Fight Aging!

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Contents

• Linking Gum Disease with the Progression of Atherosclerosis and Risk of Stroke
• A Process Used by Cells to Ingest Misfolded Proteins Might be Enhanced to Treat Neurodegenerative Conditions
• Preventing Oligomerization of β-arrestin-2 Improves Clearance of Tau via Autophagy
• Forthcoming Longevity Industry Conferences, March to May 2020
• The Next Recommendation on Lowering Cholesterol May be to Start Earlier
• Evidence for Better Blood Supply to the Hippocampus to Slow Cognitive Decline
• Longevity-Related Genes are Under Greater Evolutionary Constraint in Large and Long-Lived Mammals
• Nicotinamide Mononucleotide Supplementation Improves Neurovascular Function in Aged Mice
• Wnt/β-Catenin Signaling as a Point of Intervention to Spur Greater Neural Regeneration
• Individual Risk of Dementia is Falling, but an Aging Population Means that a Greater Incidence of Dementia Lies Ahead
• A Survey of the Evidence for Hormesis to Slow Aging in Nematode Worms
• Calorie Restriction Suppresses the Senescence-Associated Secretory Phenotype
• The Skin Microbiome Better Correlates with Chronological Age than the Gut Microbiome
• USP7 Inhibition Clears Up to Half of Irradiation Induced Senescent Cells From Mouse Tissues
• An Epigenetic Clock for Skeletal Muscle

Linking Gum Disease with the Progression of Atherosclerosis and Risk of Stroke
https://www.fightaging.org/archives/2020/02/linking-gum-disease-with-the-progression-of-atherosclerosis-and-risk-of-stroke/

Atherosclerosis is a condition characterized by the growth of fatty lesions, atheromas, in blood vessel walls. This narrows and weakens blood vessels, leading to heart disease, and then ultimately the fatal rupture or blockage of a major vessel that causes a heart attack or stroke. This degeneration of the arteries is a universal process. It occurs to various degrees in every older person, and kills perhaps a sixth of humanity at the present time. The only reason that it doesn't kill everybody is that other degenerative process of aging manage to get in first, that data suggesting that this is most likely only a matter of a few years of difference. We are as old as our arteries, as they say.

The pace at which atherosclerosis progresses is strongly driven by chronic inflammation. Excessive and constant inflammation is a feature of aging, with some people much worse off than others, and this variation in inflammatory burden goes a long way towards determining who will die, earlier than might otherwise be the case, due to the consequences of atherosclerosis. To understand why inflammation is important to this age-related condition, one needs to know something about the underlying processes that cause atherosclerotic lesions to form.

Atherosclerosis is, in essence, a condition of dysfunctional macrophages. These immune cells are responsible for clearing out unwanted, excessive, or damaged lipids, such as cholesterols, from blood vessel walls. Those lipids are handed off to HDL particles to be returned to the liver for disposal. This works just fine in youth. With age, however, a greater fraction of circulating lipids become oxidized, and macrophages do not handle oxidized lipids well at all. They become dysfunctional foam cells, packed with lipids, and issuing inflammatory signals that draw in more macrophages to suffer the same fate. An atherosclerotic lesion is a macrophage graveyard, seeded by oxidized lipids, and growing via a feedback loop of inflammatory signaling and failing, dying macrophages.

If there is greater systemic inflammation in the body, more macrophages will be drawn to lesions. It is also the case that macrophages attempting to clean up those lesions will be more prone to adopt an unhelpful inflammatory state if greater inflammatory signaling is present in the environment. Further, inflammation and excessive amounts of oxidizing molecules go hand in hand: more inflammation will thus tend to mean more oxidized cholesterols in circulation. This all contributes to a more rapid pace of progression for atherosclerosis.

What causes one older person to have a greater level of chronic inflammation than another? One important variation between individuals is the status of chronic infection. Is there a greater burden of, to pick one important example, herpesviruses such as cytomegalovirus that cannot be cleared unaided by the human immune system and that corrode the immune system over time? Another feature is the one examined in today's research materials, the health of gums. A range of evidence suggests that the localized inflammation of gum disease does not stay localized, and in fact spreads chronic inflammation throughout the body, harming the heart and the brain - and accelerating the progression of atherosclerosis, thus raising the risk of suffering a stroke.

Gum disease, inflammation, hardened arteries may be linked to stroke risk

Two studies raise the possibility that treating gum disease alongside other stroke risk factors might reduce the severity of artery plaque buildup and narrowing of brain blood vessels that can lead to a new or a recurrent stroke. However, these two studies could not conclusively confirm a cause-and-effect relationship between gum disease and artery blockage or stroke risk. "Gum disease is a chronic bacterial infection that affects the soft and hard structures supporting the teeth and is associated with inflammation. Because inflammation appears to play a major role in the development and worsening of atherosclerosis, or 'hardening' of blood vessels, we investigated if gum disease is associated with blockages in brain vessels and strokes caused by atherosclerosis of the brain vessels."

In the first study, researchers examined 265 patients (average age of 64) who experienced a stroke between 2015 and 2017, analyzing whether gum disease was associated with specific types of stroke. They found that large artery strokes due to intracranial atherosclerosis were twice as common in patients with gum disease as in those without gum disease. Further, patients with gum disease were three times as likely to have a stroke involving blood vessels in the back of the brain, which controls vision, coordination, and other vital bodily functions. Gum disease was more common in patients who had a stroke involving large blood vessels within the brain, yet not more common among those who had a stroke due to blockage in blood vessels outside the skull.

The second study focused on 1,145 people who had not experienced a stroke, selected from the Dental Atherosclerosis Risk in Communities (DARIC) Study. Researchers used two magnetic resonance images to measure blockages in arteries inside the brain. Participants were an average age of 76. Periodontal examinations were used to classify the presence and severity of gum disease. Researchers found that arteries in the brain were severely blocked (50% or more) in 10% of participants, and people with gingivitis, inflammation of the gums, were twice as likely to have moderately severe narrowed brain arteries from plaque buildup compared to those with no gum disease. After adjusting for risk factors such as age, high blood pressure, and high cholesterol, people with gingivitis were 2.4 times as likely to have severely blocked brain arteries.

A Process Used by Cells to Ingest Misfolded Proteins Might be Enhanced to Treat Neurodegenerative Conditions
https://www.fightaging.org/archives/2020/02/a-process-used-by-cells-to-ingest-misfolded-proteins-might-be-enhanced-to-treat-neurodegenerative-conditions/

The aggregation of misfolded proteins is a feature of most neurodegenerative conditions: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and so forth. These and a few more of the countless proteins present in the body can become altered, such as via misfolding, in ways that encourage other molecules of the same protein to also alter, forming structures of linked, harmful proteins that can spread through tissue or from cell to cell. Cells, particularly immune cells, are equipped with a range of mechanisms to identify and break down these problem proteins, but, for reasons that are not fully understood at the detail level, damage outpaces maintenance in the aging brain. Aggregates grow and spread, leaving a trail of cellular dysfunction and death in their wake.

In today's research materials, scientists report on their exploration of a process by which cells ingest and break down misfolded extracellular proteins. Amyloid-β might be the most interesting example of such proteins, given its role in Alzheimer's disease. The researchers note evidence for upregulation of the operation of this maintenance process to reduce the impact of amyloid-β aggregation on brain tissue; we shall see whether this progresses to the point of producing therapies in the years ahead. Certainly researchers are quite interested in upregulating the operation of processes such as autophagy and proteasomal degradation of proteins that are focused on breaking down problem proteins inside cells, so why not also enhance the ability of cells to maintain their surroundings as well?

Researchers discover how cells clear misfolded proteins from tissues

A number of diseases are believed to be caused by the gradual buildup of misfolded proteins that can aggregate together and damage neurons and other cells in the body. To help prevent this damage, cells have developed numerous quality control systems that recognize misfolded proteins within the cell and either fold them back into their correct shape or else degrade them before they start to aggregate. However, approximately 11% of human proteins exist outside of the cell, where they are subjected to even more stresses that may cause them to misfold. Alzheimer's disease is characterized by aggregates of amyloid-β protein in the extracellular space. Despite this, how aberrant extracellular proteins are degraded remains poorly understood.

A protein called Clusterin can bind to misfolded extracellular proteins and prevent them from aggregating. Researchers discovered that Clusterin can escort misfolded proteins into the cell and deliver them to the cell's garbage-disposal units - the lysosomes - where they can be degraded. The researchers also discovered that, after binding to misfolded proteins, Clusterin enters cells by binding to proteins known as heparan sulfate proteoglycans, which are present on the surface of almost all human cells. Together, Clusterin and heparan sulfate proteoglycans allow many different cell types to internalize and degrade a wide variety of misfolded extracellular proteins.

Intriguingly, the researchers also found that Clusterin and heparan sulfate proteoglycans can import amyloid-β into cells for degradation. Mutations in the gene encoding Clusterin have been linked to an increased risk of developing Alzheimer's disease, and experiments in rats have shown that injecting Clusterin into the brain can prevent amyloid β-induced neurodegeneration. "Our results therefore suggest new avenues for the possible treatment or prevention of disorders such as Alzheimer's disease that are associated with aberrant extracellular proteins."

Heparan sulfate is a clearance receptor for aberrant extracellular proteins

The accumulation of aberrant proteins leads to various neurodegenerative disorders. Mammalian cells contain several intracellular protein degradation systems, including autophagy and proteasomal systems, that selectively remove aberrant intracellular proteins. Although mammals contain not only intracellular but also extracellular proteins, the mechanism underlying the quality control of aberrant extracellular proteins is poorly understood. Here, using a novel quantitative fluorescence assay and genome-wide CRISPR screening, we identified the receptor-mediated degradation pathway by which misfolded extracellular proteins are selectively captured by the extracellular chaperone Clusterin and undergo endocytosis via the cell surface heparan sulfate (HS) receptor.

Biochemical analyses revealed that positively charged residues on Clusterin electrostatically interact with negatively charged HS. Furthermore, the Clusterin-HS pathway facilitates the degradation of amyloid β peptide and diverse leaked cytosolic proteins in extracellular space. Our results identify a novel protein quality control system for preserving extracellular proteostasis and highlight its role in preventing diseases associated with aberrant extracellular proteins.

Preventing Oligomerization of β-arrestin-2 Improves Clearance of Tau via Autophagy
https://www.fightaging.org/archives/2020/02/preventing-oligomerization-of-%ce%b2-arrestin-2-improves-clearance-of-tau-via-autophagy/

In today's research materials, scientists report on the discovery of a maladaptive response to the presence of tau aggregates in brain cells, one that makes the situation worse than it would otherwise be. Tau is one of a small number of proteins that can become altered in a way that ensures other molecules of the same protein also alter. They join together and precipitate into solid structures, known as neurofibrillary tangles in the case of tau, accompanied by a halo of disrupted biochemistry that is harmful to cell and tissue function. This spreads, seeding dysfunction as it moves from cell to cell, or throughout a tissue between cells.

Cells do attempt to fight back against the spread of broken proteins and their aggregates. Multiple mechanisms allow cells to ingest and break down aggregates present between cells, and aggregates inside cells are also fed into the same recycling machinery. It is perhaps the case that neurodegenerative conditions are age-related in large part because the machinery of autophagy, an important recycling mechanism in cells, degrades with age. The efforts to reduce molecular waste such as protein aggregates falter.

Here, researchers have found that an oligomerized form of β-arrestin-2 acts to interfere with the processes of autophagy as they attempt to remove aggregated tau protein. Normally cells recycle unwanted protein machinery and damaged structures by delivering these materials to a lysosome to be broken down, but an important component of autophagy is inhibited by oligomerized β-arrestin-2. Interestingly, preventing β-arrestin-2 from adopting this unhelpful form reduces tau pathology in mouse models of tauopathy with no apparent side-effects.

Beta-arrestin-2 increases neurotoxic tau driving frontotemporal dementia

Researchers have discovered that a form of the protein comprised of multiple β-arrestin-2 molecules, known as oligomerized β-arrestin-2, disrupts the protective clearance process normally ridding cells of malformed proteins like disease-causing tau. Monomeric β-arrestin-2, the protein's single-molecule form, does not impair this cellular toxic waste disposal process known as autophagy. The study focused on frontotemporal lobar degeneration (FTLD), also called frontotemporal dementia - second only to Alzheimer's disease as the leading cause of dementia. This aggressive, typically earlier onset dementia (ages 45-65) is characterized by atrophy of the front or side regions of the brain, or both. Like Alzheimer's disease, FTLD displays an accumulation of tau, and has no specific treatment or cure.

Both in cells and in mice with elevated tau, β-arrestin-2 levels are increased. Furthermore, when β-arrestin-2 is overexpressed, tau levels increase, suggesting a maladaptive feedback cycle that exacerbates disease-causing tau. Genetically reducing β-arrestin-2 lessens tauopathy, synaptic dysfunction, and the loss of nerve cells and their connections in the brain. Oligomerized β-arrestin-2 - but not the protein's monomeric form - increases tau.

Oligomerized β-arrestin-2 increases tau by impeding the ability of cargo protein p62 to help selectively degrade excess tau in the brain. In essence, this reduces the efficiency of the autophagy process needed to clear toxic tau, so tau "clogs up" the neurons. Blocking of β-arrestin-2 oligomerization suppresses disease-causing tau in a mouse model that develops human tauopathy with signs of dementia. "We also noted that decreasing β-arrestin-2 by gene therapy had no apparent side effects, but such a reduction was enough to open the tau clearance mechanism to full throttle, erasing the tau tangles. This is something the field has been looking for - an intervention that does no harm and reverses the disease."

β-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates

Multiple G protein-coupled receptors (GPCRs) are targets in the treatment of dementia, and the arrestins are common to their signaling. β-Arrestin2 was significantly increased in brains of patients with frontotemporal lobar degeneration (FTLD-tau), a disease second to Alzheimer's as a cause of dementia. Genetic loss and overexpression experiments using genetically encoded reporters and defined mutant constructs in vitro, and in cell lines, primary neurons, and tau P301S mice crossed with β-arrestin2 knockout mice, show that β-arrestin2 stabilizes pathogenic tau and promotes tau aggregation. Cell and mouse models of FTLD showed this to be maladaptive, fueling a positive feedback cycle of enhanced neuronal tau via non-GPCR mechanisms.

Genetic ablation of β-arrestin2 markedly ablates tau pathology and rescues synaptic plasticity defects in tau P301S transgenic mice. Atomic force microscopy and cellular studies revealed that oligomerized, but not monomeric, β-arrestin2 increases tau by inhibiting self-interaction of the autophagy cargo receptor p62/SQSTM1, impeding p62 autophagy flux. Hence, reduction of oligomerized β-arrestin2 with virus encoding β-arrestin2 mutants acting as dominant-negatives markedly reduces tau-laden neurofibrillary tangles in FTLD mice in vivo. Reducing β-arrestin2 oligomeric status represents a new strategy to alleviate tau pathology in FTLD and related tauopathies.

Forthcoming Longevity Industry Conferences, March to May 2020
https://www.fightaging.org/archives/2020/02/forthcoming-longevity-industry-conferences-march-to-may-2020/

If you are interested in joining or investing in the growing longevity industry, there are now a fair few conferences taking place each year at which it is possible to meet people, get involved, and make inroads on building a network. Since this is still a young industry, it remains a very friendly, close-knit community in which many of the participants have been involved in research or patient advocacy in the aging field for quite some time. Aging research is in many ways still a small field of research in which everyone tends to know everyone else in the inner circles, and the present longevity industry is just the first steps on a long road towards become the majority of all medical development. Growth lies ahead, and now is a great time to become involved.

Master Investor, London, March 28th 2020

The Master Investor conference series is one of ways in which Jim Mellon's network acts to promote the longevity industry: that it is a wondrous opportunity to change the human condition for the better and make a return on investment while doing it. It isn't enough to start a venture like Juvenescence and invest in a score or more of biotech startups working interventions in the aging process, one must also sell the rest of the investment community and the broader biotech community on the nature of this opportunity, leading to the establishment of bigger pools of funding for later stage companies as they emerge. None of this automatically happens; every step forward requires someone to do the work of persuasion, networking, coordination. Master Investor is a part of this process, and thus a good place for people who are not already on the inside of the longevity industry to meet people who are.

Longevity Leaders World Congress, London, April 21st 2020

Longevity Leaders World Congress is one of a range of biotech conferences run by the LSX organization in the US and UK. This remains distinctive by virtue of drawing in interested factions not present in large numbers at the other conferences yet, such as the life insurance and pensions industries. This conference is a good example of the dynamism that results when putting scientists, entrepreneurs, and investors in the same room for a few days, all interested in seeing progress towards the medical control of aging. The establishment of a growing community capable of advancing promising research from the lab to the clinic requires exactly this sort of gathering.

Undoing Aging, Berlin, May 21st 2020

Undoing Aging is of course the most important of the conferences in which academia meets industry, to discuss how to move forward towards working rejuvenation therapies. Is is organized by the SENS Research Foundation and Forever Healthy Foundation, and the tone is thus very much more ambitious than is the case elsewhere. The goal is the end of aging, not just slowing it down a little. Being held in central Europe, there is a very different mix of investors and advocates than is found in the US - a different end of the international community. It was quite a large gathering in 2019, overflowing the venue, and promises to be much the same this year.

The Next Recommendation on Lowering Cholesterol May be to Start Earlier
https://www.fightaging.org/archives/2020/02/the-next-recommendation-on-lowering-cholesterol-may-be-to-start-earlier/

The clinical work on lowering blood cholesterol that has taken place over recent years has demonstrated that if there is a lower limit beyond which low cholesterol levels become harmful, then that limit is very low indeed. Certainly below 10% of the normal human level. There are a number of uncommon mutations that produce individuals with up to half of the normal amount of blood cholesterol, people who exhibit significantly reduced risk of cardiovascular disease as a result of this difference from the norm. This is all quite interesting: why did we evolve to have the blood cholesterol that we do, if we need only a small fraction of it?

The reason why lowering blood cholesterol lowers the risk of cardiovascular disease is that atherosclerosis is caused by the dysfunction of macrophage cells in an environment rich in oxidized lipids. Atherosclerosis is age-related because oxidative stress, and thus amounts of oxidized lipids, rise with age. A lesser degree of all blood lipids means a lesser degree of oxidized lipids in the blood stream, entering blood vessel walls to aggravate and kill macrophages. This in turn results in a slowed progression of atherosclerosis. Unfortunately it really doesn't help all that much to remove existing fatty lesions produced by the processe of atherosclerosis, and it doesn't do more than slow the progression of the condition. Lowered blood cholesterol only raises the odds of avoiding the consequences of atherosclerosis, meaning stroke and heart attack when a weakened artery or large lesion ruptures, because a few years of delay are enough to allow some other consequence of aging to kill the patient first.

The advent of new and very efficient tools for lowering blood cholesterol, such as PCSK9 inhibitors, present the medical community with something of a quandary. The technology for lowering blood cholesterol has reached its natural limit. One really can't go much lower, and yet it isn't enough. It still only slows atherosclerosis, and cannot meaningfully reverse the corroded state of arteries and their fatty lesions. The research community is investigating other avenues beyond the lowering of blood cholesterol typified by statins and PCKS9 inhibitors, but in the meanwhile what should the medical community focus on? The next logical step appears to be starting treatment earlier, with an even greater focus on prevention and target metrics in healthier individuals, rather than on treating the manifestations of clinical disease.

Cholesterol lowering: to live longer, start younger?

Cardiovascular disease, particularly coronary heart disease and stroke, is a major cause of death globally. Since older age is an independent predictor of increased cardiovascular risk, the global burden of cardiovascular disease increases as populations age. Lowering low density lipoprotein (LDL) cholesterol has become an important strategy for reducing the risk of atherosclerotic cardiovascular disease (ASCVD). Recent evidence has shown that the benefits of this approach extend to patients over 75 years. Though LDL lowering is beneficial across middle to older age, two questions still arise: how early in the disease process should LDL lowering be initiated; and, are the currently recommended LDL targets ambitious enough?

It has been estimated 10-year ASCVD risk for an untreated 50 year old Caucasian male with a systolic/diastolic blood pressure of 140/90 mmHg and LDL cholesterol level of 3.4 mmol/L, is 5.3%. A 60 year old male with the same risk factors has a 10-year ASCVD risk of 11.8%, which increases to 22.6% at age 70. Older age appears to be a marker of the cumulative exposure to LDL cholesterol, along with other traditional cardiovascular risk factors. Delaying treatment until the cardiovascular risk is above a certain threshold will lead to additional years of exposure to this cumulative burden. Initiating statin therapy at say, the age of 50 rather than 60 years old, will prevent an additional 10 mmol/L/year LDL cholesterol exposure, or in other words, provide an additional 10 mmol/L/year of LDL cholesterol reduction.

More complex and older atheromatous plaques only partially regress with LDL lowering therapies, which means delayed treatment will leave older individuals at considerable residual risk of ASCVD. It makes sense to advocate for a greater focus on the lifetime exposure to elevated LDL and the benefit of LDL cholesterol lowering over longer periods of time. A primordial prevention strategy would target the development of atherosclerosis rather than simply preventing its complications. This hypothesis is supported by cohort studies which showed exposure to elevated blood pressure and cholesterol levels during young adulthood is associated with a greater risk of ASCVD later in life, independent of later adult exposures.

Evidence for Better Blood Supply to the Hippocampus to Slow Cognitive Decline
https://www.fightaging.org/archives/2020/02/evidence-for-better-blood-supply-to-the-hippocampus-to-slow-cognitive-decline/

As outlined in the research reported here, the variable physiology of the hippocampus allows for an interesting natural experiment to determine the degree to which blood supply is important in the aging of the brain. It is known that capillary density declines with age throughout the body, and this affects the supply of oxygen and nutrients to tissues. The brain is a particularly energy hungry organ, and reduced supply produces consequences. It isn't just capillary density that is important in aging, however, but also the general decline in physical fitness and ability of the heart to pump blood uphill to the brain. This lost performance becomes particularly profound in heart failure patients, but is no doubt producing detrimental consequences even when present to a lesser degree.

The hippocampus exists twice: once in each brain hemisphere. It is considered the control center of memory. Damage to the hippocampus, such as it occurs in Alzheimer's and other brain diseases, is known to impair memory. But what role does blood supply in particular play? To answer this questions, researchers used high-resolution magnetic resonance imaging (MRI) to examine the blood supply to the hippocampus of 47 women and men aged 45 to 89 years. The study participants also underwent a neuropsychological test battery, which assessed, in particular, memory performance, speech comprehension, and the ability to concentrate.

"It has been known for some time that the hippocampus is supplied by either one or two arteries. It also happens that only one of the two hippocampi, which occur in every brain, is supplied by two vessels. This varies between individuals. The reasons are unknown. Maybe there is a genetic predisposition. However, it is also possible that the individual structure of the blood supply develops due to life circumstances. Then the personal lifestyle would influence the blood supply to the hippocampus. In the cognition tests, those study participants in whom at least one hippocampus was doubly supplied generally scored better. The fact that the blood supply is fundamentally important for the brain has been extensively documented. We were therefore particularly focused on the hippocampus and the situation of a disease of the brain vessels. Little is actually known about this."

Of the study subjects, 27 did not manifest signs of brain diseases. The remaining twenty participants showed pathological alterations in brain blood vessels, which were associated with microbleeding. "In these individuals, sporadic cerebral small vessel disease had been diagnosed prior to our investigations. These individuals exhibited a broad spectrum of neurological anomalies, including mild cognitive impairment. The healthy subjects generally scored better on cognitive tests than the study participants with small vessel disease. Among the participants with disease, those with at least one hippocampus supplied by two arteries reached better scores in cognition. They particularly benefited from the double supply. This may be due to a better supply not only of blood but also of oxygen."

Longevity-Related Genes are Under Greater Evolutionary Constraint in Large and Long-Lived Mammals
https://www.fightaging.org/archives/2020/02/longevity-related-genes-are-under-greater-evolutionary-constraint-in-large-and-long-lived-mammals/

Both the evolution of aging and the comparative biology of aging between species with widely divergent lifespans are fascinating topics, though likely of limited relevance to the near future of rejuvenation therapies. Those treatments will be based on repairing cell and tissue damage as it occurs, using the understanding of the human metabolism that exists now, rather than on attempts to rebuild that human metabolism to age more slowly, a goal that will require a great deal more knowledge. The more distant future will certainly include human populations engineered from birth to exhibit enhanced longevity, however, and a greater understanding of the intersection between metabolism, genetics, and species longevity will be an essential part of that endeavor.

Although lifespan in mammals varies over 100-fold, the precise evolutionary mechanisms underlying variation in longevity remain unknown. Species-specific genetic changes have been observed in long-lived species including the naked mole-rat, bats, and the bowhead whale, but these adaptations do not generalize to other mammals. We present a novel method to identify associations between rates of protein evolution and continuous phenotypes across the entire mammalian phylogeny. Unlike previous analyses that focused on individual species, we treat absolute and relative longevity as quantitative traits and demonstrate that these lifespan traits affect the evolutionary constraint on hundreds of genes.

Specifically, we find that genes related to cell cycle, DNA repair, cell death, the IGF1 pathway, and immunity are under increased evolutionary constraint in large and long-lived mammals. For mammals exceptionally long-lived for their body size, we find increased constraint in inflammation, DNA repair, and NFKB-related pathways. Strikingly, these pathways have considerable overlap with those that have been previously reported to have potentially adaptive changes in single-species studies, and thus would be expected to show decreased constraint in our analysis. This unexpected finding of increased constraint in many longevity-associated pathways underscores the power of our quantitative approach to detect patterns that generalize across the mammalian phylogeny.

Nicotinamide Mononucleotide Supplementation Improves Neurovascular Function in Aged Mice
https://www.fightaging.org/archives/2020/02/nicotinamide-mononucleotide-supplementation-improves-neurovascular-function-in-aged-mice/

Supplementation of nicotinamide mononucleotide (NMN) is one of the approaches demonstrated to restore levels of NAD+ in the mitochondria of aged mice. NAD+ is lost with age, with the proximate causes involving declining synthesis and recycling of the molecule, but as yet there is little understanding as to how this connects to the deeper causes of degenerative aging. NAD+ is an important piece of molecular machinery in mitochondrial function, and its loss appears to be one of the factors causing a failure of mitophagy, the quality control mechanism responsible for removing worn and dysfunctional mitochondria.

Mitochondria are responsible for packaging the chemical energy store molecules, adenosine triphosphate (ATP), used to power cellular operations, and when they falter, the cell suffers. Tissue function is disrupted. This is particularly important in energy-hungry tissues such as muscles and the brain, but has an impact throughout the body. Restoring NAD+ levels appears to help; clinical trials to measure effect size in humans have not yet taken place for NMN, but initial results for nicotinamide riboside (NR) supplementation suggest that the beneficial effects on cardiovascular function in older people are in the same ballpark as those of exercise.

Aging-induced structural and functional alterations of the neurovascular unit lead to impairment of neurovascular coupling responses, dysregulation of cerebral blood flow, and increased neuroinflammation, all of which contribute importantly to the pathogenesis of age-related vascular cognitive impairment (VCI). There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in age-related neurovascular and cerebromicrovascular dysfunction. Our recent studies demonstrate that restoring cellular NAD+ levels in aged mice rescues neurovascular function, increases cerebral blood flow, and improves performance on cognitive tasks.

To determine the effects of restoring cellular NAD+ levels on neurovascular gene expression profiles, 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. Transcriptome analysis of preparations enriched for cells of the neurovascular unit was performed by RNA-seq. Neurovascular gene expression signatures in NMN-treated aged mice were compared with those in untreated young and aged control mice. We identified 590 genes differentially expressed in the aged neurovascular unit, 204 of which are restored toward youthful expression levels by NMN treatment. The transcriptional footprint of NMN treatment indicates that increased NAD+ levels promote SIRT1 activation in the neurovascular unit. Pathway analysis predicts that neurovascular protective effects of NMN are mediated by the induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic pathways.

In conclusion, the recently demonstrated protective effects of NMN treatment on neurovascular function can be attributed to multifaceted sirtuin-mediated anti-aging changes in the neurovascular transcriptome. Our present findings taken together with the results of recent studies using mitochondria-targeted interventions suggest that mitochondrial rejuvenation is a critical mechanism to restore neurovascular health and improve cerebral blood flow in aging.

Wnt/β-Catenin Signaling as a Point of Intervention to Spur Greater Neural Regeneration
https://www.fightaging.org/archives/2020/02/wnt-%ce%b2-catenin-signaling-as-a-point-of-intervention-to-spur-greater-neural-regeneration/

Wnt signaling is a complicated but well studied portion of the regulatory systems governing regeneration. Numerous groups are engaged in the commercial development of regenerative therapies that are based on manipulation of this part of mammalian biochemistry. Of the more prominent ventures, Samumed has reached phase 3 trials with treatments of this type. This open access paper walks through the evidence for Wnt signaling to be a useful point of intervention for researchers aiming to increase neurogenesis and regenerative capacity in the aging brain. This will be developed as a means of treating neurodegenerative conditions, but success would lead to treatments beneficial for all older individuals.

A common hallmark of age-dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain.

Specifically, we highlight WβC-signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct-periventricular region (Aq-PVR) Wnt-sensitive niche, which is in proximity to the substantia nigra pars compacta and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β-catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial-derived factors regulating WβC-dependent transcription of key genes orchestrating NSC proliferation, survival, migration, and differentiation.

Aging, inflammation, and oxidative stress synergize with neurotoxin exposure in "turning off" the WβC neurogenic switch via down-regulation of the nuclear factor erythroid-2-related factor 2/Wnt-regulated signalosome, a key player in the maintenance of antioxidant self-defense mechanisms and NSC homeostasis. Harnessing WβC-signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.

Individual Risk of Dementia is Falling, but an Aging Population Means that a Greater Incidence of Dementia Lies Ahead
https://www.fightaging.org/archives/2020/02/individual-risk-of-dementia-is-falling-but-an-aging-population-means-that-a-greater-incidence-of-dementia-lies-ahead/

The risk of suffering many of the most common age-related conditions is trending downwards over time, thanks to improvements in medical technology and public health, but the ever increasing size of the older segments of the population means that the incidence of those age-related conditions will nonetheless grow over time. Growth in the number of older people outweighs the reduced risk for any given individual, or at least this will be the case without much faster progress towards effective therapies than has taken place over the past few decades.

This is of great concern for those who focus more on socioeconomics than on health. The economic stress placed on centralized, government-run medical systems by this trend is perhaps one of the stronger motivations driving large-scale investment into research and development. Evidently still not strong enough, given that intervening in the aging process remains a tiny field in comparison to the rest of medicine, but we can hope that this will change given concrete results from the first rejuvenation therapies.

Across men and women and across most age groups, there has been a reduction in the prevalence of dementia over the past ten years when compared to 2008 estimates. The number of people living with dementia in the European Union (EU27) is estimated to be 7.8 million and in European countries represented by AE members, 9.7 million. Compared to its earlier estimates, this constitutes a significant reduction from 8.7 million for the EU27 and from 10.9 million for the broader European region. Women continue to be disproportionately affected by dementia with 6.6 million women and 3.1 million men living with dementia in Europe. The numbers of people with dementia in Europe will almost double by 2050 increasing to 14.3 million in the European Union and 18.8 million in the wider European region.

"It is promising to see that healthier lifestyles, better education, and improved control of cardiovascular risk factors seem to have contributed to a reduction of the prevalence of dementia. However, our report also demonstrates that the number of people living with the condition is set to increase substantially in the years ahead, which will only place greater pressure on care and support services unless better ways of treating and preventing dementia are identified. If people with dementia, their families and carers are to receive the high-quality and person-centred care they need, governments must ensure their health and care systems are ready to meet this demand and greater investments in research into the treatment and prevention of dementia are needed."

A Survey of the Evidence for Hormesis to Slow Aging in Nematode Worms
https://www.fightaging.org/archives/2020/02/a-survey-of-the-evidence-for-hormesis-to-slow-aging-in-nematode-worms/

Hormesis is the name given to the process by which lesser degrees of cellular stress and damage can result in long-term benefits to health. Cells react to molecular damage with greater repair and maintenance activities, and when that damage occurs transiently and minimally, the additional efforts to maintain function outweigh any detrimental effects. This can slow aging and extend life in a range of short-lived species. Hormesis depends on complex biochemistry, however, and similar approaches to triggering it can easily fall on the wrong side of the line, causing too much damage, or not enough of a maintenance response. Researchers here review the literature in search of a consensus in the matter of hormesis and aging in the widely studied nematode species C. elegans.

The concept of hormesis arouses great interest, because it is a near-universal and reproducible phenomenon. As a beneficial compensatory response triggered by mild stress, hormetic individuals generally exhibit better performance than the untreated controls, and the potential anti-aging effect of hormesis has attracted more attention. It seems promising to apply hormesis in aging intervention, which is evidenced by multiple studies, like the beneficial effects of moderate exercise-induced hormesis on body function and aging-related diseases. However, there are still considerable debates regarding the origin and mechanisms of aging and hormesis, such as the conflicting evidence related to the role of reactive oxygen species (ROS) in aging.

At present, most researchers take a wait-and-see attitude to hormetic treatment for human health, due to the contradictory evidence. Thus it is meaningful to conduct a systematic assessment on the existed evidences in the absence of large-scale empirical research on the correlation between hormesis and aging/anti-aging. Meta-analysis is a powerful tool to synthesize multiple or even conflicting evidence to get a clear and reliable final-evidence, achieving the purpose of quantitative review. in order to thoroughly assess the effect of hormesis on aging, in this work, 26 papers documenting the changes of aging-related indicators induced by hormesis in Caenorhabditis elegans (a significant model organism in aging research due to its unique biological features like short life cycle, strong reproductive ability and clear genetic background) were meta-analyzed.

Meta-analytic results indicated that hormesis could significantly extend the mean lifespan of C. elegans by 16.7% and 25.1% under normal and stress culture conditions, respectively. The healthspan assays showed that hormesis remarkably enhanced the bending frequency and pumping rate of worms by 28.9% and 7.0%, respectively, while effectively reduced the lipofuscin level by 15.9%. The obviously increased expression of dauer formation protein-16 (1.66-fold) and its transcriptional targets, including superoxide dismutase-3 (2.46-fold), catalase-1 (2.32-fold) and small heat shock protein-16.2 (2.88-fold), was one of the molecular mechanisms underlying these positive effects of hormesis. This meta-analysis provided strong evidence for the anti-aging role of hormesis, highlighting its lifespan-prolonging, healthspan-enhancing, and resistance-increasing effects on C. elegans. Given that dauer formation protein-16 is highly conserved, hormesis offers the theoretical possibility of delaying intrinsic aging through exogenous intervention among humans.

Calorie Restriction Suppresses the Senescence-Associated Secretory Phenotype
https://www.fightaging.org/archives/2020/02/calorie-restriction-suppresses-the-senescence-associated-secretory-phenotype/

The accumulation of senescent cells is one of the causes of aging, important in the chronic inflammation of aging, and disruptive of tissue structure and function. The practice of calorie restriction slows the progression of aging, much more so in short-lived animals than in long-lived species, and thus we should expect it to have some effect on cellular senescence. Calorie restriction is nowhere near as effective as senolytic drugs at reducing the populations of senescent cells present in older individuals, that much is evident from studies carried out in recent years. As noted here, however, it does appear to somewhat reduce the inflammatory signaling generated by senescent cells.

Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view.

Senescent cells produce a proinflammatory senescence-associated (SA) secretome, which is referred to as the SASP. Macrophages are recruited by chemotactic factors in the secretome to clear senescent cells. However, senescent macrophages secrete proinflammatory cytokines and exhibit impaired phagocytosis and chemotaxis, and a downregulated rate of cellular proliferation. It has been proposed that deficiency in the ability of aged macrophages to clear senescent cells leads to increased inflammatory response and results in chronic inflammation as SASP plays a role in the initiation of tissue inflammation. Based on previous observations and evidence of the aging process at molecular and cellular levels, we coined the term senoinflammation to provide an expanded, broader view of age-related chronic inflammation and metabolic dysfunction.

Based on studies on senoinflammation and CR, we recognized that the senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. Oxidative stress leads to improper gene regulation and genomic DNA damage during aging. Such improper gene regulation in aged senescent cells allows them to fall into a proinflammatory state, consequently changing systemic chemokine or cytokine activities. The proinflammatory SASP environment further exerts stress on the intracellular organelles, tissues, and systems, which affects the development and occurrence of metabolic disorders.

It appears that a repetitive vicious cycle occurs between SASP and metabolic dysregulation as proposed in the concept of senoinflammation, and this interactive network forms the basis of the aging process and age-related diseases. However, the secretion of proinflammatory mediators, collectively termed as SASP, in response to internal and external stress leads to the chronic inflammatory condition termed as senoinflammation. Based on CR experiments and observations, cytokine, chemokine, and metabolic pathways are significantly regulated by CR and CR mimetics in the aging process.

The Skin Microbiome Better Correlates with Chronological Age than the Gut Microbiome
https://www.fightaging.org/archives/2020/02/the-skin-microbiome-better-correlates-with-chronological-age-than-the-gut-microbiome/

Researchers here report on their assessment of age-related changes in human skin, oral, and gut microbiomes. They find that the skin microbiome is a better marker of chronological age, which might also be taken as indicating that it is a worse tool for measuring biological age. That adherence to chronological age is, after all, observed despite differences in the pace of aging that exist between individuals. A good biomarker of aging is one that reflects the burden of damage and consequent mortality, and therefore will measure a higher age in someone more burdened, rather than only correlating with the chronological progression of time.

Human gut microbiomes are known to change with age, yet the relative value of human microbiomes across the body as predictors of age, and prediction robustness across populations is unknown. In this study, we tested the ability of the oral, gut, and skin (hand and forehead) microbiomes to predict age in adults using data combined from multiple publicly available studies, evaluating the models in each cohort individually.

Intriguingly, the skin microbiome provides the best prediction of age (mean ± standard deviation, 3.8 ± 0.45 years, versus 4.5 ± 0.14 years for the oral microbiome and 11.5 ± 0.12 years for the gut microbiome). This also agrees with forensic studies showing that the skin microbiome predicts postmortem interval better than microbiomes from other body sites. Age prediction models constructed from the hand microbiome generalized to the forehead and vice versa, across cohorts, and results from the gut microbiome generalized across multiple cohorts (United States, United Kingdom, and China).

Interestingly, microbial taxa enriched in young individuals (18 to 30 years) tend to be more abundant and more prevalent than taxa enriched in elderly individuals (older than 60 yrs), suggesting a model in which physiological aging occurs concomitantly with the loss of key taxa over a lifetime, enabling potential microbiome-targeted therapeutic strategies to prevent aging.

USP7 Inhibition Clears Up to Half of Irradiation Induced Senescent Cells From Mouse Tissues
https://www.fightaging.org/archives/2020/02/usp7-inhibition-clears-up-to-half-of-irradiation-induced-senescent-cells-from-mouse-tissues/

Researchers here report on the discovery of a novel mechanism by which senescent cells can be selectively destroyed. Short-term senolytic treatments to date seem to cluster tightly into two categories: (a) largely ineffective, and (b) able to destroy between 25-50% of senescent cells in tissues. Few have achieved greater clearance so far, and few lie in between these two outcomes. In the present environment, of ample seed stage funding and enthusiasm for targeting senescent cells as a treatment for aging, it seems likely that someone will pick up this new approach for clinical development in the near future.

Although cellular senescence is an important tumor-suppressive mechanism, emerging evidence demonstrates that the accumulation of senescent cells (SnCs) with age and after genotoxic or cytotoxic cancer therapy can lead to various age-related diseases and pathological conditions. The selective removal of SnCs depends on identifying their Achilles' heels, which can be targeted to selectively kill SnCs. Several senolytic targets have been identified, resulting in the discovery of a series of senolytic agents that can selectively kill SnCs in culture and effectively remove SnCs in mice. Unfortunately, some of these agents exhibit toxicities that may prevent their safe use in the clinic, particularly for systemic therapy. For example, navitoclax, a selective BCL-2/BCL-XL dual inhibitor, is a potent senolytic agent but can induce thrombocytopenia, an on-target and dose-limiting toxicity that has prevented its FDA-approval. Therefore, further studies are needed to identify new senolytic targets that can be exploited for the development of safer senolytic agents.

Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.

An Epigenetic Clock for Skeletal Muscle
https://www.fightaging.org/archives/2020/02/an-epigenetic-clock-for-skeletal-muscle/

Epigenetic clocks are multiplying year by year. Each is a weighted algorithmic combination of the status of various methylation sites on the genome, built by analyzing the epigenome of many different people at different ages in order to arrive at correlations with chronological age, or, more usefully, with metrics such as mortality risk that reflect biological age, the burden of molecular damage and its consequences. This process of building a new clocks is the easier half of the challenge, however. The hard part, that still lies ahead, is to determine what exactly it is that these clocks measure. What do these characteristic epigenetic changes of age actually reflect, in terms of the underlying processes of aging? That is a challenging question to answer well, but answers are needed if epigenetic clocks are to be used to speed up development of rejuvenation therapies by measuring biological age before and after a short treatment.

Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets.

In the current study, we aimed to address the poor performance of the pan-tissue clock in muscle by developing a muscle-specific epigenetic clock. We hypothesise that by using a large number of human skeletal muscle DNA methylation profiles, we can develop a muscle-specific epigenetic clock that outperforms the pan-tissue clock and that can estimate chronological age with high accuracy. We utilised DNA methylation data to estimate epigenetic age in a total of 682 male and female skeletal muscle samples aged 18-89. We also conducted an epigenome-wide association study (EWAS) to discover genes whose methylation change with age in skeletal muscle.

The newly developed clock uses 200 cytosine-phosphate-guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine-phosphate-guanine dinucleotides of the pan-tissue clock. This new clock significantly outperforms the previous pan-tissue clock and can calculate the epigenetic age in skeletal muscle with a mean accuracy of 4.9 ± 4.5 years across 682 samples. This muscle clock will be of interest and potential use to researchers, clinicians, and forensic scientists working in the fields of skeletal muscle, chronic diseases, and ageing. In the future, we intend to evaluate how environmental factors, such as exercise and diet, could influence ageing via this newly developed clock.