Fight Aging! Newsletter, February 12th 2024

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit:

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An Interview with Karl Pfleger

Karl Pfleger is one of the more prolific angel investors in the longevity industry. Naturally he is an investor in Repair Biotechnologies, the company that I co-founded with Bill Cherman and which is currently focused on a gene therapy approach to reversal of atherosclerosis. In addition to his investment and conference-going activities, Pfleger runs the very useful Aging Biotech Info resource, which has expanded from the starting point of a list of companies in the longevity industry to its present state of listing of a great many more items: conferences, books, blogs, interventions, diagnostics, and so forth. In the podcast interview linked below, topics include epigenetic clocks and the need for improvement in measurement of biological age, current interventions, and the state of the field as a whole.

Unlocking the Secrets of Lifespan Extension With Karl Pfleger

I worked at Google for about a decade doing practical, big data, machine learning stuff and then I decided to refocus my attention on things that would most help the world, most help the most people in the world. And cursory analysis suggested that besides the poorest of the poor, you know, living in sub-Saharan Africa and places like that on less than 2 a day, the the highest leverage other thing in the world was to fight against the aging process, because aging is what kills the vast majority of people, 70% globally, 92 and a half percent plus in Western developed countries. That's really a science and technology play more than a lobbying political play. So I decided and also I lived in the San Francisco Bay Area, which was kind of ground zero for that science and the biotech and the entrepreneurship and so I just basically whole hog switched fields and have just been ramping up the bio knowledge ever since. I started with philanthropy then got into investing and I'm also doing a whole bunch of other things involved in community building and information dissemination.

I started in the field in the mid 2010s, there was it was much smaller field. It's grown considerably, which is great. It's still a very small corner of the overall biotech world. But but it's growing because there's an inevitable logic of treating these biological causes that underlie so many different bad conditions. But when I got into the field, it was small, but there was still quite a lot written about it. There were books and there were blogs, and it was a lot of blobs of text, and there were some companies already in the space, and I decided to get into investing in the 2016-ish and started investing in biotech companies in 2017. One of the things I did once I started doing that was every time I went to a conference or an event where any company was mentioned, I wrote it down on the list and quickly my list of companies was 100 to 120 companies.

You know, I hadn't investigated each one, so I wasn't sure whether I counted each one as, you know, really being an aging and longevity related company or not. But so it was all new. So I didn't have an exact count 100, 120. And I kept reading these stories of people talking who were giving an overview of the whole aging or longevity field, talking about how there's 30 companies where there's 40 companies or usually there's 25 companies, something like that. And I was like, wow, these people don't know about a lot of the companies. And I would talk to the professors who work in the field. So just north of me here in San Francisco, there's a place called the Buck Institute for Research on Aging. It's the largest independent. It's essentially a sort of Ivy League Stanford or MIT level biology department, sitting all by itself without the rest of the university around it. Every single one of the 20 pitches are all focused specifically on the biology of aging. And that was the most ground zero at academia for aging stuff. And they didn't even realize how many companies there were at the moment.

So I decided that instead of keeping my list of companies as sort of some kind of internal secret to make my investing better, I would just open source it, essentially. And so I put it together and put it on this website. I called it Aging Biotech Info, and I made it just pro-bono, open, free for everybody. And it's worked pretty well. The goals, the use cases I envisioned when I started it were I wanted the post-docs and Ph.D. students and even professors to realize they had an exit ramp from academia if they wanted to do something else. As they could start a company. And I wanted the investors, the tech people in Silicon Valley, the VC groups, to realize that they should be putting more than a few percent in this field, that there was a lot more going on than they thought, and they should be ramping up to five, ten, 15% of their mostly tech portfolios, which they have done. I'll never know how much this website contributed to any of that, but that has certainly helped.

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Advocating for Epigenetic Reprogramming as a Potential Rejuvenation Therapy

Partial epigenetic reprogramming emerges from the intersection of understanding how cells behave in cancerous tissue and during embryonic development. In the developing embryo there is a point at which adult germline cells convert themselves into embryonic stem cells, discarding forms of damage and dysfunction characteristic of adult cells and restoring a youthful pattern of the epigenetic markers attached to the genome that control its shape in the cell nucleus and thus gene expression. Some of the genes involved are known to also operate in cancers, in which replication and reprogramming runs wild, but which use many of the same mechanisms as the embyro.

Given exploratory work to date, it seems possible to pick apart the regulatory systems controlling (a) change of cell type via dedifferentiation, and (b) restoration of youthful epigenetic markers. That second item is highly desirable. If researchers could reset the epigenetics of aged cells, they would become more youthful. Given enough cells reset in this way, tissues and organs would become more youthful in function. Some forms of age-related molecular damage can't be repaired in this way, such as persistent metabolic waste or nuclear DNA damage, but evidence from studies of epigenetic reprogramming in aged mice suggest that there are sizable gains that can be achieved via this approach, provided that cancerous transformation of cells can be kept at bay.

One might argue that given the existence of Altos Labs (3 billion), Retro Biosciences (180M), and at least another 100M in investment in various epigenetic reprogramming ventures, there is little need to advocate for epigenetic reprogramming as a road to rejuvenation. That road will be traveled in the years ahead regardless of the thoughts that any of the rest of us might have on the matter. The funding is there, a great many researchers are working on the challenges involved, the big questions will be answered, initial therapies will be cautiously deployed in small parts of the body such as the eye, and whether or not expression of reprogramming factors throughout much of the body, via small molecules or gene therapy, is viable as a basis for rejuvenation therapies will be much more clear a few years from now.

Epigenetic Reprogramming as a Key to Reverse Ageing and Increase Longevity

The pursuit for the fountain of youth has long been a fascination amongst scientists and humanity. Ageing is broadly characterized by a cellular decline with increased susceptibility to age-related diseases, being intimately associated with epigenetic modifications. Recently, reprogramming-induced rejuvenation strategies have begun to greatly alter longevity research not only to tackle age-related defects but also to possibly reverse the cellular ageing process. Hence, in this review, we highlight the major epigenetic changes during ageing and the state-of-art of the current emerging epigenetic reprogramming strategies that leverage transcription factors. Notably, partial reprogramming enables the resetting of the ageing clock without erasing cellular identity. Promising chemical-based rejuvenation strategies harnessing small molecules, including DNA methyltransferase and histone deacetylase inhibitors are also discussed.

Moreover, in parallel to longevity interventions, the foundations of epigenetic clocks for accurate ageing assessment and evaluation of reprogramming approaches are briefly presented. Going further, with such scientific breakthroughs, we are witnessing a rise in the longevity biotech industry aiming to extend the health span and ideally achieve human rejuvenation one day. In this context, we overview the main scenarios proposed for the future of the socio-economic and ethical challenges associated with such an emerging field. Ultimately, this review aims to inspire future research on interventions that promote healthy ageing for all.

Numerous intriguing questions remain unanswered. (1) What are the specific molecular mechanisms behind epigenetic dysfunction that contribute to the ageing process and how do these correlate with the different hallmarks of ageing? (2) To what extent can the current in vitro aged animal models be translatable to the human ageing process in its entirety? Will emerging humanized in vitro 3D models such as organoids accelerate longevity research? (3) Realistically, how far are we from reprogramming-induced epigenetic rejuvenation interventions in human clinical trials? Will these rejuvenate organs and even the entire human body? Could these prevent and eradicate ageing-related diseases safely? (4) In the future, could epigenetic reprogramming be a routine medical procedure to reverse the biological age and extend human healthspan? Would these interventions be effective in both young and elderly individuals? How far could we go? (5) How reliable could epigenetic clocks be in research and clinical settings for developing and prescribing novel healthspan-prolonging interventions? (6) Will legislative and policy frameworks be able to keep pace with the scientific breakthroughs in the young science of anti-ageing treatments? How will bioethicists, society, and medical professionals perceive these emerging findings?

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Intermittent Fasting Produces Indeterminate Effects on BDNF Levels in Humans

The circulating level of brain-derived neurotrophic factor (BDNF) is a widely-researched target for intervention. Increased BDNF seems to be wholly beneficial, particularly in its effects on neurogenesis, the production of new neurons and their integration into existing neural networks in the brain. Neurogenesis declines over the course of adult life, and is necessary to the function of memory and maintenance of brain tissue. Circulating BDNF, where levels also decline with age, might be the most convenient of the available mechanisms with which to affect neurogenesis. It can be increased by exercise, butyrate supplementation, and by interventions targeting the gut microbiome. Separately, BDNF also appears to influence muscle aging, reduce inflammatory microglial activation, increase dopamine levels, and slow metabolic aging, among other effects.

If exercise can increase circulating BDNF, what about intermittent fasting and calorie restriction? There is some evidence for this to work. In today's open access paper, researchers review the literature and find the results to be very varied, however. This suggests that either specific protocols are needed, or other factors interact meaningfully with reduced calorie intake, or both. It remains the case that both intermittent fasting and calorie restriction have been demonstrated to be great for long-term health, but it is always interesting to find evidence for a mechanism that may not be improved by these practices.

Effect of Calorie Restriction and Intermittent Fasting Regimens on Brain-Derived Neurotrophic Factor Levels and Cognitive Function in Humans: A Systematic Review

The potential positive interaction between intermittent fasting (IF) and brain-derived neurotrophic factor (BDNF) on cognitive function has been widely discussed. This systematic review tried to assess the efficacy of interventions with different IF regimens on BDNF levels and their association with cognitive functions in humans. Interventions with different forms of IF such as caloric restriction (CR), alternate-day fasting (ADF), time-restricted eating (TRE), and the Ramadan model of intermittent fasting (RIF) were targeted.

A systematic review was conducted for experimental and observational studies on healthy people and patients with diseases published from January 2000 to December 2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statements (PRISMA) for writing this review. Sixteen research works conducted on healthy people and patients with metabolic disorders met the inclusion criteria for this systematic review. Five studies showed a significant increase in BDNF after the intervention, while five studies reported a significant decrease in BDNF levels, and the other six studies showed no significant changes in BDNF levels due to IF regimens. Moreover, five studies examined the RIF protocol, of which, three studies showed a significant reduction, while two showed a significant increase in BDNF levels, along with an improvement in cognitive function after RIF.

The current findings suggest that IF has varying effects on BDNF levels and cognitive functions in healthy, overweight/obese individuals and patients with metabolic conditions. However, few human studies have shown that IF increases BDNF levels, with controversial results. In humans, IF has yet to be fully investigated in terms of its long-term effect on BDNF and cognitive functions. Large-scale, well-controlled studies with high-quality data are warranted to elucidate the impact of the IF regimens on BDNF levels and cognitive functions.

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The Death of Death, in English

The authors of the Death of Death are regulars on the conference circuit for aging research, the longevity industry, and patient advocacy for the treatment of aging as a medical condition. The book was originally in Spanish, and has finally been translated into English. It is a popular science overview of progress towards technologies that will first slow aging, then enable the control of aging, and eventually, at some point, produce large gains in healthy human life span, postponing death by aging essentially indefinitely. The book and its authors also unapologetically and straightforwardly stand in opposition to the horrors of having to decline, become sick, and die, when one would rather not. I think that we need a lot more of that sort of sentiment in the world. Less acceptance, and more raging against the dying of the light, is the path that leads to the medical technologies of rejuvenation.

The Death of Death

It is commonly thought that death is the natural consequence of life. In time, everything decays. Sooner or later, the old must make way for the new. In that case, won't death always be with us?

Actually, biology provides many indications that there is no necessity for living creatures to age and die. The more that we study biology, the more we can appreciate that life has an innate potential to keep on living. That's what we learn from various unicellular organisms, and also from the sad example of cancer cells. It is also what we learn from organisms that have negligible senescence: although these animals become chronologically older, they don't become biologically older, meaning that their likelihood of dying in the next twelve months remains constant from maturity onward. In other words, nature already possesses intrinsic mechanisms for rejuvenation, damage repair, and indefinite life spans. It's the task of rejuveneers - the engineers of methods of rejuvenation - to understand, improve, and augment these mechanisms, so that humans, likewise, can experience indefinite lifespans.

Different organisms have evolved to have different lifespans. Indeed, some creatures have evolved to have negligible senescence. But aren't these lifespans fixed?

On the contrary, over recent decades, a great deal of evidence has emerged about the plastic nature of lifespan. Numerous experiments have increased the typical lifespan - and typical healthspan - of creatures such as worms, fruit flies, mice, rats, fish, and more. Among other things, we now know about large numbers of genes that control parts of the aging process, about the role of the enzyme telomerase to allow cells to keep on dividing, about a range of "pillars" of aging, about the problems caused by the accumulation of different types of damage within and between cells, and, crucially, about interventions that have the potential to comprehensively address each of these types of damage - by removing, renewing, repairing, or reprogramming aspects of our biological makeup.

For more than a hundred years, scientists have been talking about extending human lifespan. So far, progress is slow. Since the year 1997, no one has reached an age higher than 119 years. Transferring potential treatments from mice to humans frequently hits problems. Isn't a significant extension of human lifespans something for the far future, rather than an imminent possibility?

We need to be aware of the common pathway for major technological breakthroughs. The hopes of visionaries often proceed slowly and disappointingly before reaching tipping points and then leaping forward. Prior to the tipping points, a general scepticism often prevailed, before being forgotten. Examples can be found in the fields of transport, communications, energy, and computation. The solution of aging will move along the same trajectory from "impossible" to "indispensable". In practical terms, what will accelerate progress is the parallel emergence of what will likely become the world's largest industry - the anti-aging industry - and the world's largest activist community - the anti-aging community. Until recently, many scientists were shy to speak of their ideas for solving aging, but they are increasingly finding their voice. A combination of science, business, finance, activism, and governments will drive the realisation of a new paradigm: that aging can, and should, be treated and cured.

Even though these new treatments may arrive in a few decades, that will be too late for many people, who may succumb to disease beforehand. What advice is available for them?

The best advice - "Plan A" - is to take steps to remain in good health long enough that it will be possible to take advantage of rejuvenation treatments when they become available. In other words, remain alive long enough to be able to live forever. However, there's a "Plan B" option that people should consider as well: low temperature cryopreservation at the time that they are declared legally dead. Arguments against cryonics mirror those against the reversal of aging: supposedly, it can't be done, and even if it could be done, it shouldn't be done. In both cases, the arguments are mistaken. There's plenty of evidence that cryonics can provide an "ambulance to the future" so that people who have the misfortune to die "at the wrong time" can be given another chance to reunite with family and friends.

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Reversing Age-Related Frailty Reduces Cardiovascular Risk and Mortality

Frailty is an inevitability for everyone on some timescale, given the present state of medical technology. It is not, however, an inevitability for early old age. It can be postponed for decades. Further, if someone becomes frail in earlier old age, that frailty may be reversible given sufficient effort put into treatment and lifestyle changes, particularly those involving resistance exercise. A perhaps surprisingly large fraction of the progressive loss of muscle mass and strength with age is a matter of lack of use, a sedentary lifestyle, and other factors that provoke metabolic dysfunction and inflammation. Some fraction of the chronic inflammation of aging can be reduced or evaded.

The study population in today's open access paper is notable for the sizable reduction in risk of mortality and cardiovascular disease exhibited in the cohort that managed to reverse their slide into pre-frailty or outright frailty. For a moment let us set aside the means by which these patients achieved this goal, and why they succeeded where others failed. Just looking at the data, this should be taken as one more compelling reason to fund the development of therapies that can effectively reverse frailty for everyone, not just the fortunate few, by meaningfully targeting the driving factors of failing muscle tissue and and overly-inflammatory immune system.

Association of changes in frailty status with the risk of all-cause mortality and cardiovascular death in older people: results from the Chinese Longitudinal Healthy Longevity Survey (CLHLS)

Few studies have investigated the association between changes in frailty status and all-cause mortality, inconsistent results were reported. What's more, studies that evaluated the effect of changes of frailty on cardiovascular death in older population are scanty. Therefore, the present study aims to investigate the association of such changes with the risk of all-cause mortality and cardiovascular death in older people, using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS).

A total of 2,805 older participants from two consecutive waves (i.e. 2011 and 2014) of the CLHLS were included for analysis. Based on the changes in frailty status from wave 2011 to wave 2014, participants were categorized into 4 subgroups, including sustained pre/frailty, robustness to pre/frailty, pre/frailty to robustness, and sustained robustness. Study outcomes were all-cause mortality and cardiovascular death, and Cox regression analysis examined the association of changes in frailty status with outcomes.

From wave 2011 to wave 2014, 33.2% of the participants had frailty transitions. From wave 2014 to wave 2018, there were 952 all-cause mortalities and 170 cardiovascular deaths during a follow-up of 9530.1 person-years, and Kaplan-Meier analysis demonstrated that cumulative incidences of the two outcomes were significantly lower in more robust participants. Compared with the subgroup of sustained pre/frailty, the fully adjusted hazard ratios (HRs) of all-cause mortality were 0.61, in the subgroup of robustness to pre/frailty, 0.51 in the subgroup of pre/frailty to robustness, and 0.41 in the subgroup of sustained robustness, respectively. The fully adjusted HRs of cardiovascular death were 0.79 in the subgroup of robustness to pre/frailty, 0.45 in the subgroup of pre/frailty to robustness and 0.51 in the subgroup of sustained robustness when comparing to the subgroup of sustained pre/frailty, respectively. Stratified analysis and extensive sensitivity analyses revealed similar results.

In conclusion, frailty is a dynamic process, and improved frailty and remaining robust are significantly associated with lower risk of all-cause mortality and cardiovascular death in older people.

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Greater Individual Wealth Correlates with Longer Life Expectancy

Individual wealth correlates with life expectancy, with an effect size that is in the same ballpark as those related to lifestyle choices involving exercise, diet, and consequences thereof. It remains unclear as to why wealth correlates with life expectancy. It is a part of a tangled web of correlations including intelligence, education, social status, personality traits, access to and ability to use medical services, as well as the suspicion that genetic associations with at least some of those line items (largely intelligence) may also independently affect health. Theorizing is easy, but assessing the relative contributions of the various proposed mechanisms is a challenge; proposing to fix the issue by top-down redistribution is naive for a number of reasons, perhaps the least of which being that absent an understanding of the mechanisms there is no guarantee that it would work.

This longitudinal cohort study analyzed the association between wealth and survival among participants in the Health and Retirement Study (1992-2018), a nationally representative panel study of middle-aged and older (≥50 years) community-dwelling, noninstitutionalized US adults. The data analysis was performed between November 15, 2022, and September 24, 2023. Household wealth was assessed on study entry, calculated as the sum of all assets minus the value of debts and classified into deciles. Weibull survival models were used to estimate the association between per-person wealth decile and survival, adjusting for age, sex, marital status, household size, and race and ethnicity. Changes in longevity that might occur under alternative wealth distributions were then estimated.

The sample included 35,164 participants (mean age at study entry, 59.1 years). The hazard of death generally decreased with increasing wealth, wherein participants in the highest wealth decile had a hazard ratio of 0.59 for death compared with those in the lowest decile, corresponding to a 13.5-year difference in survival. A simulated wealth distribution of perfect equality would increase populationwide median longevity by 2.2 years, fully closing the mortality gap between the US and the OECD average. A simulated minimum inheritance proposal would increase populationwide median longevity by 1.7 years; a simulated wealth distribution similar to Japan's would increase populationwide median longevity by 1.2 years; and a simulated baby bonds proposal would increase populationwide median longevity by 1.0 year.

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Further Exploration of Drainage Pathways for Cerebrospinal Fluid

Considerable progress has been made in recent years in mapping the pathways by which cerebrospinal fluid drains from the brain into the body, many of which were only recently discovered. The present consensus is that the progressive loss of this drainage with advancing age is likely important in the development of neurodegenerative conditions, allowing molecular waste such as amyloid-β to build up in the brain. Researchers here discuss a new branch of the system of cerebrospinal fluid drainage that passes behind the nose. Like the related cribriform plate pathway, this makes it off interest in the development of Alzheimer's disease, as the pathology of this condition starts in a nearby region of the brain.

In our brains, waste products generated as byproducts of metabolic activity are expelled through cerebrospinal fluid (CSF). Accumulation of waste in the brain, if not properly expelled, can damage nerve cells, leading to impaired cognitive function, dementia, and other neurodegenerative brain disorders. Hence, the regulation of CSF production, circulation, and drainage has long been a focus of scientific attention, especially in relation to age-related conditions like Alzheimer's disease and other neurodegenerative diseases.

The brain produces around 500 mL of this fluid per day, which is drained from the subarachnoid space. Among the known drainage routes are lymphatic vessels around the cranial nerves and the upper region of the nasal cavity. Despite well-documented evidence of lymphatics aiding CSF clearance, identifying the exact anatomical connections between the subarachnoid space and extracranial lymphatics has posed a challenge due to their extremely complex structure.

Researchers tackled this problem using transgenic mice with lymphatic fluorescent markers, microsurgeries, and advanced imaging techniques. Their efforts revealed a detailed network of lymphatic vessels at the back of the nose that serves as a major hub for CSF outflow to deep cervical lymph nodes in the neck. These lymphatics were found to have distinct features, including unusually shaped valves and short lymphangions. The study also demonstrated that pharmacological activation of the deep cervical lymphatics enhanced CSF drainage in mice. The researchers were able to successfully modulate cervical lymphatics using phenylephrine (which activates α1-adrenergic receptors, causing smooth-muscle contraction) or sodium nitroprusside (which releases nitric oxide, inducing muscle relaxation and vessel dilation). Importantly, this feature was preserved during aging, even when the nasopharyngeal lymphatic plexus had shrunk and was functionally impaired.

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A Mechanism by Which Fasting Suppresses Inflammation via the Inflammasome

Some of the benefits of fasting in later life derive from suppression of the chronic, unresolved inflammatory signaling characteristic of old age. As is usually the case in such matters, how much of the overall beneficial effect of fasting on long-term health, mortality, and life expectancy is due to this mechanism remains an open question. Similarly, while researchers here focus on one specific way in which inflammation is suppressed following fasting, via an interaction with the inflammasome, whether this specific interaction is a large or a small contribution to the whole remains to be determined, even given the interesting comparison with nonsteroidal anti-inflammatory drugs.

Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated.

Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages.

Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

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More Thought Needed on Causes versus Consequences in the Hallmarks of Aging

The hallmarks of aging are exactly that, hallmarks. They are not intended to be a list of causative mechanisms, though it appears that some people take it that way, particularly if it is supportive to their research and development program choices. Some of the hallmarks of aging overlap with the Strategies for Engineered Negligible Senescence (SENS) list of proposed causative mechanisms of aging, and the hallmarks paper itself clearly owes much to earlier SENS publications, as well as parallel proposals such as the Seven Pillars of Aging. It is important to target causes rather than consequences when it comes to aspects of aging, as only the treatment of causes is likely to be effective. The field is overdue a more broad, high-profile critique and consideration of the hallmarks of aging from the perspective of identifying causative mechanisms for intervention, rather than simply describing aging.

In a recent review article researchers conducted an exhaustive literature review and described an updated 12 hallmarks of aging. The updated model of aging comprehensively captures the key characteristics of the aging phenotype and incorporates new pathways that play a crucial role in age-related processes. Although the updated hallmarks of aging provide a useful framework for describing the phenotype of aging, aging itself is a result of mechanistically complex and interrelated processes that happen during the lifespan of the organism. Here, I propose to shift the focus from a systematic description and categorization of the hallmarks of aging to a model that separates the early, molecular origins of changes from cellular and tissue responses and represents the sequential and causative character of changes in aging. The proposed model aims to prompt discussion among the aging research community, guide future efforts in the field, and provide new ideas for investigation.

When the original 9 hallmarks of aging were first introduced in 2013, little was known about the mechanisms of aging. Since then, many research groups have described various mechanisms underlying this process, introducing the concept of the sequential character of changes in time and the molecular basis of the process. Therefore, I believe that the hallmarks of aging will benefit from the inclusion of information of temporal and sequential character of the process of aging. The aging process is commonly divided into early and late events, with a clear distinction between aging phenotypes and the underlying molecular events. Aging encompasses molecular, physiological, and phenotypic changes with different clinical relevance and different short-term or long-term outcomes if targeted using pharmacological interventions. Therefore, I propose a "three-wheeled gears" model to describe the early (upstream), intermediate, and late (downstream) events.

Any type of stress/disturbance can induce epigenetic changes, transcriptional noise, nuclear DNA damage and mitochondrial DNA damage, loss of cell membrane integrity, and oxidative stress, among other molecular disturbances. Intermediate events of aging encompass cellular responses to stress-induced molecular alterations and include activation of inflammation, proteostasis, autophagy, senescence, establishing energy homeostasis, and rewiring of cellular metabolism. If not resolved, molecular and cellular alterations due to repeated stress throughout the life of the individual trigger late events of aging, which manifest as aging phenotypes. Late events of aging result in progressive deterioration of organ function and include stem cell exhaustion, organ dysfunction, loss of tissue integrity, immune system dysfunction, for example, chronic low levels of inflammation, and alterations in tissue-tissue interactions and cell-cell communication. Molecular, cellular, and phenotypic processes of aging are interconnected, and progression in one process induces the progression of all other processes.

At present, investigational therapeutic approaches targeting aging phenotypes are geared mostly toward reverting aging symptoms rather than targeting the underlying molecular and cellular mechanisms. However, recognizing the aging phenotype is crucial for deciphering the mechanisms underlying aging and age-related diseases. We cannot fully delineate complex biological processes such as aging without addressing the molecular and cellular mechanisms that contribute to the different characteristics of aging and without dissecting the temporal and causal sequence of events.

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A Mitochondrial View of Muscle Aging

The hundreds of mitochondria present in every cell are primarily responsible for generating adenosine triphosphate, a chemical energy store molecule used to power cell operations. Mitochondria are the descendants of ancient symbiotic bacteria, and carry a small circular genome, the mitochondrial DNA. They replicate as needed, can fuse together and swap component parts, and damaged mitochondria are removed by cell maintenance processes. Mitochondrial function declines with age for a variety of reasons that include damage to mitochondrial DNA and changes in the expression of genes involved in replication, fusion, and quality control. How much of a contribution does this make to muscle aging? To determine that will require therapies such as mitochondrial transplantation that can repair the mitochondrial dysfunction of aging without changing other aspects of aged tissues.

Healthy lifestyles, such as those that include regular physical activity and a balanced diet, are a powerful means to prevent chronic disease and age-related functional decline. A common denominator of health improvements resulting from good exercise and diet habits is the optimization of metabolic processes. These processes include energy metabolism and, thus, the activity of mitochondria. Mitochondria represent hubs not only of cellular metabolism but also of the regulation of redox states, inflammatory response, and immunity, as well as many other cellular features. Mitochondria have emerged as highly flexible organelles that, quickly - and sometimes persistently - adapt to changing conditions in response to systemic or cellular challenges. Next to exercise and diets that promote mitochondrial health, transient exposures to environmental stressors, such as to altitude/hypoxia or extreme temperatures, also induce mitochondrial adaptations.

In this paper, we discuss how different systemic and cellular challenges trigger specific and overlapping mitochondrial responses that - under the right conditions - may translate into protective mitochondrial adaptations. We specifically focus on adaptations in skeletal muscle and sarcopenia, the age-related loss of skeletal muscle mass, strength, and function. Such responses rely on mechanisms such as mitochondrial stress responses and quality control; therefore, these mechanisms are believed to be required to maintain mitochondrial health. The resulting adaptations increase the capacity of mitochondria to respond to future stressors (e.g., altered oxygen or substrate availability), which otherwise might trigger pathological processes. Considering potential synergistic/anti-synergistic and complementary/competitive effects among lifestyle factors and environmental challenges on mitochondria, we argue that recommendations can be developed to increase performance, prevent sarcopenia, and improve healthy aging.

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A Novel HDAC1/2 Inhibitor Improves Measures of Tissue Function in Aged Mice

Researchers here report on the results of a drug screen focused on mimicking the transcriptional changes that occur in a number of interventions shown to modestly slow aging in short-lived species. They find an inhibitor of histone deacetylases HDAC1 and HDAC2 achieves this outcome, and note that in mice this drug candidate can produce positive changes in a number of measures of tissue function. Further studies will have to explore longer-term effects, dosing, and side-effects. Histone decacetylases influence the structure of the nuclear genome, and thus also influence gene expression quite broadly. Understanding how and why benefits result from this drug candidate will be a long-term undertaking. Further one should probably expect a sizable chance of undesirable side-effects, given what is known of this class of small molecule drug. Other histone deacetylases are under development for treatment of a range of conditions. Inhibition of HDAC1 seems positive here, but other research has shown that upregulation is beneficial in the context of aging neurons.

Aging increases the risk of age-related diseases, imposing substantial healthcare and personal costs. Targeting fundamental aging mechanisms pharmacologically can promote healthy aging and reduce this disease susceptibility. In this work, we employed transcriptome-based drug screening to identify compounds that emulate transcriptional signatures of long-lived genetic interventions. We discovered compound 60 (Cmpd60), a selective histone deacetylase 1 and 2 (HDAC1/2) inhibitor, mimicking diverse longevity interventions.

In extensive molecular, phenotypic, and bioinformatic assessments using various cell and aged mouse models, we found Cmpd60 treatment to improve age-related phenotypes in multiple organs. Cmpd60 reduces renal epithelial-mesenchymal transition and fibrosis in kidney, diminishes dementia-related gene expression in brain, and enhances cardiac contractility and relaxation for the heart. In sum, our two-week HDAC1/2 inhibitor treatment in aged mice establishes a multi-tissue, healthy aging intervention in mammals, holding promise for therapeutic translation to promote healthy aging in humans.

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Glial Cell Senescence Impairs α-Synuclein Clearance, Contributing to Parkinson's Disease

Parkinson's disease arises from the spread of misfolded α-synuclein and associated toxicity. α-synuclein is one of the few proteins in the body capable of misfolding in ways that encourage other molecules of the same protein to also misfold, forming solid aggregates and a surrounding halo of altered biochemistry that changes cell behavior for the worse, or kills those cells. The immune system is capable of mounting a defense against this sort of issue, but as noted here, the immune response to protein aggregates in the central nervous system is dampened by an increasing burden of cellular senescence and inflammatory signaling in the supporting cells of the brain.

Parkinson's disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra. Aging is a significant risk factor for PD. The accumulation of senescent glial cells in the aged brain contributes to PD progression by inducing chronic neuroinflammatory processes. However, although the insufficient degradation of α-syn aggregates results in PD deterioration, the possible alteration in the ability of α-syn clearance in senescent glia has received little attention.

In this study, we investigated how aging and glial senescence affect the capacity of α-syn clearance. We found that following the intra-striatal injection of human α-syn (hu-α-syn) preformed fibril, hu-α-syn pathology persisted more in aged mice compared with younger mice and that aged microglia exhibited greater accumulation of hu-α-syn than younger microglia. Moreover, in vitro assay revealed that the clearance of hu-α-syn was primarily dependent on the autophagy-lysosome system rather than on the ubiquitin-proteasome system and that the capacity of hu-α-syn clearance was diminished in senescent glia because of autophagy-lysosome system dysfunction. Overall, this study provides new insights into the role of senescent glia in PD pathogenesis.

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Further Assessing the Effects of Air Pollution on Mortality

There is ample evidence to show that air pollution correlates with increased mortality, and a number of natural experiments have allowed researchers to compare populations with similar socioeconomic status and different levels of air pollution, in order to demonstrate that effects do not result from wealth disparities. The consensus on why air pollution correlates with mortality is that interaction between particulates and lung tissue provokes greater systemic inflammatory signaling. That raised chronic inflammation accelerates the progression of all of the common fatal age-related conditions.

We aimed to report real-world longitudinal ambient air pollutants levels compared to WHO Air Quality Guidelines (AQG) and analyze multiple air pollutants' joint effect on longevity, and the modification and confounding from the climate and urbanization with a focus on the oldest-old. This study included 13,207 old participants with 73.3% aged 80 and beyond, followed up from 2008 to 2018 in 23 Chinese provinces. We used the Cox-proportional hazards model and quantile-based g-computation model to measure separate and joint effects of the multiple pollutants. We adjusted for climate and area economic factors based on a directed acyclic graph.

In 2018, no participants met the WHO AQG for PM2.5 and O3, and about one-third met the AQG for NO2. The hazard ratio (HR) for mortality was 1.07 per decile increase in all three pollutants, with PM2.5 being the dominant contributor according to the quantile-based g-computation model. In the three-pollutant model, the HRs for PM2.5 and NO2 were 1.27 and 1.08 per 10 μg/m3 increase, respectively. The oldest-old experienced a much lower mortality risk from air pollution compared to the young-old. The mortality risk of PM2.5 was higher in areas with higher annual average temperatures. The adjustment of road density considerably intensified the association between NO2 and mortality. The ambient PM2.5 and O3 levels in China exceeded the WHO AQG target substantially. Multiple pollutants coexposure, confounding, and modification of the district economic and climate factors should not be ignored in the association between air pollution and mortality.

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IL-15 Improves the Ability of Natural Killer Cells to Attack Cancerous Tissue

Cancerous tissue co-opts the immune system, suppressing its ability to destroy cancerous cells, and even gaining the assistance of immune cells in encouraging the growth of a tumor. There are many different mechanisms by which this happens, varied by immune cell type and form of cancer, comparatively few of which are well mapped and well understood. The active and well-funded cancer research community continues to explore the potential to interfere in these harmful interactions between cancer and immune system. The approach noted here is one of many, and typical of this sort of research program in that it targets a specific subset of immune cells.

Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning, and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells.

We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.

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Bypassing Causes to Focus on Repairing Damaged Synapses in Alzheimer's Disease

Should we expect an approach focused on repair of synapses in neurodegenerative conditions like Alzheimer's disease, while leaving the causative mechanisms of the condition operating intact, to have a large effect on patient outcomes? Given what is known of the underlying mechanisms of protein aggregation, neuroinflammation, and other problems that ultimately kill neurons, not just damage them, it seems possible that synaptic repair might do well in the early stages of cognitive impairment, but later do little to help as the condition progresses. Regardless, it is interesting to consider to degree to which neural function could in principle be maintained in the face of damaging mechanisms, without actually addressing those mechanisms.

While newly approved drugs for Alzheimer's show some promise for slowing the memory-robbing disease, the current treatments fall far short of being effective at regaining memory. Since most current research on potential treatments for Alzheimer's focuses on reducing the toxic proteins, such as tau and amyloid beta, that accumulate in the brain as the disease progresses, researchers veered away from this route to explore an alternative. The work hinges on a protein called KIBRA, named because it is found in the kidney and the brain. In the brain, it is primarily localized at the synapses, which are the connections between neurons that allow memories to be formed and recalled. Research has shown that KIBRA is required for synapses to form memories, and the team has found that brains with Alzheimer's disease are deficient in KIBRA.

The team first measured the levels of KIBRA in the cerebrospinal fluid of humans. They found that higher levels of KIBRA in the cerebrospinal fluid, but lower levels in the brain, corresponded to the severity of dementia. To figure out how KIBRA affects synapses, the team created a shortened functional version of the KIBRA protein. In laboratory mice that have a condition mimicking human Alzheimer's disease, they found that this protein can reverse the memory impairment associated with this type of dementia. They found that KIBRA rescues mechanisms that promote the resilience of synapses. "Interestingly, KIBRA restored synaptic function and memory in mice, despite not fixing the problem of toxic tau protein accumulation. Our work supports the possibility that KIBRA could be used as a therapy to improve memory after the onset of memory loss, even though the toxic protein that caused the damage remains."

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