the eosinophils survive to produce a lasting benefit? The former seems more plausible.

Age-related impairments reversed in animal model

For many years scientists speculated that chronic low-grade inflammation accelerates aging processes and the development of age-related disorders. Researchers have now demonstrated that a certain kind of immune cells, known as eosinophils, which are predominantly found in the blood circulation, are also present in belly fat of both humans and mice. Although classically known to provide protection from parasite infection and to promote allergic airway disease, eosinophils located in belly fat are responsible to maintain local immune homeostasis. With increasing age the frequency of eosinophils in belly fat declines, while the number of pro-inflammatory macrophages increases. Owing to this immune cell dysbalance, belly fat turns into a source of pro-inflammatory mediators accumulating systemically in old age.

In a next step, the researchers investigated the possibility to reverse age-related impairments by restoring the immune cell balance in visceral adipose tissue. "In different experimental approaches, we were able to show that transfers of eosinophils from young mice into aged recipients resolved not only local but also systemic low-grade inflammation. In these experiments, we observed that transferred eosinophils were selectively homing into adipose tissue." This approach had a rejuvenating effect on the aged organism. As a consequence, aged animals showed significant improvements in physical fitness as assessed by endurance and grip strength tests. Moreover, the therapy had a rejuvenating effect on the immune system manifesting in improved vaccination responses of aged mice.

Eosinophils regulate adipose tissue inflammation and sustain physical and immunological fitness in old age

Adipose tissue eosinophils (ATEs) are important in the control of obesity-associated inflammation and metabolic disease. However, the way in which ageing impacts the regulatory role of ATEs remains unknown. Here, we show that ATEs undergo major age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in both humans and mice. We find that exposure to a young systemic environment partially restores ATE distribution in aged parabionts and reduces adipose tissue inflammation. Approaches to restore ATE distribution using adoptive transfer of eosinophils from young mice into aged recipients proved sufficient to dampen age-related local and systemic low-grade inflammation.

Importantly, restoration of a youthful systemic milieu by means of eosinophil transfers resulted in systemic rejuvenation of the aged host, manifesting in improved physical and immune fitness that was partially mediated by eosinophil-derived IL-4. Together, these findings support a critical function of adipose tissue as a source of pro-ageing factors and uncover a new role of eosinophils in promoting healthy ageing by sustaining adipose tissue homeostasis.

It is becoming apparent that cellular senescence in supporting cells of the brain is a significant contributing factor in the development and progression of neurodegenerative conditions such as Alzheimer's disease. Researchers have demonstrated that partial clearance of senescent microglia and astrocytes via the senolytic dasatinib, a small molecule that can pass the blood-brain barrier, reverses neuroinflammation and disease pathology in animal models. Here, researchers review what is known of the senescence of astrocytes, one of the largest group of supporting cells in the brain, in the context of Alzheimer's disease. Given the way that the evidence is shaping up, there is a decent chance that the best of the first generation of usefully effective Alzheimer's treatments will turn out to be senolytics that clear senescent cells in the brain.

Alzheimer's disease (AD) is a chronic degenerative disorder of the brain related to progressive decline of memory and cognition. The disease is characterized by brain atrophy, extracellular accumulation of beta-amyloid peptide (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and loss of synapses and dysfunctions of neurotransmission, as well as neuroinflammation.

Many of the cellular pathologies of AD present on neurons, such as neuronal extracellular deposits of Aβ, intracellular deposition of NFTs, and Lewy bodies. These classical pathologies are still central to diagnosing AD. However, although neurons have significant correlations with AD, other cell types and factors in the brain may also contribute to cognitive decline during AD. Additionally, astrocytes are the major glial cells and are vital for the normal physiological functions of the central nervous system (CNS). They perform critical roles in regulation of homeostasis and metabolism of the neurons, mediating uptake and recycling of neurotransmitters. Astrocytes also play a key role in maintenance of the blood-brain barrier (BBB). They also act as modulators of synaptic plasticity and transmission, supporting the view that astrocytes play an integral role in the initiation and progression of cognitive decline and AD.

Aging is considered the most significant risk factor for the occurrence and development of AD. The incidence of AD has been shown to increase with advancing age and cellular senescence. Studies regarding to the link and role of senescence in age-related diseases have become increasingly common, and are gradually becoming a new research area. Transcriptome analysis of AD and the aged human brain showed neurons and other non-neuronal CNS cell types including astrocytes, microglia, and oligodendrocytes displayed senescence-associated phenotypes.

Senescent astrocytes showed decreased normal physiological function and increased secretion of senescence-associated secretory phenotype (SASP) factors, which contribute to Aβ accumulation, tau hyperphosphorylation, and the deposition of NFTs in AD. Astrocyte senescence also leads to a number of detrimental effects, including induced glutamate excitotoxicity, impaired synaptic plasticity, neural stem cell loss, and blood-brain barrier (BBB) dysfunction.

Thus, therapies to alleviate astrocyte senescence could prevent the onset of AD or delay its progress. In many age-related disorders such as osteoarthritis, atherosclerosis, and diabetes mellitus type 2, the removal of senescent cells of transgenic mice models has shown an impaired associated pathology and extended the healthy lifespan. Success has also been observed in a mouse model of tau-associated pathogenesis. This study was the first to demonstrate a causal relationship between glial senescence and neurodegeneration. In this study, accumulations of senescent astrocytes and microglia were found in tau-associated neurodegenerative disease model mice. Elimination of these senescent cells via a genetic approach can reduce tau deposition and prevent the degeneration of cortical and hippocampal neurons.

Most recently, it was shown that clearance of senescent oligodendrocyte progenitor cells in AD model mice with senolytic agents could lessen the Aβ plaque load, reduce neuroinflammation, and ameliorate cognitive deficits. This seno-therapeutic approach is currently being tested in neurodegenerative diseases and despite expected challenges and difficulties, more detailed investigation is warranted.

Link: https://doi.org/10.3389/fnagi.2020.00148

In recent years, researchers have shown that osteocalcin levels decline with age. Restoring osteocalcin in mice has been shown to reverse age-related loss of memory via increased BDNF. In fact, BDNF shows up as a common mechanism of action for many interventions shown to improve cognitive function, such as restoring a more youthful gut microbiome. Among other things, increased BDNF means increased neurogenesis, the process by which new neurons are generated and integrated into neural circuits. This is certainly essential to memory function, but also to maintenance and function of the brain more generally.

As we age, all of us inevitably lose bone. Research shows that humans reach peak bone mass in their 20s; from then onwards, it is a slow decline that can eventually lead to frailty and diseases such as osteoporosis in old age. Over the past decade, new findings have suggested that this reduction in bone mass may also be linked to the weakening of muscles - referred to in medical terms as sarcopenia - as well as the memory and cognitive problems that many of us experience as we grow older. This appears to be connected to the levels of osteocalcin in the blood, through its role as a master regulator, influencing many other hormonal processes in the body.

"Osteocalcin acts in muscle to increase the ability to produce ATP, the fuel that allows us to exercise. In the brain, it regulates the secretion of most neurotransmitters that are needed to have memory. The circulating levels of osteocalcin declines in humans around mid-life, which is roughly the time when these physiological functions, such as memory and the ability to exercise, begin to decline."

Researchers have conducted a series of experiments in which he has shown that by increasing the levels of osteocalcin in older mice through injections, you can actually reverse many of these age-related ailments. "Osteocalcin seems to be able to reverse manifestations of ageing in the brain and in muscle. What is remarkable is that if you give osteocalcin to old mice, you restore memory and you restore the ability to exercise to the levels seen in a young mouse. That makes it potentially extremely attractive from a medical point of view." Scientists have also found that for humans, one way of naturally maintaining the levels of this hormone in the blood, even as we age, is through exercise, something that makes intuitive sense, as physical activity has long been known to have anti-ageing properties.

Link: https://www.theguardian.com/science/2020/jul/04/does-the-key-to-anti-ageing-lie-in-our-bones

The disposibility theory of aging is one of numerous evolutionary theories of aging that seek to explain why aging exists and is near universal across species. In this case, aging is viewed as the inevitable result of trade-offs between resources allocated to reproduction versus resources allocated to tissue maintenance. Like near all evolutionary theories, and particularly those relating to aging, the models and the science are much debated.

Since there is some variation between individuals within a species, one should expect to find a distribution of outcomes for any given trade-off when comparing large numbers of individuals of a given species. In this case, for this view of the origin of aging, we should expect to see that greater reproductive success correlates with a worse outcome in later life. Meaning a faster decline, more age-related disease, and a shorter life expectancy.

In today's open access paper, researchers compare parity (number of children carried to term) with later frailty in a human population. They indeed observe that more births tends to correlate with greater age-related frailty. The challenge with human data is that one can always come up with other plausible explanations for this effect, completely unrelated to fundamental biology. That the effect is similar in men and women somewhat sabotages any thoughts of a biological or physiological cost to childbirth as a dominant mechanism, for example.

Frailty: A cost incurred by reproduction?

The disposability theory of ageing proposes that investing in reproduction, at the cost of somatic maintenance, leads to senescence. In humans, the theory predicts that those with more children will have shorter lives. Researchers used a historical dataset from the British aristocracy to demonstrate that females with the longest life span had fewer children relative to the whole sample. Indeed, almost 50% of females who lived to 80 years and over were childless. A similar relationship between parity and longevity was found in males. The paper was criticized in the literature, particularly with regards to the quality of the data. Despite a sustained research effort and strong theoretical expectations, evidence to support a reproduction-longevity trade-off in humans is not strong. Studies of historical and contemporary cohorts have not found a consistent association between parity and longevity - no association, as well as positive and negative associations, have all been reported.

Most studies to date have tested evolutionary theories of senescence by focusing on the relationship between parity and survival (usually measured in terms of longevity). However, it is possible that survival is too crude a measure of senescence and, as a result, the 'real' cost incurred by reproduction has not been elucidated. Whilst studies have examined other health outcomes, such as physical, functional and cognitive impairment, self-rated health and limiting long-term illnesses in older males and females, findings have not been consistent. Examining the relationships between parity and individual domains of health may not be the best methodology to address the hypothesis because impairment profiles vary significantly in the older adult population and measures of individual domains do not capture all adults with poor health. 'Frailty', on the other hand, is a multidimensional measure of health status that may help to better define the long-term consequences (whether they be harms or benefits) of human reproduction.

The aims of this study were to examine the cross-sectional relationship between parity and later life frailty (represented by the Frailty Index) and to explore whether this relationship is influenced by sex. Data from the English Longitudinal Study of Ageing (ELSA) were used to test two key hypotheses: firstly, that higher parity is associated with greater frailty, indicating a 'parity-frailty trade-off' and secondly, that sex differences in frailty are greater at higher parities than at lower parities due to sex differences in the physiological costs of childbearing.

We found that the most parous adults were the most frail, providing weak evidence for a 'parity-frailty trade-off'. The relationship between parity and frailty was similar for both sexes, and thus the results suggest that behavioral and social factors associated with rearing many children may be more relevant to the parity-frailty relationship than the physiological burden of childbearing. Parity-frailty trade-off may manifest in older males and females with high parity due to economic strain, disruption of occupational attainment, and psychological stress. In addition, high parity may negatively influence lifestyle habits such as dietary choices and physical activity in both sexes. These behavioural factors increase the risk of obesity and its metabolic complications, which in turn, increase the risk of frailty.

An alternative theory is that selection effects confound the relationship between high parity and frailty. For example, lower levels of education level are associated with particular reproductive characteristics, such as early parenthood and higher overall parity, as well as later life frailty. However, in this study, education was not found to have a significant impact on the parity-frailty relationship.

Stem cell activity declines with age throughout the body. In some cases this is because stem cells become less active in response to changes in the signaling environment. In other cases, the cells are damaged or the populations greatly reduced. The consequence of this decline is that fewer daughter somatic cells are produced to make up losses, repair damage, and maintain tissue function. A slow decline into organ dysfunction results, contributing to the onset of age-related disease, disability, and mortality. Finding ways to reverse this process is a very important component of of the broader field of rejuvenation research.

Tissue stem cell exhaustion is a key hallmark of aging, and in this study, we characterised its manifestation in the distal lung. We compared the lungs of 3- and 22-month old mice. We examined the gross morphological changes in these lungs, the density and function of epithelial progenitor populations and the epithelial gene expression profile. Bronchioles became smaller in their cross-sectional area and diameter. We found that bronchiolar cell density remained stable with aging, but inferred rates of progenitor cell self-renewal and differentiation were reduced, indicative of an overall slowdown in cellular turnover.

Alveolar Type II progenitor cell density and self-renewal were maintained per unit tissue area with aging, but rates of inferred differentiation into Type I cells, and indeed overall density of Type I cells was reduced. Microarray analysis revealed age-related changes in multiple genes, including some with roles in proliferation and differentiation, and in IGF and TGFβ signalling pathways. By characterising how lung stem cell dynamics change with aging, this study will elucidate how they contribute to age-related loss of pulmonary function, and pathogenesis of common age-related pulmonary diseases.

Link: https://doi.org/10.1038/s41598-020-66966-y

Researchers here note one example of the many differences that exist between good and poor fitness in older people. The response to exercise is materially different between fit and sedentary individuals at all levels of cellular metabolism. The microRNA contents of exosomes, a class of extracellular vesicle that carries signals between cells, is one of these countless differences. It is possible that this sort of exploratory study may lead to therapies based on delivery of manufactured exosomes containing specific microRNAs, and there is certainly a growing industry of companies working on exosome manufacture to support such an effort.

Exercise has multi-systemic benefits and attenuates the physiological impairments associated with aging. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. However, the impact of regular exercise and acute exercise on circulating exosomal microRNAs (exomiRs) in older populations remains unknown. In the present study, we analyzed circulating exomiR expression in endurance-trained elderly men (n = 5) and age-matched sedentary males (n = 5) at baseline (Pre), immediately after a forty minute bout of aerobic exercise on a cycle ergometer (Post), and three hours after this acute exercise (3hPost).

Following the isolation and enrichment of exosomes from plasma, exosome-enriched preparations were characterized and exomiR levels were determined by sequencing. The effect of regular exercise on circulating exomiRs was assessed by comparing the baseline expression levels in the trained and sedentary groups. The effect of acute exercise was determined by comparing baseline and post-training expression levels in each group. Regular exercise resulted in significantly increased baseline expression of three exomiRs (miR-486-5p, miR-215-5p, miR-941) and decreased expression of one exomiR (miR-151b). Acute exercise altered circulating exomiR expression in both groups. However, exomiRs regulated by acute exercise in the trained group (7 miRNAs at Post and 8 at 3hPost) were distinct from those in the sedentary group (9 at Post and 4 at 3hPost).

Pathway analysis prediction and reported target validation experiments revealed that the majority of exercise-regulated exomiRs are targeting genes that are related to IGF-1 signaling, a pathway involved in exercise-induced muscle and cardiac hypertrophy. The immediately post-acute exercise exomiR signature in the trained group correlates with activation of IGF-1 signaling, whereas in the sedentary group it is associated with inhibition of IGF-1 signaling. While further validation is needed, including measurements of IGF-1/IGF-1 signaling in blood or skeletal muscle, our results suggest that training status may counteract age-related anabolic resistance by modulating circulating exomiR profiles both at baseline and in response to acute exercise.

Link: https://doi.org/10.3389/fphys.2020.00605

With the growing interest in the accumulation of senescent cells as an important cause of aging, and more funding flowing into this part of the field, researchers are uncovering numerous direct links between cellular senescence and age-related conditions. Senescent cells cause harm to tissues via their inflammatory secretions, the senescence-associated secretory phenotype (SASP). The SASP is damaging, but there are usually too few senescent cells, even in later life, to have a significant effect on tissue dysfunction through their localized actions. There may be exceptions to that rule, but the evidence to date strongly suggests that the SASP is the dominant mechanism in the contribution of cellular senescence to degenerative aging.

One of the many conditions in which cellular senescence is implicated is vascular calcification, the inappropriate deposition of calcium that stiffens blood vessels and heart tissue. Senescence causes some cells, senescent cells and others, triggered by the SASP, to behave as though they are maintaining bone. Stiffening of blood vessels causes the chronic raised blood pressure of hypertension and consequent pressure damage to fragile tissues throughout the body and brain. This downstream harm is so important that forcing a lower blood pressure can significantly reduce age-related mortality, even without addressing the deeper causes.

The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification

The deterioration of arterial anatomy and physiology that occurs during chronological aging is a risk factor for cardiovascular morbidity and all-cause mortality. Aged arteries are characterized by functional changes of vascular smooth muscle cells (VSMCs) from a contractile and quiescent status to a senescent phenotype. VSMCs approaching senescence acquire the senescence-associated secretory phenotype (SASP) that consists of the secretion of a variety of soluble molecules, mostly pro-inflammatory cytokines and chemokines, growth factors, and matrix-remodeling enzymes. SASP factors are released in the blood circulation and act locally in a paracrine manner to spread senescence to neighboring cells; in this way, they contribute to the development of a sterile, low-grade, chronic age-associated systemic and tissues inflammation known as "inflammaging" considered the main risk factor for the most common age related diseases, included cardiovascular diseases.

Senescent VSMCs express bone-related genes, like Runt-related transcription factor 2 (Runx2), alkaline phosphatase, and osteocalcin that favor their maladaptive switching to an osteoblastic phenotype and eventually, the onset of vascular calcification (VC), a cardiovascular complication characterized by hydroxyapatite crystals deposition and mineralization of the arterial wall. Accordingly, during aging or in pathological conditions including chronic kidney disease (CKD), atherosclerosis, or type 2 diabetes (T2D), the molecular mechanisms that promote VSMCs senescence support their osteogenic transdifferentiation and VC.

MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors, and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J Mir34a-/- mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.

A sizable portion of the variable efficacy of first generation stem cell therapies as presently practiced may be due to a poor quality of cells following expansion in culture. Regardless of quality, near all such cells die shortly after transplantation. Few clinics and few approaches to cell therapy lead to lasting survival and engraftment of transplanted cells, and beneficial effects are largely mediated by the short period of signaling produced by these cells. A range of approaches have been taken in attempts to make transplanted cells more robust: methodological improvements in the process of obtaining and culturing cells for transplant; transplanting a scaffold material along with cells; providing cells with supporting signals or nutrients; engineering cells to produce proteins that will help in survival; culling senescent cells from the culture prior to transplantation. Adding to these, researchers here report on the use of mitochondrial transfer, taking advantage of a process that does occur naturally, in which cells take up mitochondria from the surrounding medium.

Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is considered a promising therapeutic approach for bone defect repair. However, during the transplantation procedure, the functions and viability of BMSCs may be impaired due to extended durations of in vitro culture, aging, and disease conditions of patients. Inspired by spontaneous intercellular mitochondria transfer that naturally occurs within injured tissues to rescue cellular or tissue function, we investigated whether artificial mitochondria transfer into pre-transplant BMSCs in vitro could improve cellular function and enhance their therapeutic effects on bone defect repair in situ.

Mitochondria were isolated from donor BMSCs and transferred into recipient BMSCs of the same batch and passage. Subsequently, changes in proliferative capacity and cell senescence were evaluated. After that, in vivo experiments were performed by transplanting mitochondria-recipient BMSCs into a rat cranial critical-size bone defect model. Micro CT scanning and histological analysis were conducted at 4 and 8 weeks after transplantation to evaluate osteogenesis in situ. Finally, in order to establish the correlation between cellular behavioral changes and aerobic metabolism, OXPHOS (oxidative phosphorylation) and ATP production were assessed and inhibition of aerobic respiration by oligomycin was performed.

Mitochondria-recipient BMSCs exhibited significantly enhanced proliferation and migration, and increased osteogenesis upon osteogenic induction. The in vivo results showed more new bone formation after transplantation of mitochondria-recipient BMSCs in situ. Increased OXPHOS activity and ATP production were observed, which upon inhibition by oligomycin attenuated the enhancement of proliferation, migration, and osteogenic differentiation induced by mitochondria transfer. Thus mitochondria transfer is a feasible technique to enhance BMSC function in vitro and promote bone defect repair in situ through the upregulation of aerobic metabolism.

Link: https://doi.org/10.1186/s13287-020-01704-9

It is well understood that an older maternal age at birth results in offspring that are less robust, meaning a shorter life expectancy, lesser degrees of reproductive success, and so forth. The question asked here is how this effect can have persisted in the face of evolutionary competition: why do we not see organisms that can produce equally viable offspring at later ages? This is one slice of the broader evolutionary question of why aging happens at all, and why it is near universal in the animal kingdom. The present consensus on the evolution of aging, insofar as there is a consensus, is the antagonistic pleiotropy hypothesis. Selection pressure is stronger in younger individuals, leading to mechanisms and biological systems that are beneficial in youth but harmful in later life. This, of course, is entirely adequate to explain the observation that older mothers have less robust offspring; it is one narrow manifestation of aging.

In many species, survival and reproduction decrease with advancing age, a process known as "senescence." The evolution of senescence is a long-standing problem in life history theory and has been studied extensively in the laboratory, with mathematical models, and in the field. The evolution of senescence is explained by the age-specific patterns of the strength of selection, measured as selection gradients. Age-specific selection gradients on mortality and fertility decrease with age. Thus, traits expressed early in life have a larger impact on fitness than those expressed later. As a result, selection will favor traits that lead to negative effects on survival and fertility at older ages if there are even small beneficial effects in youth.

"Maternal effect senescence" is defined as the reduced success or quality of offspring with advancing age of the mother. Advanced maternal age has known negative effects on offspring health, lifespan, and fertility in humans and other species. In many taxa, including rotifers, Daphnia, Drosophila, and soil mites, offspring from older mothers have shorter lives, lower reproductive success, or both. Field studies of several species of mammals and birds have shown that offspring with older parents exhibit lower survival and recruitment and increased rates of senescence. In humans, advanced maternal age is associated with reduced lifespan and health. In Caenorhabditis elegans, Daphnia, and rotifers, advanced maternal age also increases offspring size, alters development time, and increases variability in gene expression.

Maternal effect senescence remains an interesting problem in life history evolution. Producing high-quality offspring that live long and prosper should, all else being equal, provide a selective advantage. Thus, the reduced quality of the offspring of old mothers demands an evolutionary explanation. We developed a more general multistate model that can incorporate maternal age effects on age-specific survival and fertility throughout the life cycle and with which we can easily calculate selection gradients on any of those rates as joint functions of age and maternal age.

We fit these models to data from individual-based culture experiments on the aquatic invertebrate, Brachionus manjavacas (Rotifera). By comparing models with and without maternal effects, we found that maternal effect senescence significantly reduces fitness for B. manjavacas and that this decrease arises primarily through reduced fertility, particularly at maternal ages corresponding to peak reproductive output. We also used the models to estimate selection gradients, which measure the strength of selection, in both high growth rate (laboratory) and two simulated low growth rate environments. In all environments, selection gradients on survival and fertility decrease with increasing age. They also decrease with increasing maternal age for late maternal ages, implying that maternal effect senescence can evolve through the same process as in the theory of the evolution of age-related senescence.

Link: https://doi.org/10.1073/pnas.1919988117

In recent years academic interest has grown in the study of the gut microbiome. Researchers are making inroads into understanding the considerable influence of these microbial populations over the progression of health and aging. The gut microbiome may be as influential as physical activity in these matters. The balance of microbial populations shifts unfavorably over time, for reasons that are yet to be fully mapped and understood. This leads to greater numbers of inflammatory microbes, or those that produce harmful byproducts, and fewer microbes that produce beneficial metabolites. Researchers have identified some of the more important beneficial metabolites that decline with age, such as indoles, butyrate, and propionate. In the research materials I'll point out today, the authors note a harmful metabolite, trimethylamine, that is produced in greater amounts in older individuals.

What to do about these issues? It is possible in principle to supplement missing metabolites, as they are identified. Removal of harmful metabolites is more challenging as a general rule, for all that it seems plausible in the specific case of trimelthylamine. A better approach to the problem is to fix the age-related disruption of the microbiome. Various options exist: fecal microbiota transplants, for example, are already used in human medicine, and transplanting young microbes into old individuals has been shown to be beneficial in animal studies, a method to reset the balance of microbial populations. Equally, less comprehensive methods such as innoculation against flagellin, to rouse the immune system into destroying more of the harmful microbes present in the gut, are also possible. It is also the case that very aggressive use of probiotics might work, though not yet all that well explored at the high doses likely required.

What makes arteries age? Study explores new link to gut bacteria, diet

Eat a slab of steak or a plate of scrambled eggs, and your resident gut bacteria get to work immediately to break it down. As they metabolize the amino acids L-carnitine and choline, they churn out a metabolic byproduct called trimethylamine, which the liver converts to trimethylamine-N-Oxide (TMAO) and sends coursing through your bloodstream. Previous studies have shown that people with higher blood levels of TMAO are more than twice as likely to have a heart attack or stroke and tend to die earlier. But to date, scientists haven't completely understood why.

The researchers measured the blood and arterial health of 101 older adults and 22 young adults and found that TMAO levels significantly rise with age. (This falls in line with a previous study in mice, showing the gut microbiome - or your collection of intestinal bacteria - changes with age, breeding more bacteria that help produce TMAO). Adults with higher blood levels of TMAO had significantly worse artery function, the new study found, and showed greater signs of oxidative stress, or tissue damage, in the lining of their blood vessels. When the researchers fed TMAO directly to young mice, their blood vessels swiftly aged.

Preliminary data also show that mice with higher levels of TMAO exhibit decreases in learning and memory, suggesting the compound could also play a role in age-related cognitive decline. On the flip side, old mice that ate a compound called dimethyl butanol (found in trace amounts in olive oil, vinegar and red wine) saw their vascular dysfunction reverse. Scientists believe that this compound prevents the production of TMAO. Everyone - even a young vegan - produces some TMAO. But over time, eating a lot of animal products may take a toll.

Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans

Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation.

In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation. Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events.

Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation.

Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide.

Researchers here show that declining cortisol levels cause macrophage cells of the innate immune system to become more inflammatory with age. This contributes to the state of chronic inflammation in older individuals that accelerates the onset and progression of age-related disease. The aging immune system becomes overactive (inflammaging) and less capable (immunosenescence), and its chronic inflammation acts to disrupt tissue maintenance and cell behavior in numerous harmful ways. Loss of cortisol is only a proximate cause of chronic inflammation, however, and the present research says little of how this relates to deeper causes of aging. Nonetheless, it is one of many lines of research that indicate the importance of inflammation to the aging process.

A persistent state of inflammation can cause serious damage to our bodies. One consequence is that chronic inflammatory diseases, such as atherosclerosis or arthritis, are far more prevalent in older patients. What was uncertain up until now was what actually caused these inflammatory responses to flare up. Researchers have now provided some important insight: the inflammatory process is linked to the fact that the amount of cortisol generated in the body decreases as we get older.

Cortisol and its inactive form cortisone, commonly referred to as stress hormones, are released by the adrenal gland. The hormone cortisol acts as a biochemical signalling molecule and is involved in numerous metabolic processes in the body. Cortisol deficiency in the body leads to an inflammatory response. "The serum level of cortisol in the body is lower in the elderly. Moreover, macrophages, an important type of immune cells, can convert inactive cortisone to active cortisol, but this ability declines with increasing age. What we observe is what we could call "macroph-ageing" - the age-induced disruption of macrophage functions."

Macrophages are important cells within the immune system that use signalling molecules to control other immune cells. They play a critical role in determining the extent of our body's inflammatory response. However, macrophage function becomes impaired with increasing age. This can lead to an increase in the quantities of pro-inflammatory signalling molecules, which in turn drives the activity of other inflammatory cells of the body's immune system.

Researchers found that one particular protein is implicated in the malfunctioning of macrophages in the elderly. The protein is known as GILZ and its levels are regulated in part by cortisol. A lower cortisol level causes macrophages to produce less GILZ, which in turn means that the macrophages simply continue to release inflammatory signalling molecules. The team found that GILZ levels are indeed lower in older subjects. To find out whether that in itself was enough to cause an inflammatory response, researchers genetically deactivated the GILZ protein. The data confirmed that the macrophages were activated and there was a resulting increase in chronic inflammatory processes.

Link: https://www.eurekalert.org/pub_releases/2020-07/su-ara070120.php

Excessive growth of blood vessels beneath the retina is a proximate cause of blindness in conditions such as macular degeneration. Researchers here provide evidence for physical activity to be influential in the pace at which this process of tissue damage takes place. The usual conclusion to such research is provided, which is to head off into the space of developing pharmaceuticals to mimic some fraction of the effects of exercise on metabolism. Given that calorie restriction mimetic research has been ongoing for more than 20 years, with all too little to show for it, no-one should be holding their breath awaiting viable exercise mimetic drugs with meaningfully large effect sizes.

Exercise reduced the harmful overgrowth of blood vessels in the eyes of lab mice by up to 45%. This tangle of blood vessels is a key contributor to macular degeneration and several other eye diseases. The study represents the first experimental evidence showing that exercise can reduce the severity of macular degeneration, a leading cause of vision loss. "There has long been a question about whether maintaining a healthy lifestyle can delay or prevent the development of macular degeneration. The way that question has historically been answered has been by taking surveys of people, asking them what they are eating and how much exercise they are performing. That is basically the most sophisticated study that has been done. The problem with that is that people are notoriously bad self-reporters - and that can lead to conclusions that may or not be true. This study offers hard evidence from the lab for very first time."

Enticingly, the research found that the bar for receiving the benefits from exercise was relatively low - more exercise didn't mean more benefit. "Mice are like people in that they will perform a spectrum of exercise. As long as they had a wheel and ran on it, there was a benefit. The benefit that they obtained is saturated at low levels of exercise." An initial test comparing mice that voluntarily exercised versus those that did not found that exercise reduced the blood vessel overgrowth by 45%. A second test, to confirm the findings, found a reduction of 32%.

The scientists aren't certain exactly how exercise is preventing the blood vessel overgrowth. There could be a variety of factors at play, including increased blood flow to the eyes. "It is fairly well known that as people's eyes and vision deteriorate, their tendency to engage in physical activity also goes down. It can be a challenging thing to study in older people. How much of that is one causing the other? The next step is to look at how and why this happens, and to see if we can develop a pill or method that will give you the benefits of exercise without having to exercise."

Link: https://newsroom.uvahealth.com/2020/06/30/exercise-can-slow-or-prevent-vision-loss-study-finds/

There are innumerable studies showing small gains in mouse life span. Most cannot be reproduced, particularly the older ones, those that took place before it was common knowledge in the research community that one has to very aggressively control for accidental calorie restriction. If an intervention makes mice eat less, then they will tend to live longer, even if the intervention is modestly toxic. The improvements to health and longevity produced by calorie restriction in short-lived species are larger than near all other interventions assessed to date.

Nonetheless, mechanisms that reliably (and usually modestly) slow aging in short-lived species do exist, acting to adjust metabolism into a more favorable state. Many are connected to calorie restriction, in which stress response processes are upregulated, and are as a consequence fairly well studied. Numerous interventions exist to manipulate these mechanisms, but it is not expected that sizable results in mice will translate to sizable results in humans, at least not for this class of approach. The benefit to longevity is observed to scale down as species life span increases. This may be because famine is seasonal, and thus evolutionary adaptation that allows passage through famine to reproduce on the other side must produce proportionally larger gains in life span in short-lived species than in long-lived species.

Interestingly, the intervention described in today's open access paper was an accidental discovery by researchers working outside the field of aging research. A gene related to epilepsy, Brd2, turned out to be connected to a number of longevity-associated cellular processes. Inhibition of Brd2 extends mouse life span by a large enough amount to suggest that it is a real effect, though by much less than is achieved via calorie restriction.

Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice

Although it is thought that aging results from the cumulative effects of molecular and cellular damage, we serendipitously discovered that a Brd2-haploinsufficient (Brd2+/-; denoted HET) mouse model we developed to study epilepsy had a much longer lifespan compared to wild type (Brd2+/+; denoted WT) mice. In pursuing the mechanism by which BRD2, a bromodomain (BET) protein, predisposed to epilepsy, we found that HETs, which are overtly normal, not only have significantly longer lifespans but also show healthier-aging phenotypes, including reduced cancer incidence and improved kidney function, as compared to wildtype mice.

There are several genes and molecular processes that are known to influence longevity in mice. Many of those genes are in turn influenced by Brd2. For example, Brd2 haploinsufficiency downregulates IGF signaling, and IGF signaling is decreased in calorically restricted mice - a dietary intervention that increases lifespan. Similarly, Brd2 haploinsufficiency up-regulates genes in the Sirtuin pathway, and up-regulation of the Sirtuin pathway is associated with increased lifespan. Specifically, Sirtuin 1 (SIRT1) and its homologs regulate longevity-related processes such as DNA repair, genome stability, inflammation, apoptosis, cell cycle progression and mitochondrial respiration. Reduced expression of Brd2 also increases p53, Nqo1, and Hmox1 expression, all of which reduce oxidative stress. In addition, upregulation of p53 increases genomic stability, promotes DNA repair, and increases lifespan. Because Brd2 haploinsufficiency is tied to multiple longevity-related genes and molecular processes, reduced expression of Brd2 could be a fundamental - and heritable - factor influencing lifespan.

Here, we show that Brd2 haploinsufficiency (Brd2+/-) extends lifespan and increases healthspan in C57B6/J mice. In Brd2+/- mice, longevity is increased by 23%, and, relative to wildtype animals (Brd2+/+), cancer incidence is reduced by 43%. In addition, relative to age-matched wildtype mice, Brd2 heterozygotes show healthier aging including: improved grooming, extended period of fertility, and lack of age-related decline in kidney function and morphology. Our data support a role for haploinsufficiency of Brd2 in promoting healthy aging. We hypothesize that Brd2 affects aging by protecting against the accumulation of molecular and cellular damage. Given the recent advances in the development of BET inhibitors, our research provides impetus to test drugs that target BRD2 as a way to understand and treat/prevent age-related diseases.

It is well established that sedentary behavior correlates with a greater risk of age-related disease, higher mortality, and shorter life expectancy. It is tough to prove the direction of causation when using human epidemiological data, however, meaning whether it is the case that exercise is beneficial to health, or, alternatively, that more robust people tend to exercise more. Data from animal studies robustly demonstrates that a lack of exercise is harmful to long-term health, however. It would be surprising for that not to hold up in humans.

As people age, maintaining sufficient physical activity (PA) levels is especially important as physiological decline begins to accelerate after the age of fifty. Sarcopenic changes in the muscle are associated with a decline in resting metabolic rate and glucose metabolism, contributing to increased fat accumulation and insulin resistance. Over time, these changes may negatively affect blood pressure, metabolic function, and overall cardiovascular health. Physical activity has been shown to attenuate the rate and degree to which these cardiometabolic changes occur. However, despite the well-known health benefits of PA, fewer than 30% of adults over the age of 50 engage in the recommended amount of moderate-to-vigorous PA (MVPA).

The high prevalence of sedentary behavior (SB) among older adults is of significant concern as it likely contributes to the minimization of time spent in PA. More than 25% of older adults engage in 6 hours or more of SB daily. Many cardiometabolic outcomes could be improved simply if older adults reduced their SB by increasing the time they spend in light PA (LPA). For many older adults, this is likely a more achievable and realistic goal than increasing time spent in MVPA.

Data was drawn from a convenience sample of 54 community-dwelling individuals (12 males, 42 females; mean age = 72.6 ± 6.8 years). Cardiometabolic biomarkers assessed included systolic blood pressure (SBP) and diastolic blood pressure (DBP), body mass index, waist circumference, and fasting blood glucose and cholesterol parameters. SB was assessed via accelerometry over a 7-day period, and measures included daily time in SB, number and length of sedentary bouts, the number and length of breaks between sedentary bouts, moderate-to-vigorous physical activity (MVPA), and light physical activity (LPA).

Adjusted regression analyses showed that daily sedentary time was positively associated with DBP and inversely associated with HDL cholesterol. Sedentary bout length was also associated with DBP and HDL cholesterol. Replacement of 10 minutes of SB a day with LPA was associated with improved DBP and HDL cholesterol. In conclusion, sitting for prolonged periods of time without interruption is unfavorably associated with DBP and HDL cholesterol.

Link: https://doi.org/10.1155/2020/3859472

Whether and how specific portions of the adult brain produce new neurons and integrate them into functional neural circuits, a process known as neurogenesis, is of great importance to the future of regenerative medicine for the brain. It is probably easier to beneficially adjust the operation of existing tissue maintenance mechanisms than to safely deliver cells to a tissue that has no such capacity for regeneration. In the brain in particular, fine structure is enormously important to function, so comparatively blunt approaches to the delivery of replacement cells may prove challenging to implement safely.

In mammals, neural stem cells (NSCs) in the early embryonic period are called neuroepithelial cells. In the adult brain, most NSCs are quiescent. However, NSCs in the ventricular-subventricular zone (V-SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) slowly divide to generate transit amplifying progenitor cells (TAPs) via a state called activated neural stem cells (aNSC) and thus generate new neurons. Such adult neurogenesis in the mammalian brain was first suggested in the 1960s, and neurogenesis has been found to occur primarily in the V-SVZ and SGZ throughout life. New neurons generated in these two neurogenic areas are incorporated into neural circuits and play important roles.

The attenuation of adult neurogenesis in the V-SVZ has been reported to cause abnormal olfactory and sexual behavior in mice. In addition, new neurons generated in the SGZ are also integrated into DG neural circuits and play an important role in the formation of short-term memory. The attenuation of neurogenesis in the mouse SGZ has been reported to result in the impairment of new memory formation. These new neurons are also important for the formation of spatial memories. Furthermore, new integrated neurons in the DG have the function of organizing past memories and alleviating the stress response. However, adult neurogenesis decreases with age, mainly due to a decrease in NSCs and TAPs. Several studies have reported that this reduction is likely to be caused by decreases in extrinsic signals that support the proliferation of NSCs, including mitotic signals such as EGF and FGF-2, and increases in systemic pro-aging factors.

Since the existence of adult NSCs and adult neurogenesis was confirmed, studies on adult neurogenesis have been intensively conducted with the expectation of applying NSCs and neurogenesis for regenerative medicine. Although the mobilization of endogenous NSCs has been studied as one of regenerative approaches to restore lost brain function in cerebrovascular diseases, traumatic brain injuries, neurodegenerative diseases, etc., there are still many issues to be solved, such as the depletion of NSCs and the directed migration of new neurons. From a fundamental point of view, identifying the regulatory mechanisms of adult neurogenesis and its age-related decline will undoubtedly lead to future regenerative medicine strategies.

Link: https://doi.org/10.1186/s41232-020-00122-x

The company Ponce De Leon Health claims that a recent pilot study of calcium alpha-ketoglutarate supplementation results in an average reduction of 8.5 years of epigenetic age via the DNA methylation test offered by TrueMe Labs. This being the supplement industry, expect to have to wade through a lot of dubious and excessive marketing to find any solid information about what actually happened here. The best pace to start is with the 2019 paper on the effects of calcium alpha-ketoglutarate in mice, which is a reputable study authored by reputable researchers. Delivered late in life, this intervention reduced frailty to a meaningful degree, but with only a modest effect on life span. It did not reduce senescent cell burden, but did reduce inflammatory signaling - and chronic inflammation is an important aspect of degenerative aging.

The important point to consider here is that the TrueMe Labs assay is not a relabeling of any of the more established epigenetic clocks, those with significant research associated with their behavior. It is is its own beast, an independently developed test. It uses only 13 DNA methylation sites, and so it is very possible that it is much more sensitive to some interventions than others, in comparison to, say, the original Horvath clock, depending on which mechanisms influence those sites. Thus one cannot take any of the established research into the better studied clocks and use it to inform expectations as to how the TrueMe Labs assay will behave. 8.5 years might sound like a large effect size, but it is impossible to say whether or not that is the case.

That is the challenge with all epigenetic clocks, frankly. None are yet strongly connected to underlying mechanisms of aging; it is hard to say what any specific change or outcome actually represents in terms of metabolic processes. The assays will produce a number, but that number cannot be compared between clocks, and it cannot be compared between interventions. It cannot even be used to say how good any specific intervention might be, without a great deal of further calibration for that specific intervention. Not that one would learn that by reading the Ponce De Leon Health marketing materials. A cynic might suggest that they shopped for the clock that would produce the most sizable outcome for their intervention. Whether or not that is the case here, I'm sure that this strategy will become prevalent.

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes.

Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

Pilot Study Results Suggest Epigenetic Age Reversal

Ponce de Leon Health initially worked with Dr. Brian Kennedy, who was, at the time, based at the Buck Institute for Research on Aging, searching for compounds that were generally recognized as safe (GRAS) but that had the potential to influence aging in mammals. The company screened over 300 GRAS compounds and identified compounds that could modulate a number of pathways that are linked to aging. Dr. Kennedy subsequently joined Ponce de Leon Health as its Chief Scientific Officer, and the company has been busy testing and preparing to translate these findings to people. Its strategy has been to test its products on mammalian models that closely emulate human aging in order to give the best chance of translating beneficial results to us.

For consumer testing the company gave participants Rejuvant and measured their epigenetic ages using DNA methylation testing. This supplement contains a proprietary form of calcium alpha-ketoglutarate, which the FDA considers to be GRAS. The company believes that Rejuvant works by slowing down the rate of age-related DNA methylation and reducing the inflammation caused by senescent cells, two proposed reasons why we age.

There is some evidence for near-infrared light to stimulate mitochondrial function and thus improve cell and tissue function where mitochondrial function has been impaired, such as in aging. It has been tested in models of Parkinson's disease, in which mitochondrial dysfunction is known to be important, and here researchers provide evidence for it to help compensate for failing photoreceptor function in age-related retinal degeneration. It is worth noting that improved mitochondrial function is a hypothesis to explain the observed benefits - which are quite modest in the grand scheme of things. It is a plausible hypothesis, but how exactly near-infrared light is producing this outcome is not yet fully understood.

In humans around 40 years-old, cells in the eye's retina begin to age, and the pace of this ageing is caused, in part, when the cell's mitochondria, whose role is to produce energy (known as ATP) and boost cell function, also start to decline. Mitochondrial density is greatest in the retina's photoreceptor cells, which have high energy demands. As a result, the retina ages faster than other organs, with a 70% ATP reduction over life, causing a significant decline in photoreceptor function as they lack the energy to perform their normal role.

Researchers built on their previous findings in mice, bumblebees, and fruit flies, which all found significant improvements in the function of the retina's photoreceptors when their eyes were exposed to 670 nanometre (long wavelength) deep red light. "Mitochondria have specific light absorbance characteristics influencing their performance: longer wavelengths spanning 650 to 1000nm are absorbed and improve mitochondrial performance to increase energy production."

For the study, 24 people (12 male, 12 female), aged between 28 and 72, who had no ocular disease, were recruited. All participants' eyes were tested for the sensitivity of their rods and cones at the start of the study. Rod sensitivity was measured in dark adapted eyes (with pupils dilated) by asking participants to detect dim light signals in the dark, and cone function was tested by subjects identifying coloured letters that had very low contrast and appeared increasingly blurred, a process called colour contrast.

Researchers found the 670nm light had no impact in younger individuals, but in those around 40 years and over, significant improvements were obtained. Cone colour contrast sensitivity (the ability to detect colours) improved by up to 20% in some people aged around 40 and over. Improvements were more significant in the blue part of the colour spectrum that is more vulnerable in ageing. Rod sensitivity (the ability to see in low light) also improved significantly in those aged around 40 and over, though less than colour contrast.

Link: https://www.ucl.ac.uk/news/2020/jun/declining-eyesight-improved-looking-deep-red-light

Researchers here report on an interesting discovery: upregulation of a single protein, A2B receptor, adjusts metabolism in mice in the direction of more muscle mass and less fat mass. This treatment can reverse some of the normal trajectory of aging for muscle and fat mass in older animals, turning back muscle loss and fat gain. This is one of a number of similar desirable enhancements to cellular metabolism discovered over the past few decades - see the work on follistatin upregulation, for example. It is typically a long road from this sort of discovery in mice to initial tests in human subjects, particularly given the lack of any existing approved A2B receptor agonist drugs.

On their surface, cells carry numerous different "antennas", called receptors, which can receive specific signal molecules. These then trigger a specific reaction in the cell. One of these antennas is the A2B receptor. The surfaces of some cells are virtually teeming with it, for example in the so-called brown adipose tissue. Brown adipose tissue, unlike its white-colored counterpart, is not used to store fat. Instead, it burns fat and thereby generates heat.

"We took a closer look at the A2B receptors in brown adipose tissue. In the course of this we discovered an interesting association: The more A2B a mouse produces, the more heat it generates." Which means the A2B antennas somehow seem to increase the activity of the brown fat cells. But a second observation was even more exciting: Despite their increased fat burning, the animals weigh hardly less than mice with fewer receptors. They are slimmer, but at the same time have more muscles. In fact, the researchers were able to show that the muscle cells of mice also carry the A2B receptor. When this is stimulated by a small molecule agonist, muscle growth in the rodents is increased.

As they age, mice increasingly lose muscle mass - similar to humans. And just like us, they also tend to gain a lot of fat around the hips over the years. However, if they receive the agonist that activates the A2B receptor, these aging effects are inhibited. Their oxygen consumption (an indicator of energy dissiption) increases by almost half; moreover, after four weeks of treatment they have as much muscle mass as a young animal. In order to see whether the results were also meaningful for humans, the researchers examined human cell cultures and tissue samples. They found that in people with a large number of A2B receptors, the brown adipose tissue works at a higher rate. At the same time, their muscle cells consume more energy, which may indicate that they are also more active and may be more likely to be regenerated.

Link: https://www.uni-bonn.de/news/144-2020

There is no situation so terrible that it will not be silently accepted as set in stone, only given that it has lasted for long enough to become routine. So it is with aging, and all of the pain, suffering, and death that accompanies it. The present furor surrounding COVID-19 is unusual for casting at least a little light upon the point that infectious disease largely kills older people, and in very large numbers, year in and year out. In the normal course of affairs, no-one cares until it is their turn to be old, frail, and vulnerable.

The immune system decays with age, becoming simultaneously overactive (inflammaging) and incompetent (immunosenescence). It doesn't just fail at the vital tasks of defending against pathogens and destroying cancerous and senescent cells, but also actively contributes to the onset and progression of inflammatory conditions of aging, from cardiovascular disease to dementia. The principal causes of immune aging are easily described: the thymus atrophies with age, slowing the supply of matured T cells to a trickle by age 50; hematopoietic stem cells responsible for creating immune cells become dysfunctional and damaged; lacking reinforcements, immune cell populations become rife with exhausted, senescent, broken and misconfigured cells.

In the commentary I'll point out today, the authors point out that mortality due to fungal infections is a particularly neglected aspect of the age-related decline of the immune system. The cost is high, and far too little attention is given to this issue - just as, in the broader picture, far too little attention is given to the issue of immune aging as a whole, and the enormous cost in suffering and death that it causes. Too few programs are attempting to reverse the causes of immune aging, even though this is a realistic goal, with many proof of concept studies in mice achieving positive results over the past few decades. As a species, we prioritize poorly.

Fungal infections in humans: the silent crisis

Humankind has been plagued by infectious diseases throughout history, and the ongoing COVID-19 pandemic is a daunting reminder that this susceptibility persists in our modern society. After all, communicable diseases remain one of the leading causes of death worldwide. Unfortunately, some of these "microbial threats" have been underestimated and neglected by healthcare authorities, although they endanger millions of lives each year all over the world.

Fungal infections (FIs) represent an example of such overlooked emerging diseases, accounting for approximately 1.7 million deaths annually. To put these numbers in perspective, tuberculosis is reported to cause 1.5 million deaths/year and malaria around 405,000 deaths/year. The medical impact of FIs, however, goes far beyond these devastating death rates: FIs affect more than one billion people each year, of which more than 150 million cases account for severe and life-threatening FIs. Importantly, the number of cases continues to constantly rise. Thus, FIs are increasingly becoming a global health problem that is associated with high morbidity and mortality rates as well as with devastating socioeconomic consequences.

A crucial factor that contributes to the rising number of FIs is the drastic increase of the at-risk population that is specifically vulnerable to FIs, including elderly people, critically ill or immunocompromised patients. The overall lifespan increase due to the achievements of modern medicine and social advancements, the growing numbers of cancer, AIDS, and transplantation patients with the concomitant subscription of immune-modulating drugs as well as the excessive antibiotic use compose risk factors and niches for the development of FIs. Furthermore, the increasing usage of medical devices such as catheters or cardiac valves leads to a higher risk for the formation of biofilms. Biofilms represent an assembly of highly diverse, complex and eminently organized cells embedded in an extracellular matrix that conveys protection from physical and/or chemical insults. Thus, biofilms are often resistant to existing treatments and, in fact, are considered to essentially contribute to the high mortality rates associated with invasive FIs.

There is no doubt that the threat imposed by FIs will continue to increase worldwide with a number of obstacles (including resistance development) that need to be overcome. This demands rapid and innovative action at different levels. The search for therapeutic treatment options needs to be intensified. In sum, FIs are crucial contributors to the new old threat of infectious diseases, and upgrading our antifungal armamentarium by improving existing and/or devising novel antifungal strategies remains an urgent medical challenge.

The present consensus on how particulate air pollution (such as wood smoke from cooking fires, still commonplace in much of the world) causes an acceleration of age-related disease and mortality is that this is a matter of inflammation. Particules lodge in the lungs, and there spur chronic inflammation that drives onset and progression of all common age-related conditions. The evidence for this to be a causal relationship seems fairly compelling, based on studies of similar populations with different particulate exposure that rule out socioeconomic factors. It is certainly the case that more polluted regions are usually less wealthy regions, and it is certainly the case that wealth influences life expectancy, but wealth doesn't appear to be the driving mechanism here.

A new analysis of 16 years of publicly accessible health data on 68.5 million Medicare enrollees provides broad evidence that long-term exposure to fine particles in the air - even at levels below current EPA standards - leads to increased mortality rates among the elderly. Based on the results of five complementary statistical models, including three causal inference methods, the researchers estimate that if the EPA had lowered the air quality standard for fine particle concentration from 12 μg/m3 down to the WHO guideline of 10 μg/m3, more than 140,000 lives might have been saved within one decade.

A number of studies have documented a strong correlation between long-term exposure to fine particulate and greater human mortality, but some concern has remained about the causal nature of the evidence, and whether it is sufficient to inform revisions to air quality standards. Some scientists argue that modern causal inference methods can provide such evidence, using the right data.

Analyzing a massive dataset through five distinct approaches, including two traditional statistical methods and three causal inference methods, researchers derived broad evidence consistent with a causal link between long-term particulate exposure and mortality. Modeling a 10 μg/m3 decrease of fine particle concentration between 2000 and 2016 resulted in a 6% to 7% decrease in mortality risk. Based on their model results, the researchers estimated that more than 140,000 lives might have been saved if the current U.S. standard for fine particle concentration had been lowered to 10 μg/m3 between 2007 and 2016.

Link: https://www.eurekalert.org/pub_releases/2020-06/aaft-sfs062620.php

The common neurodegenerative conditions are associated with various different forms of protein aggregation; a few proteins in the body have toxic alternative forms that can spread and cause harm to cells. Alzheimer's disease is associated with amyloid-β and tau, Parkinson's disease with α-synuclein, and so forth. But the decay of the aging brain is not a nice neat process in which one individual exhibits one clear-cut pathology with clear-cut symptoms indicative of that pathology. All protein aggregates occur in every aged person to some degree, and they interact with one another, alongside other mechanisms such as vascular issues in the brain. Diagnosis of a dementia is a case of crudely trying to fit a broad category of symptoms to a broad category of pathology. Just because the situation looks like Alzheimer's doesn't mean it is Alzheimer's by the textbook definition. It is inevitably a messy, complex situation.

"One of the things that we've learned in the last decade or so is that a lot of people that we think have dementia from Alzheimer's disease, actually don't. There are other brain diseases that cause the same kind of symptoms as Alzheimer's, including some that we only recently figured out existed." Researchers used brain autopsy data from 375 older adults. This work builds on the work last year to discover another form of dementia caused by TDP-43 proteinopathy now known as LATE.

Misfolded TDP-43 protein, which was discovered in 2006, is the "newest brain bad guy." Although TDP-43 exists normally in a non-disease causing form, it is seen in multiple debilitating diseases in addition to LATE, including ALS and frontotemporal dementia. As researchers reviewed clinical and brain autopsy data for research participants, they noticed there were significantly more people than expected that had not only Alzheimer's pathology but also pathology indicating Lewy bodies (alpha synuclein) and TDP-43. "They had every neurodegeneration causing pathology that we know about. There was not a name for this, so we came up with one: quadruple misfolded proteins, or QMP."

The group then obtained more data to conduct a study of how often QMP occurred and what that meant for the participant with QMP. The study found that about 20% of the participants with dementia had QMP, and their dementia was the most severe. "This is not great news, because it means that even if we could completely cure Alzheimer's disease, we still have to deal with TDP-43 and alpha synuclein, and they are common in old age. But, we have to understand exactly what we are up against as we try to stop dementia. We still have so much to learn."

Link: https://www.eurekalert.org/pub_releases/2020-06/uok-inj062620.php

Cell and tissue biology always turns out to be more complicated than we would all prefer. Present understanding is rarely complete to the point at which all obstacles are known. It is one of the reasons why the development of new classes of medical therapy is a challenging business. Consider the topic of autophagy in aging, for example. Autophagy is the name given to a collection of processes responsible for recycling unwanted and damaged molecules and structures in the cell. Material is conveyed, in one way or another depending on the type of autophagy, to a lysosome and engulfed. Lysosomes are membrane-bound packages of enzymes capable of breaking down just about anything a cell is likely to encounter.

The efficiency of autophagy declines with age. There is evidence for loss of function in the processes moving materials to a lysosome, and much more evidence for lysosomes themselves to become dysfunctional. Increased autophagy is involved in most of the approaches discovered to date that slow aging via alterations of cellular metabolism. This includes calorie restriction and other forms of mild stress that trigger cells into increased maintenance activities, leading to a net gain in function. Equally, too much autophagy is harmful to cells, and in some tissues it appears that autophagy increases rather than decreases with aging. It may also be becoming less efficient, but challenges arise in the matter of how to measure a complicated system of many component parts that is both more active and less effective. Loss of efficiency may only be visible via some forms of measurement, leading to contradictory reports in the scientific literature.

Pro-Senescence and Anti-Senescence Mechanisms of Cardiovascular Aging: Cardiac MicroRNA Regulation of Longevity Drug-Induced Autophagy

Pre-clinical and clinical evidence show that caloric restriction (CR) is an effective method to ameliorate cardiovascular pathologic remodeling and to improve cardiovascular function. For example, in a rat model for myocardial infarction and post-ischemic heart failure, 1-year long CR mitigated pathologic left ventricular remodeling and improved cardiac function and inotropic reserve. An average 11% CR for a 2-year period reduced cardiometabolic risk factors and increased predictors of health span and longevity in a healthy human clinical trial.

One of the underlying mechanisms for the anti-aging effect of CR is induction of autophagy, a process that removes senescent cells from tissues and thus prevent spreading of cellular senescence. It is now well established that autophagy is a converging point for the beneficial effects of longevity drugs such as rapamycin, other rapalogs, metformin, and resveratrol.

Optimal levels of autophagy is an evolutionarily-conserved intracellular catabolism process essential to preserve cellular homeostasis in response to the same or similar stressors that induce cellular senescence. Cellular senescence, an important hallmark of aging, is a critical factor that impairs repair and regeneration of damaged cells in cardiovascular tissues. Therefore, therapeutic targeting of autophagy can be an effective approach to mitigate cardiovascular diseases. In particular, cardiomyopathy caused by diabetes involves extensive deregulation of cardiac mitochondrial function and induction of mitochondrial autophagy (mitophagy) that may start as a survival mechanism, but can cause cell death when excessive.

Autophagy encompasses highly regulated cellular processes to maintain cellular homeostasis and proteostasis, and eliminates potentially harmful cellular stressors that induce cell death. The highly-conserved autophagy machinery forms double-membraned autophagosomes to sequester portions of the cytoplasm and organelles, and trafficks these autophagosomes to lysosomes for degradation. Various forms of autophagy including macroautophagy, microautophagy, and chaperone-mediated autophagy all lead to turnover of intracellular components.

While autophagy is a catabolic process that degrades damaged organelles, misfolded proteins, and other harmful stressors, it also generates new building blocks (for example amino acids), energy for anabolism in conditions of nutrient deprivation, and promotes self-renewal and differentiation of pluripotent stem cells which is essential for repair of damaged tissue. Autophagy dysregulation tilts the balance from autophagy being the protective mechanism to exerting detrimental effects on cells leading to apoptosis, to whole-organ dysfunction, and organismal demise. Therefore, better understanding of the underlying molecular mechanisms of therapeutic induction of autophagy is of utmost importance, and the levels of autophagy need to be carefully monitored.

Excess visceral fat tissue generates chronic inflammation via a range of mechanisms, including an accelerated creation of senescent cells. Most of the commmon age-related conditions have an inflammatory component, and thus people who are overweight or obese suffer a raised risk of age-related disease, higher lifetime medical costs, and a shorter life expectancy. This is illustrated here in yet another study showing that greater BMI and waist circumference (the latter a better measure of visceral fat burden) correlate with greater risk of dementia.

Researchers collected data from 6,582 people in a nationally representative sample of the English population aged 50 years and over, from the English Longitudinal Study of Ageing. Three different sources were used to ascertain dementia: doctor diagnosis, informant reports and hospital episode statistics. It was found that people whose BMI was 30 or higher (at obese level) at the start of the study period had a 31% greater risk of dementia, at an average follow-up of 11 years, than those with BMIs from 18.5-24.9 (normal level).

There was also a significant gender difference in the risk of dementia associated with obesity. Women with abdominal obesity (based on waist circumference) had a 39% increased risk of dementia compared to those with a normal level. This was independent of their age, education, marital status, smoking behaviour, genetics (APOE ε4 gene), diabetes and hypertension - and yet this association was not found among the male participants. When BMI and waist circumference were viewed in combination, obese study participants of either gender showed a 28% greater risk of dementia compared to those in the normal range.

Prior evidence suggests that obesity might cause an increased risk of dementia via its direct influence on cytokines (cell signalling proteins) and hormones derived from fat cells, or indirectly through an adverse effect on vascular risk factors. Some researchers have also suggested that excess body fat may increase dementia risk through metabolic and vascular pathways that contribute to the accumulation of amyloid proteins or lesions in the brain. "It is possible that the association between obesity and dementia might be potentially mediated by other conditions, such as hypertension or anticholinergic treatments. While not explored in this study, the research question of whether there an interactive effect between obesity and other midlife risk factors, such as hypertension, diabetes, and APOE ε4 carrier status, in relation to dementia will be investigated in upcoming work."

Link: https://www.ucl.ac.uk/news/2020/jun/obesity-linked-higher-dementia-risk

Researchers here expand upon a fortuitous discovery that inhibition of the gene PTB causes a number of cell types to change into neurons, using this finding as the basis for a treatment that might be applied to a range of neurodegenerative conditions in which neurons are lost. When used in an animal model of Parkinson's disease, PTB inhibition causes astrocytes, a class of supporting cell in the brain, to become neurons. Symptoms of the condition are removed, indicating that some of the former astrocytes take over the duties of the vital population of dopaminergenic neurons that is lost in Parkinson's disease.

Several years ago, a postdoctoral researcher was using a technique called siRNA to silence the PTB gene in connective tissue cells known as fibroblasts. It's a tedious process that needs to be performed over and over. He got tired of it and instead used a different technique to create a stable cell line that's permanently lacking PTB. At first, the postdoc complained about that too, because it made the cells grow so slowly. But then he noticed something odd after a couple of weeks - there were very few fibroblasts left. Almost the whole dish was instead filled with neurons. In this serendipitous way, the team discovered that inhibiting or deleting PTB transforms several types of mouse cells directly into neurons.

Recently, researchers applied this finding in what could one day be a new therapeutic approach for Parkinson's disease and other neurodegenerative diseases. Just a single treatment to inhibit PTB in mice converted native astrocytes, star-shaped support cells of the brain, into neurons that produce the neurotransmitter dopamine. As a result, Parkinson's disease symptoms disappeared. The treatment works like this: The researchers developed a noninfectious virus that carries an antisense oligonucleotide sequence - an artificial piece of DNA designed to specifically bind the RNA coding for PTB, thus degrading it, preventing it from being translated into a functional protein and stimulating neuron development.

The researchers administered the PTB antisense oligonucleotide treatment directly to the mouse's midbrain, which is responsible for regulating motor control and reward behaviors, and the part of the brain that typically loses dopamine-producing neurons in Parkinson's disease. A control group of mice received mock treatment with an empty virus or an irrelevant antisense sequence. In the treated mice, a small subset of astrocytes converted to neurons, increasing the number of neurons by approximately 30 percent. Dopamine levels were restored to a level comparable to that in normal mice. What's more, the neurons grew and sent their processes into other parts of brain. There was no change in the control mice. By two different measures of limb movement and response, the treated mice returned to normal within three months after a single treatment, and remained completely free from symptoms of Parkinson's disease for the rest of their lives. In contrast, the control mice showed no improvement.

Link: https://ucsdnews.ucsd.edu/pressrelease/one-time-treatment-generates-new-neurons-eliminates-parkinsons-disease-in-mice

The age-related decline of the immune system has several causes, but the involution of the thymus is an important one. The thymus is responsible for the production of mature T cells of the adaptive immune system, but the organ atrophies with age. The supply of new T cells falls off dramatically in later life, and without these reinforcements, the adaptive immune system becomes ever more populated with broken, misconfigured, senescent, exhausted, and outright harmful T cells.

A few research groups and companies are investigating ways to restore the thymus, typically by provoking it to regrow. A number of approaches have been demonstrated to accomplish this goal in mammals, with varying degrees of success and reliability. Only two have been shown to work in humans, the growth hormone approach of Intervene Immune, and sex steroid ablation, as used in prostate cancer and hematopoietic stem cell transplant patients.

Today's open access paper provides confirming evidence for the atrophy of the thymus to be a function of changes in the progenitor cells of the thymic epithelium, responsible for providing daughter somatic cells to populate this tissue. If stem cells and progenitor cells become dysfunctional, a slow atrophy of the surrounding tissues is more or less exactly what one would expect. This is seen in the loss of muscle mass and strength with aging, for example, relating to the declining activity of muscle stem cells. This work is interesting in the context of past demonstrations of cell therapies for thymus regrowth, in which thymic epithelial cells are delivered in animal studies.

Ageing compromises mouse thymus function and remodels epithelial cell differentiation

Ageing of the immune system first manifests as a dramatic involution of the thymus. This is the primary lymphoid organ that generates and selects a stock of immunocompetent T cells. The thymus is composed of two morphological compartments that convey different functions: development of thymocytes and negative selection against self-reactive antigens are both initiated in the cortex before being completed in the medulla. Both compartments are composed of a specialized stromal microenvironment dominated by thymic epithelial cells (TECs).

Thymic size is already compromised in humans by the second year of life, decreases further during puberty, and continuously declines thereafter. With this reduced tissue mass, cell numbers for both lymphoid and epithelial cell compartments decline. This is paralleled by an altered cellular organization of the parenchyma, and the accumulation of fibrotic and fatty changes, culminating in the organ's transformation into adipose tissue. Over ageing, the output of naïve T cells is reduced and the peripheral lymphocyte pool displays progressively worsened T cell populations.

To resolve the progression of thymic structural and functional decline we studied TEC using single-cell transcriptomics across the first year of mouse life. Unexpectedly, we discovered that the loss and quiescence of TEC progenitors are major factors underlying thymus involution. The function of mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core immunological functions of the thymus.

Senolytic drugs that destroy senescent cells, and later on, other senotherapies that either prevent senescence or block the senescence-associated secretory phenotype (SASP), are going to be very important in the treatment of aging. Senescent cells accumulate with age and are highly damaging to tissues. Via the SASP, even comparatively small numbers of lingering senescent cells actively disrupt health and tissue function, driving age-related disease and mortality. Removing these errant cells causes quite rapid rejuvenation in animal studies, meaningfully reversing the progression of numerous age-related conditions. Other approaches to the treatment of aging attempted to date have so far failed to produce results that are as robust and impressive as the data emerging from the study of senolytics. Within a few years we'll know just how well that translates to humans for at least a few conditions, as a number of clinical trials are presently underway or planned.

Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin. In preclinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multimorbidity, and accelerated aging phenotypes. In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae. Early clinical trials have thus far focused on safety and target engagement of senolytic agents that clear senescent cells. We hypothesize that these pharmacologic interventions may have transformative effects on geriatric medicine.

Multiple interventions that target primary aging processes are currently being explored. Senescent cell burden represents one fundamental aging process that has been carefully studied. Targeting it at the preclinical level by genetic and pharmacologic reduction has yielded compelling findings that support the geroscience hypothesis. Translation of promising pharmacologic interventions in the form of senotherapeutic agents has begun to assess safety and target engagement.

Reduction in senescent cell burden could be transformative to clinical practice, especially geriatric medicine. Clinically relevant primary endpoints for older adults will likely include aspects of both objective and subjective physical functioning, since these are predictive of morbidity and mortality, contribute to risks of cognitive decline and injury, are prominent components of geriatric syndromes, and are consistent with measurable improvements being made in the short term. Biomarker discovery will be facilitated by larger clinical trials, measurement of changes in multiple analytes in multiple target specimens, and replication of biomarker feasibility and utility across multiple sites within a single study and among different studies. In the longer term, it should be possible to assess the delays in onset of chronic diseases and geriatric syndromes with compression of morbidity, using interventions based on reduction of senescent cell burden and other interventions in the aging process.

Link: https://doi.org/10.1016/j.molmed.2020.03.005

Researchers have discovered a number of mitochondrial peptides that influence cell and tissue health. Here, it is demonstrated that upregulation of humanin is sufficient to extend life in nematode worms. Since humanin levels decrease with age, and since long-lived families tend to have higher levels of humanin, it is hoped that upregulation can be the basis for therapies to modestly slow the progression of aging. There has been a fair amount of research along these lines in recent years, such as showing that delivery of humanin improves cognition in aged mice. It is an interesting part of the field.

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. Humanin is the first member of this new class of mitochondrial-derived signaling peptides that now includes MOTS-c and SHLP1-6. The humanin gene is found as a small open reading frame within the 16s rRNA gene of the mitochondrial genome. It is highly conserved in chordates but can also be found in species as distant as the nematode, suggesting that humanin is an ancient mitochondrial signal used to communicate to the rest of the organism.

Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence.

Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer's disease. Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.

Link: https://doi.org/10.18632/aging.103534