Fight Aging!

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: https://www.fightaging.org/newsletter/

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Contents

• Against Prioritizing Environmentalism Over Human Health
• Demyelination Accelerates Amyloid-β Aggregation
• Senolytic Treatments as a Strategy to Improve Immune Function in Late Life
• Mitochondrial Transplant Alleviates Stress-Induced Mitochondrial Dysfunction in Rat Brains
• Notes from the 2023 Age-Related Disease Therapeutics Summit
• Thymus Atrophy in Middle Age
• Age-Related Dysfunction of Water Homeostasis
• Bowhead Whales Exhibit Efficient DNA Repair
• Retroviral Activation as a Component of Neuronal Aging
• Soluble ADAM10 to Reduce Amyloid-β in the Brain
• AGEs Produce Harmful Effects via Interaction with RAGE
• Fat Infiltration of Muscle Correlates with Age-Related Cognitive Decline
• Evidence of Causality in the Relationship Between Excess Body Weight and Accelerated Progression of Aging
• Taurine Supplementation Slows Aging, Extends Life in Mice
• Targeting Pro-Inflammatory Cytokine IL-17 to Slow Skin Aging

Against Prioritizing Environmentalism Over Human Health
https://www.fightaging.org/archives/2023/06/against-prioritizing-environmentalism-over-human-health/

It is fair to say that the mainstream of environmentalism prioritizes conservation of the environment over human comfort and health. Environmental concerns are high on the list of objections raised against treating aging as a medical condition, because most people believe that this will lead to a larger population, and also believe that population increases cannot occur without degrading the environment. Both of those beliefs are false, the latter evidently so given the improvements in the environment created since the 1950s, over a period of considerable population growth. Models strongly suggest that the future is one in which population growth diminishes with increasing wealth, as is already happening in countries like Japan, and we certainly live in a world in which the wealth of individuals and populations is increasing, quite rapidly in the poorest regions.

In this context, it is interesting to see commentary from someone who values both (a) the high profile goals of environmentalism, and (b) the high profile goals of efforts to treat aging and thereby extend the healthy human life span. There is no reason as to why we can't have the cake and eat it in this case. Given the will, we can have both great longevity and the world recreated as an unspoiled garden. The conflicts between these goals are illusionary, an outcome of mistaken ideas as to what greater longevity will mean, and how technological progress and economic incentives work to create new resources and greater abundance, not simply exhaust the resources we have.

Geroscience and climate science: Oppositional or complementary?

Two of this century's most significant public health challenges are climate change and healthy aging. The future of humanity will be both warmer and older than it is today. Taken in isolation from each other, tackling either one of the novel public health challenges of climate change or healthy aging requires foresight, scientific innovation, and collaborative governmental action. However, the public health challenges of the 21st century are even more Herculean because climate change and population aging are occurring simultaneously. And this means that science communication concerning what constitutes empirically valid and morally defensible ways of navigating these dual public health challenges must be sensitive to both the interdependence of the environment and the mechanisms of aging, as well as the common (mis)perceptions about the potential conflict between the goals of climate science and geroscience.

It is a common and accepted role for scientists to get involved in public policy debates, especially if their research pertains to public health. "Responsible biology" entails that scientists conceive of themselves as artisans working for the public good, and thus, they have a moral obligation to reflect on the ends (and not just the means) of scientific research. Is it socially responsible, in a warming planet of a population exceeding 8 billion people, for science to aspire to develop gerotherapeutic drugs? That is, drugs that target pathways involved in aging with the aim of reducing the burden of aging-related diseases and increasing lifespan and healthspan. This question is, for the field of geroscience, the "elephant in the room." It is a question the field must tackle head on vs avoid, lest it risk marginalizing the science of healthy aging.

Unlike scientific innovation for pharmaceuticals treating specific diseases, like cancer, heart disease, or Alzheimer's, biomedical gerontology often faces concerns that arise from what has been called "gerontologiphobia" - "the irrational fear that aging research is a public menace bound to produce a world filled with non-productive, chronically disabled, unhappy senior citizens consuming more resources than they produce." Climate anxiety among younger persons, coupled with "egalitarian advocacy" (a motivation to take action and enact equality-based change), may lead to "succession"-based ageism - the belief that older adults should step aside to free up coveted opportunities. The case for shifting public health priorities from the goal of making further increases in lifespan for older populations via disease control toward the goal of increasing the human healthspan via rate (of aging) control can help abate the assumptions of intergenerational conflict underpinning such problematic sentiments.

Rather than conceptualizing the distributional effects of an applied gerontological intervention as something that would only benefit persons in late life (e.g., increasing lifespan), and climate change as something that only imposes health and economic risks primarily on younger generations, attention must be given to the reality that aging and climate change are intricately connected. Not only are older persons at higher risk for climate change mortality, but the health of the environments we inhabit (including planetary health) influence aging and the healthspan. Rate (of aging) control would improve the quality of life of adults at all ages and for future generations versus simply increasing the number of years of survival for the older persons of today. In addition, the economic benefits of slowing aging will better enable populations (especially those in lower income countries) to invest in the adaptations (e.g., changing land and cropping practices; installing better-draining pavements to deal with floods; improving water storage and use) necessary to minimize some of the harms of climate change.

Demyelination Accelerates Amyloid-β Aggregation
https://www.fightaging.org/archives/2023/06/demyelination-accelerates-amyloid-%ce%b2-aggregation/

Nerves require myelin sheathing in order to function correctly. With age, some degree of dysfunction in myelin maintenance takes place, with consequent cognitive and other nervous system degeneration as a consequence. This loss of myelin integrity takes place to a lesser degree than is the case in severe demyelinating conditions such as multiple sclerosis. Nonetheless, that lesser degree may be contributing to the early stages of Alzheimer's disease by reducing immune clearance of amyloid-β aggregates.

At present a question hovers over the role of amyloid-β in Alzheimer's disease due to the failure of amyloid-clearing immunotherapies to improve patient outcomes in the clinic. The research and development communities remain largely wedded to the idea that amyloid-β aggregation will turn out to be relevant to the early onset of the condition, but it remains to be seen as to whether even that is correct, accepting that later stages have moved on to other primary mechanisms of harm associated with neuroinflammation and tau aggregation.

Poorly insulated nerve cells promote Alzheimer's disease in old age

Intact myelin is critical for normal brain function. Researchers have shown that age-related changes in myelin promote pathological changes in Alzheimer's disease. Their work focused on a typical feature of the disease; Alzheimer's is characterized by the deposition of certain proteins in the brain, the so-called amyloid beta peptides (Aβ). The Aβ peptides clump together to form amyloid plaques. In Alzheimer's patients, these plaques form many years and even decades before the first symptoms appear. In the course of the disease, nerve cells finally die irreversibly and the transmission of information in the brain is disturbed.

Using imaging and biochemical methods, the scientists examined and compared different mouse models of Alzheimer's in which amyloid plaques occur in a similar way to those in Alzheimer's patients. For the first time, however, they studied Alzheimer's mice that additionally had myelin defects, which also occur in the human brain at an advanced age. Researchers saw that myelin degradation accelerates the deposition of amyloid plaques in the mice' brains. The defective myelin stresses the nerve fibers, causing them to swell and produce more Aβ.

At the same time, the myelin defects attract the attention of the brain's immune cells called microglia. Normally, microglia detect and eliminate amyloid plaques, keeping the buildup at bay. However, when microglia are confronted with both defective myelin and amyloid plaques, they primarily remove the myelin remnants while the plaques continue to accumulate. The researchers suspect that the microglia are 'distracted' or overwhelmed by the myelin damage, and thus cannot respond properly to plaques.

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease

The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter of which is associated with secondary neuroinflammation. As oligodendrocytes support axonal energy metabolism and neuronal health, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD.

Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage.

Senolytic Treatments as a Strategy to Improve Immune Function in Late Life
https://www.fightaging.org/archives/2023/06/senolytic-treatments-as-a-strategy-to-improve-immune-function-in-late-life/

Senescent cells accumulate in tissues throughout the body with age. Cells become senescent constantly throughout life, largely by reaching the Hayflick limit on replication, but a small number due to potentially cancerous mutations, or other forms of damage and stress. Senescent cells are rapidly removed by the immune system in youth, keeping their numbers low, but the balance between creation and destruction is disrupted with aging. There is greater stress, but perhaps more importantly the immune system becomes less efficient, less able to clear senescent cells in a timely fashion. Since senescent cells actively secrete pro-inflammatory, pro-growth signals, they are a disruptive, harmful influence on tissue structure and function with present for the long term in even comparatively small numbers.

It is fair to say that near every tissue and system in the body examined to date suffers from a late life presence of lingering senescent cells and their inflammatory secretions. These cells contribute meaningful to the onset and progression near every age-related condition. This includes the decline of the immune system into immunosenescence and inflammaging. It would be surprising indeed to find that removal of senescent cells failed to improve late life immune function in humans, considering what we know of the mechanisms involved, and the impressive array of evidence from animal studies. Even only considering the point that senescent cells encourage constant, unresolved inflammation, their removal should be beneficial to immune function.

The ageing immune system as a potential target of senolytics

The immune system is essential in protecting the body from various pathogenic mechanisms and infection, in particular, there are significant changes to immune function as we age. Recent studies have suggested that the cellular senescence of immune cells impairs clearance of pathogenic material, increasing the risk of severe infections and mortality. These processes lead to the build-up of inflammatory mediators, causing inflammageing - a state of chronic immune activation that is associated with blunted innate and adaptive immune responses. The cumulative effect of these processes triggers downregulation of immune responses, via mechanisms such as defective lymphocyte responses and a reduction in regulatory immune cells. Thus leading to deterioration of the immune system with age, termed immunosenescence. Thus, clearance of senescent immune cells could be beneficial to the immune system, as has been witnessed in other tissues. This has driven research into modalities which can delay, or reverse, these age-related immune changes.

Current senolytics aim to clear all senescent cells, regardless of their cell type, however, refining this to target specific senescent cell populations may be of benefit, by increasing the efficacy of drugs whilst reducing potential side effects, as seen in other fields such as cancer therapies. One of the major concerns of an ageing immune system is its diminished immune response, which in part is driven by senescent immune cells. This effect of an ageing immune system can be seen clinically, as older populations are at greater risk of succumbing to serious infections and have poorer efficacies with regards to vaccines. Senolytics targeting senescent immune cells may provide a solution to help improve immunity within elderly populations.

Targeting senescent immune cells has further drawn interest in the treatment of age-related diseases. Recent studies have implicated senescent immune cells in driving senescence and ageing in tissues including the liver in mouse and rat models, although the precise mechanism behind this is yet to be determined. Given these findings, it is tempting to speculate that senescent immune cells are driving similar age-related changes in other tissues and organs. Targeting senescent immune cells therapeutically could therefore provide benefits beyond that of targeting individual tissue-based senescent cell populations.

Although current senolytics may have some degree of senescent immune cell clearance, a senolytic specifically targeting senescent immune cells has not yet been developed. Given the impact of senescent immune cells on the pathophysiology of age-related disease and the diminution of the immune response, senolytics targeting these cells may have multi-faceted benefits. Additionally, whilst research is still in early stages, pre-clinical models show that senolytics could modulate a more favourable immune response to infection in older mice and humans.

Mitochondrial Transplant Alleviates Stress-Induced Mitochondrial Dysfunction in Rat Brains
https://www.fightaging.org/archives/2023/06/mitochondrial-transplant-alleviates-stress-induced-mitochondrial-dysfunction-in-rat-brains/

Mitochondrial transplantation is potentially a way to restore more youthful mitochondrial function without the need for a far greater understanding of exactly how exactly mitochondria become dysfunctional with age. Cells will readily ingest mitochondria from the surrounding intercellular space and make use of them. If those mitochondria work well in comparison to the state of the cell's native mitochondria, then cell function will be improved for some time. Animal studies suggest that the effect is lasting. In that context, it is always interesting to see studies in which outcomes are assessed for mitochondrial transplantation from young animals into old animals, as in today's open access paper.

Other approaches to reducing the age-related decline in mitochondrial function have been implemented based on a combination of advances in scientific understanding and fortunate discoveries in small molecule screens. These largely appear to work at least in part via improved mitophagy, the quality control process responsible for recycling worn and broken mitochondria. Unfortunately, these treatments fail to improve on exercise when it comes to enhancing measures of health. This category of interventions in includes increasing NAD levels via delivery of precursors, urolithin A and its effects on mitochondrial dynamics, mitochondrially targeted antioxidants such as mitoQ, and so forth.

While potentially more interesting approaches are under development, such as copying mitochondrial DNA into the cell nucleus to provide a backup source of proteins when mitochondrial DNA becomes damaged, these are still very much works in the progress. Even given that a company has held clinical trials for a gene therapy to introduce a backup copy of one mitochondrial gene, there are still a range of other mitochondrial genes to deal with in this way. Mitochondrial transplantation is somewhat closer to the clinic, however. The only significant roadblock is the efficient manufacture of large numbers of mitochondria, and several venture funded companies are working on solutions.

Chronic stress-induced apoptosis is mitigated by young mitochondria transplantation in the prefrontal cortex of aged rats

Apoptosis is common and often comorbid with aging and stress-related mood disorders. Evidence suggests that fresh mitochondria could reverse age-related dysfunctions in organs, especially in the brain. Therefore, this study investigated the effect of young mitochondria administration on the apoptosis process in the prefrontal cortex (PFC) of aged rats exposed to chronic stress.

Aged (22 months old) male rats were randomly assigned into four groups: aged control (AC), aged rats treated with young mitochondria (A+M), aged rats subjected to chronic stress for four weeks (A+St), and aged rats subjected to chronic stress and treated with young mitochondria (A+St+M). A+M and A+St+M groups received a single intracerebroventricular injection (10 μl) of fresh mitochondria isolated from the brain of young rats. Finally, the levels of malondialdehyde (MDA), cytochrome c (Cyt c), Bax, Bcl-2, and Caspase-3 expression were investigated in the PFC.

The results of the present study demonstrated that the transplantation of young mitochondria ameliorated oxidative stress in the PFC of aged and chronic stress-exposed aged rats, as indicated by diminished MDA levels and reduced Cyt c release. Young mitochondria also markedly attenuated apoptosis markers in the PFC of aged and chronic stress-exposed aged groups, which was characterized by down-regulated expression levels of pro-apoptotic proteins, Bax and caspase-3, and up-regulated expression levels of anti-apoptotic protein Bcl-2. These results suggest mitochondrial transplant therapy could reverse cell viability and mitochondrial dysfunction-induced apoptosis in the PFC tissue of aged rats subjected to stressful stimuli.

Notes from the 2023 Age-Related Disease Therapeutics Summit
https://www.fightaging.org/archives/2023/06/notes-from-the-2023-age-related-disease-therapeutics-summit/

The former Longevity Therapeutics conference series was renamed to the Age-Related Disease Therapeutics Summit and held its fifth event recently in San Francisco. It was a smaller meeting than in past years, perhaps a result of the recent downturn in the global financial and investment environment. Few investors were present. Nonetheless, one can usually learn something interesting from the presenting biotech founders and executives. I took a few notes while I was there to present on progress at Repair Biotechnologies, and they follow in the order of the conference program.

Birget Schilling from the Buck Institute for Research on Aging discussed the role of cellular senescence in bone aging. She focused on techniques for discovering signatures of aging in human bone tissue, looking at protein expression and composition of the bone extracellular matrix. This included the use of bone organoid models derived from patient cells and patient tissue samples. This was a snapshot of early-stage investigative research, some distance from any preclinical development and application to medicine.

Abdlkadar Rahmo from SMSbiotech, a cell therapy company, presented on the merits of in vitro human cell and tissue models of aging. Using such models can be cost-effective, but there are of course meaningful differences between an in vitro model and tissue in a living organism, and a great deal of work remains to be accomplished in standardization and reliability. The primary focus was on organoids derived from patient tissue samples, and a number of different models were described, including skin, brain, and intestinal structures. The company works on a specific type of adult stem cell found in human tissus that they call small mobile stem (SMS) cells. The company uses these cells in the manufacture of cell models, as SMS cells readily produce extracellular matrix that encourages blood vessel formation.

A panel discussed how to better improve translation from animal models to humans, always a challenge in every field. The general sentiment was that greater use of human organoids enables a more rapid process of fundamental discovery, skipping over animal studies until later in the process. It remains challenging to match animal models to diseases sufficiently well to avoid issues, and the field is littered with models that may be too artificial to be useful, but finding out that this is the case is a lengthy, expensive process. Making animal models better is a tough problem, and it was suggested that use of human organoids will at some point take over from that project. It was also suggested that gene therapies make animal models more useful, as there is a greater known consistency in the way the therapy interacts with animal versus human biochemistry.

Adam Kaplin of MyMD Pharmaceuticals presented on their inhibitory molecule that targets TNF-alpha and other important cytokines in inflammation and oxidative stress. Treatment dials down chronic inflammation in age-related disease and autoimmune disease. It is presently in clinical trials for sarcopenia and rheumatoid arthritis. Some of the fine details of the cytokine profiles following dosing were outlined. They believe their molecule is somewhat more selective for excessive inflammatory signaling versus needed inflammatory signaling than is the case for earlier inhibitors, which is an important issue in this part of the field. They demonstrate in mice that this inhibition of excessive inflammation can slow aging meaningfully, improving function and reducing mortality to a greater degree than rapamycin.

I presented on recent progress at Repair Biotechnologies. We develop a gene therapy, lipid nanoparticle delivery of mRNA, that can selectively clear excess intracellular free cholesterol. Our latest data shows sizable, rapid, safe reversal of the pathology of NASH in mouse models of the condition. We can also reverse atherosclerosis, removing plaque lipids in the same rapid, safe manner in animal models. We aim to conduct our first pre-IND meeting with the FDA later this year, and thereafter work towards an initial clinical trial in humans.

Peter Fedichev of Gero presented on their analysis of aging and disease. They make extensive use of machine learning to produce insights from large longitudinal data sets, both animal and human. Their view is one of regulatory systems and disturbance of homeostasis, a growing instability in regulation of complex processes in the body. Mice are less stable than humans, less resilient to disturbance of homeostasis, and a longer species life span might be considered a matter of better maintained stability. Gero tests a variety of approaches known to slow aging in mice in the context of their computational models for regulation of aging, seeking a better understanding of how exactly these treatments act on the body. From analysis of human data they identify a point of regulation and potential therapeutic, then confirm in mice, and thereafter hope to bring their best candidates into human trials.

Robin Mansukhani of Deciduous Therapeutics presented on their approach to clearing senescent cells via adjusting behavior of the immune system. They are advocates of the view that the growing burden of senescent cells with age is primarily an issue of immune dysfunction, though this is a multifaceted failure in many different immune cell types and recognition processes. The company is focused on natural killer T cells, and use small molecules to provoke these immune cells into more actively recognizing and destroying senescent cells. A single dose produces lasting improvement in senescent cell clearance, retraining aged immune cells into greater activity. Deciduous uses this approach to therapy to treat pulmonary fibrosis and type 2 diabetes, both conditions associated with cellular senescence, and are working towards clinical trials.

Doug Ethell of Leucadia Therapeutics discussed progress towards a small implantable device, essentially just a sensor-controlled valve, that restores cerebrospinal fluid drainage through the cribriform plate behind the nose. The company's preclinical evidence, including imaging of a large human study population and studies in ferrets, support a role for impaired drainage through the cribriform plate in the early development of Alzheimer's disease. The channels of the cribriform plate ossify and close with age. Without efficient drainage, metabolic waste of all sorts, including extracellular amyloid aggregates, accumulates in the brain, and this leads to neurodegeneration. At this point, the company is a year or so away from initial human trials of their device.

Michael Fossel of Telocyte started by outlining a view of aging as a growing imbalance between dynamic, constantly active processes of (a) damage and dysfunction versus (b) repair and restoration. This led to a discussion of changes in average telomere length as an important feature in tissues in aging, while noting that measuring telomere length in leukocytes from a blood sample is uninformative as to the state of the body. In this view, extending telomeres with telomerase expression is not targeting a cause of aging, but it is intervening at a convenient point in the processes of aging to adjust cell behavior for the better, restore more youthful epigenetic patterns to some degree, and improve tissue function. The company currently has unnamed sources of sufficient funding to conduct clinical trials of telomerase gene therapy as a treatment for various diseases of aging including Alzheimer's disease, but the timeline is unclear.

Jerry McLaughlin of Life Biosciences focused on their efforts in the hot field of partial reprogramming. They use an OSK cocktail, leaving out MYC from the original Yamanaka factors in order to prevent dedifferentiation and tumor formation. This approach, as with other reprogramming approaches, can reverse the characteristic epigenetic changes associated with aging, producing rejuvenation. They deliver an AAV carrier with a payload of conditionally activated OSK, only expressed in the presence of doxycycline. Their target indications for the clinic involve retinal damage and aging, as the eye is an isolated site and a good target for AAV gene therapies. They presented recent positive data on treatment of optic neuropathy in a non-human primate, resulting from ischemic damage in the retina. The treated primates showed a lesser loss of a measure of visual function, and exhibited improved survival of axons in the retina. The company is aiming for an initial clinical trial to start in late 2024.

Louis Hawthorne of NaNotics outlined the basis for their technology, a silica nanoparticle decorated with binding agents and covered by a shield layer that can efficiently remove specific molecules from the bloodstream without interacting with cell surfaces. Essentially a programmable sponge, and much more effective than antibodies. Mounting evidence points to various signal molecules in the bloodstream that increase in amount with age as contributing to various age-related diseases. One might consider pro-inflammatory cytokines, for example. Some groups have used expensive plasmapheresis to remove specific inflammatory molecules with good results, such as soluble tumor necrosis factor receptors (sTNFR) removal in the treatment of cancer, and NaNotics aims to do much the same thing more effectively. PD-L1 is another oncology target, and the company are moving to human trials in 2024 on the strength of a Mayo Clinic collaboration.

James Peyer of Cambrian Bio painted an interesting picture: that the challenge for our field is not that we cannot run trials for aging, nor designating aging as a disease, but that geroprotective drugs as a class of therapy require preventative trials for multiple comorbidities that are too lengthy to be economically viable in the current regulatory framework, given venture capital mindsets on duration of funds and need for return in a given timeframe. Thus we need to build new types of long-term research and development organizations, ones with sufficient funding to run multi-disease prevention trials over a longer timeframe than is presently possible. This way of thinking about the market is how Cambrian Bio came about, a well-capitalized entity intended to take programs all the way from academia through to these long clinical trials. Cambrian Bio has a sizable number of subsidiary biotechs, mostly stealth mode. Peyer talked about one of them, Telos Biotechnology. The company is focused on the ability of telomere lengthening to improve the performance of CAR-T cells in cancer therapy. The hypothesis is that current challenges in producing sufficient numbers of CAR-T cells for older patients has a lot to do with shorter telomeres and thus more replicative senescence during expansion in culture. The resulting cells are also less effective. The company develops an approach to increase telomere length in these CAR-T cells during expansion in cell culture, making a big difference in the cost-effectiveness and efficacy of CAR-T therapy.

Lorna Harries of SENISCA discussed progress on a platform for adjusting age-related dysregulations in RNA processing, such as altered RNA splicing resulting from changing expression of splicing factors, in order to suppress the burden of cellular senescence. Restoration of lost splicing factor expression can prevent and even reverse cellular senescence. Interestingly it also repairs some of the DNA damage characteristic of senescent cells. (This doesn't work in oncogene-induced senescence, where there is catastrophic DNA damage). To achieve this goal, the company uses a portfolio of oligonucleotides that can alter expression of various splicing factors and their regulators. The company is initially targeting idiopathic pulmonary fibrosis, as are many groups that work on clearance of senescent cells, and showed in vitro data in cells taken from pulmonary fibrosis patients, demonstrating restored markers of cell function. They have similar data for other cell models of age-related diseases connected to cellular senescence, such as cartilage degeneration.

Marco Quarta of Rubedo Life Sciences presented on the poorly catalogued differences that exist between senescent cell types, by origin and tissue type. It seems unlikely that any one small molecule senolytic would be able to effectively target all senescent cells. Chemotherapy and checkpoint inhibitor survivors exhibit increased senescent cells and reduced quality of life, but different chemotherapies apparently produce different states of cellular senescence, with varying vulnerability to specific senolytic drugs. So it may not be as straightforward as hoped to use senolytics to prevent lasting side-effects of cancer treatment. This example extends into other conditions and origin of senescence. Thus the company works on a big data, machine learning platform to identify senescent states associated with specific tissues and conditions, and then screen new senolytic small molecules tailored to these senescent cell states. They are aiming for an initial clinical trial in 2024.

Viktoria Kheifets of Alkahest discussed the current state of the art in altering levels of specific blood factors in order to suppress detrimental metabolic changes characteristic of aging. Alkahest is owned by a large medical-industrial blood plasma organization, acting as a research arm that can develop new commerical uses for its products. They see blood plasma as a master communication highway, transferring information between cells throughout the body. The company presently undertakes a great deal of data collection and analysis of the contents of blood samples in various ages and conditions, identifying clusters of various molecules and matching them to phenotypes. They then conduct studies in mice to see if plasma fraction transfusion can produce meaningful therapeutic benefits by altering specific plasma molecule levels. It is unclear as to which of the current preclinical programs will in fact be taken forward to the clinic, as this depends on the slow economic calculations of the large owning company. One interesting item is that the company has tried delivery of only albumin into old animals, and have seen no meaningful benefit. You might recall that there is some question over whether dilution of plasma works to improve health because albumin is delivered with the saline, and the result depends on replacement of existing, perhaps age-damaged, albumin. This may not be the case, and it is really the dilution of other harmful factors that causes improved health.

Szilard Voros of G3 Therapeutics talked about efforts to use big data analysis, of omics and epidemiological databases of thousands of individuals assessed over time, to rationally design entire clinical programs targeting age-related diseases, from the mechanistic target through to predicted odds of success of a clinical trial of a small molecule targeting that mechanism. The company has built a vast set of data, down to the level of expression patterns in specific tissues, and uses that data to move therapeutics towards the clinic.

Andrei Gudkov of Roswell Park Cancer Center presented a contrarian position on senescent cell biochemistry. Researchers used a mouse model which they lethally irradiated and then rescued by replacement of bone marrow, expecting greater cellular senescence and accelerated aging, but while the mice had a 20% shorter life span, their late life frailty was actually reduced in comparison to controls. Oddly, these mice also exhibited no sign of increased cellular senescence using traditional biomarkers such as P16 and inflammatory signaling. Their conclusion was that most P16 and SA-beta-gal expressing cells in old tissues that are pumping out inflammatory cytokines are actually macrophages, not what are presently thought of as senescent cells. Strangely, mesenchymal cells of these irradiated mice immediately become senescent when put into culture and forced to divide, while remaining non-senescent and non-dividing in vivo. Also the mice have impaired wound healing and excessive appearance of senescent cells in injuries. Further, if they are given a high fat diet grow fat, then they exhibit raised mortality. This is all connected to cell proliferation. The implication is that the mice have genotoxic stress due to radiation-induced DNA damage, but this dormant harm is only realized when cells are forced to proliferate. This all says something interesting about how senescence and DNA damage interact, that damage can remain dormant, a potential for senescence to be realized later.

A panel discussion focused on choice of biomarkers as important in achieving success in clinical trials. When setting up a clinical trial, one has to convince the regulators that the a proposed biomarkers are appropriate. A poor choice, whether it originates with the company or the FDA, can doom a trial even if the therapy actually works. Biomarkers might be (a) predictive, in the pre-disease state, though few clinical trials are conducted for prevention, or (b) diagnostic to establish the state and progression of established disease. One also needs easily measured biomarkers that determine the degree to which the therapy is active in a patient. In the best of worlds, these choices are obvious and straightforward. But it is rarely that simple, particularly in the matter of aging or new mechanisms of action.

Joshua McClure of Maxwell Biosciences presented on the company's broad anti-inflammatory platform derived from innate immune system antimicrobial peptides, which is progressing towards clinical trials. These factors were discovered using big data analysis of heterochronic parabiosis studies, looking at old and young blood and comparative omics profiles. The company has taken the non-dilutive funding approach to fundraising, and has been largely funded by government research grants rather than venture capital. Their primary candidate molecules are derived from LL37, a ubiquitous antimicrobial peptide that appears to have a range of other helpful, protective functions both connected and unconnected to immune function. The preclinical data is quite impressive, and this therapy may go on to improve outcomes in many infections, cancers, and other conditions.

Hans Keirstead of Immunis presented on their approach to culturing stem cells in order to produce a secretome as a drug that can improve immune function, reducing immunosenescence and inflammaging. This manufacture isn't as easy as it might sound. Standardization of any sort of product that involves cell populations is a challenge. That it is hard and expensive and failure-prone to manufacture cell therapies is a large part of why there is strong interest in moving to cell secretions as a basis for therapies derived from what we know about how cell therapies influence tissues. It is easier to control cells in a dish to produce a secretome that can be assessed on ~10 marker proteins than it is to produce cells for transplant. Delivering a secretome to improve immune function to mice produces a wide range of benefits, and the hope is that enough of this will translate to humans to succeed in clinical trials for indications that have traditionally been targeted for the development of stem cell therapies.

Hanadie Yousef of Juvena Therapeutics discussed their approach to therapy. The company has used proteomic analysis of secretomes from various cell types known to promote regeneration in order to identify regulatory molecules that are enriched in scenarios of regeneration. They use machine learning based on the library of proteins they created in order to predict which secreted molecules are likely to be useful for given indications. They then engineer improved versions of these proteins. Their lead protein is at the pre-IND stage, initially to treat a form of muscular dystrophy, and they hope to start clinical trials by the end of 2024.

David Furman of the Buck Institute for Research on Aging talked initially about a project to build a large omics database of human imune aging. This data led to an unbiased search for makers of inflammaging, which lead to the inflammatory age (iAge) clock. This clock correlates with health outcomes and mortality, as one might expect given what is known of the role of inflammation in aging. A company and drug discovery program resulted, and various candidate drugs that reduce iAge have been tested in human trials. The presentation moved on to the use of accelerated aging models to make studies run more rapidly. This specific effort involves the apparent acceleration of aging that occurs as a result of time spent in microgravity. A company, Cosmica, to run drug discovery programs targeting mechanisms of aging more rapidly than is usually possible based on this class of accelerated aging, using organoids in a microgravity environment, with human astronaut data for validation. Perhaps the most interesting point here is that measures of accelerated aging in astronauts reverse once back on the ground again, and one might ask: what are the driving biological mechanisms of that restoration? The company believes that the primary mechanisms they are observing are related to cell mechanosensing of the extracellular matrix, and microgravity disrupts this in ways that somewhat mimic some of the biochemistry-driven issues with cell/extracellular matrix interaction that occur in aging.

Noah Davidson of Rejuvenate Bio discussed progress towards the clinic for their leading gene therapies. They use AAV as a vector platform, and intend to take its use beyond the present correction of rare genetic disorders into a broader set of age-related conditions. They are primarily focused on cardiac disease, picking genes and mutations that have been shown to extend life in mice and that will address specific issues that occur in cardiac diseases, such as fibrosis and mitochondrial dysfunction. They screened combinations of upregulation and downregulation of various genes, and settled on the current favored combination of FGF1 and anti-TGF-beta-1 - increasing FGF1 expression and decreasing circulating TGF-beta-1 using a binding receptor fragment. They have been using the therapy in companion dogs for a few years, with a good safety profile. A single treatment is expected to last for a decade or longer, but the expression is inducible; it requires taking a pill daily to activate expression of the therapeutic genes, for an additional layer of control of the therapy. The company aims to expand out into a broad veterinary market for dogs, and thus will provide supportive data for clinical development of the same class of therapy for human use.

A panel discussed how aging-focused biotech companies might better build bridges to large pharma entities, which are typically slow to engage meaningfully with any change in the state of the science and the industry. This quite quickly turned into an exchange about the various groups that are trying to circumvent the established regulatory environment, and build alternative paths to clinical application and revenue. It seems clear that many people in the longevity industry as it stands put pharma entities in the same category as regulators: a mountain that lies ahead, an unpleasant but necessary task of engagement if one is to play the game as the rules are written. The conversation then moved on to the power of data. A truly curative, impressive therapy will shape the system around it, and will find a way, the obstacles will melt away. In the matter of aging, the biggest challenge is how to measure such an impressive therapy in order to prove that it is in fact impressive in something less than a decade-long study.

Alexander Picket of Juvenescence talked about a drug development program leading on from the discovery of a small population of humans with a loss of function mutation in PAI-1 and who appear to exhibit a longer life expectancy as a result, an additional seven years. This gene lives at the border of immune function and fibrinolytic system responsible for clotting, and has a lot of activities beyond that. It touches on cellular senescence, for example. There was some discussion of how, even given this very obviously interesting mechanism, and a drug that replicates the effect to some degree, it is still complicated and hard to find a way through the regulatory system as it exists today. A lot of this involves downstream effects of government regulation of medicine, insurers, and medical pricing, as at the end of the day the large funding sources will only invest in clinical trials for drugs wherein a profit can be made, and regulation ensures that many types of treatment simply cannot be profitable in any of the ways they are permitted to be deployed.

Pankaj Kapahi of the Buck Institue for Research on Aging discussed glycation in aging. Advanced glycation endproducts (AGEs) produce a number of issues, such as inflammation due to interaction with receptors and the reaction of the immune system to glycated proteins, and also cross-linking in the extracellular matrix. This is most evident in the sugar-heavy dysfunctional metabolism of diabetics, but in aging it seems likely that persistent AGEs also generate meaningful pathology. The research here focused on methylglyoxal, a precursor of AGEs. Scientists found a way to reduce methylglyoxal levels in the body using a cocktail of supplements. This led to a spinout company Juvify Health and a supplement product. In mice this improves insulin metabolism and reduces body weight in addition to achieving the expected biochemical measures such as degree of glycation of proteins. The body weight change appears to be because targeting AGEs in this way suppresses hunger mechanisms, and the mice eat less, which is an interesting finding.

The theme for the industry at this time appears to be that many clinical trials of novel therapeutics targeting mechanisms of aging will start up in the next few years, assuming funding can be found. Impressive data tends to attract that funding. Market downturns don't last, and the next boom period will be characterized by the advent of a range of methods to greatly enhance immunity, slow aging, and turn back specific age-related conditions presently resistant to treatment. Interesting times!

Thymus Atrophy in Middle Age
https://www.fightaging.org/archives/2023/06/thymus-atrophy-in-middle-age/

Researchers here present data for excess weight to accelerate the involution of the thymus, a process that is no doubt sensitive to mechanisms such as the increased inflammation that accompanies obesity. The thymus is an organ in the chest, the destination for thymocytes created in the bone marrow. Thymocytes mature into T cells of the adaptive immune system over a period of weeks in the thymus. Unfortunately, active thymus tissue is progressively replaced by fat over the course of adult life. A good fraction of middle-aged people have negligible tissue remaining, and thus a negligible supply of new T cells. Without reinforcements, the adaptive immune system steadily collapses into a collection of senescent, malfunctioning, exhausted cells, incapable of fending off pathogens or clearing harmful senescent or potentially cancerous cells.

Fatty degeneration of thymus (or thymus involution) has long been considered a normal ageing process and the role of thymus in adults has drawn little attention. However, there is emerging evidence that thymic involution is linked to T cell aging, chronic inflammation, and increased morbidity. Other factors than chronological age have been proposed to affect the involution rate. However, thymus involution and its determinants have been little studied at a general population level.

In the present study, we investigated the imaging characteristics of thymus on computed tomography (CT) in a Swedish middle-aged population. In total, 1,048 randomly invited individuals (aged 50-64 years, 49% female) were included and thoroughly characterized. CT evaluation of thymus included measurements of attenuation, size, and a 4-point scoring system. A majority, 615 (59%) showed complete fatty degeneration, 259 (25%) predominantly fatty attenuation, 105 (10%) half fatty and half soft-tissue attenuation, while 69 (6.6%) presented with a solid thymic gland with predominantly soft-tissue attenuation.

Age, male sex, high BMI, abdominal obesity, and low dietary intake of fiber were independently associated with complete fatty degeneration of thymus. Also, fatty degeneration of thymus as well as low CT attenuation values were independently related to lower proportion of naïve CD8+ T cells, which in turn was related to lower thymic output, assessed by T-cell receptor excision circle (TREC) levels. In conclusion, among Swedish middle-aged subjects, nearly two-thirds showed complete fatty degeneration of thymus on CT.

Age-Related Dysfunction of Water Homeostasis
https://www.fightaging.org/archives/2023/06/age-related-dysfunction-of-water-homeostasis/

Dehydration can be an issue in older people. As in every complex system in the body, the mechanisms by which hydration is regulated become dysfunctional with advancing age. Researchers here look at the brain region responsible for regulating some of the response to dehydration, cataloging altered gene expression in search of the more important mechanisms involved in the vulnerability of old people to harmful levels of dehydration.

Ageing is accompanied by an increased prevalence of disorders of body salt and water composition. As revealed by the UK Dehydration Recognition In Our Elders (DRIE), 20% of residents in care are dehydrated. Many elderly patients admitted to the hospital present osmotic balance disorders, and dehydration (DH) is often a cause of morbidity and mortality in senior citizens. Thus, to improve healthy living among the elderly, we need to understand why salt and water imbalances occur in this age group. Both peripheral and central mechanisms controlling salt and water homoeostasis change with age. Ageing is accompanied by a gradual decline in renal function, with urine-concentrating capacities reduced in the elderly compared to younger subjects. This diminished ability to conserve bodily water, accompanied by reduced thirst and insufficient water intake after fluid deprivation, makes the elderly more prone to DH.

Ageing is associated with altered neuroendocrine function. In the context of the hypothalamic supraoptic nucleus (SON), which makes the antidiuretic hormone arginine vasopressin, ageing alters acute responses to hyperosmotic cues, rendering the elderly more susceptible to dehydration. Chronically, vasopressin has been associated with numerous diseases of old age, including type 2 diabetes and metabolic syndrome.

We compared the transcriptomes of the SON in adult and aged euhydrated rats and found massive changes in gene expression associated with ageing, including genes involved in extracellular matrix (ECM) organisation and cell adhesion. It is known that the SON has a complex and dynamic ECM that has been implicated in its physiological functioning. The transcriptomic response to dehydration is overall blunted in aged animals compared to adults, and there is a specific enrichment of differentially expressed genes related to neurodegenerative processes in the aged cohort, suggesting that dehydration itself may provoke degenerative consequences in aged rats.

Dysfunctional water homoeostasis in ageing is associated with the inappropriate release of the antidiuretic hormone arginine vasopressin (AVP). The capabilities of the AVP system to respond to osmotic stress decrease with age. In the aged animal, the capacity of the AVP system to respond to dehydration is attenuated. These deficits may be associated with dysfunction in mechanisms controlling transcription, mRNA stability, or translation. Indeed, we have previously shown that the steady-state response to dehydration of a number of selected gene transcripts is attenuated in aged animals. This appears to be a transcriptome level effect, with many of the common genes regulated by dehydration showing a blunted response in aged animals compared to adults. This generalised attenuation of the transcriptomic response to dehydration is likely to greatly affect SON function and overall osmoregulatory effectiveness.

Bowhead Whales Exhibit Efficient DNA Repair
https://www.fightaging.org/archives/2023/06/bowhead-whales-exhibit-efficient-dna-repair/

All large mammals must evolve ways to suppress cancer risk more effectively than their smaller relatives. More mass means more cells, and thus more chances for a cell to suffer the mutations that will lead to cancer. Elephants evolved additional copies of P53 and other tumor suppression genes, for example. Bowhead whales, on the other hand, appear to manage with more efficient DNA repair mechanisms. We can hope that some of these explorations may lead to ways to improve human resistance to cancer. Improved DNA repair in particular is an attractive goal, given that DNA damage is linked to aging in a number of ways, such as via somatic mosaicism and the possibility of causing detrimental epigenetic change.

At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg. In spite of its very large number of cells, the bowhead is not highly cancer-prone, an incongruity termed Peto's Paradox. This has been explained by the evolution of additional tumor suppressor genes in larger animals, which is supported by research on elephants demonstrating expansion of the p53 gene.

However, we show here that bowhead whale fibroblasts undergo oncogenic transformation after disruption of fewer tumor suppressors than required for human fibroblasts. Instead, analysis of DNA repair revealed that bowhead cells repair double-strand breaks with uniquely high efficiency and accuracy compared to other mammals. Further, we identified two proteins, CIRBP and RPA2, that are present at high levels in bowhead fibroblasts and increase the efficiency and fidelity of DNA repair in human cells.

These results suggest that rather than possessing additional tumor suppressor genes as barriers to oncogenesis, the bowhead whale relies on more accurate and efficient DNA repair to preserve genome integrity. This strategy, one that does not eliminate cells but repairs them, may be critical for the long and cancer-free lifespan of the bowhead whale. Our work demonstrates the value of studying long-lived organisms in identifying novel longevity mechanisms and their potential for translation to humans.

Retroviral Activation as a Component of Neuronal Aging
https://www.fightaging.org/archives/2023/06/retroviral-activation-as-a-component-of-neuronal-aging/

In recent years, researchers have implicated the activation of transposable elements such as retrovirus sequences in degenerative aging. Transposable elements are largely the remnants of ancient viral infections, and have the ability to copy themselves in the genome. In youth, transposable elements are effectively suppressed, but with advancing age this suppression falters. Transposable elements can then act as a form of DNA damage, as well as provoking cell dysfunction via other means, such as inflammatory signaling resulting from innate immune sensing of viral signatures, which may meaningfully contribute to harmful outcomes in aging.

The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Efforts have been made to reveal molecular events that trigger aging-related dysfunctions in FL, however intrinsic alterations in neurons in response to aging are not completely understood.

Using the neuronal aging-in-a-dish model derived from human embryonic stem cells, we genetically perturbed the expression of Lamin B1 and Lamin B2 in human neurons and pinpointed that decreased B-type lamins drive the activation of endogenous retrovirus (ERV) retrotransposons during neuronal aging, which leads to elevated senescence and inflammation. Our study demonstrated that this in vitro human neuronal model could mimic the aging-related phenotypes of neurons from primate brains and study cell-autonomous mechanisms underlying primate neuronal aging.

ERV element activation has been reported to be associated with cellular senescence. In addition, increased expression of ERV elements was found to contribute to neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the links between ERV derepression and physiological brain aging have not been established. For the first time, our study revealed that ERV retrotransposable elements are derepressed in aged human neurons, which activate cGAS signaling, exacerbating neuroinflammation, thus providing a vivid paradigm of how this cascade functions in a highly physiologically and pathologically relevant context, the aging brain.

We previously found that the inhibition of reverse transcription of the endogenous retrovirus can alleviate cartilage degeneration and aging-related inflammation. In this study, we further found that treatment with abacavir can attenuate the augmented inflammation and protein aggregates in human neurons during prolonged culture and in the neurons of FL from aged mice, indicating ERV targeting as a promising strategy to delay brain aging and extend healthspan.

Soluble ADAM10 to Reduce Amyloid-β in the Brain
https://www.fightaging.org/archives/2023/06/soluble-adam10-to-reduce-amyloid-%ce%b2-in-the-brain/

The research and development community continues to focus on amyloid-β as a primary target in Alzheimer's disease, despite the failure to produce meaningful benefits in patients in human clinical trials of immunotherapies targeting amyloid-β. It may yet prove to be the case that safer approaches than immunotherapies, used widely to reduce amyloid-β prior to the development of symptoms, could lower incidence of Alzheimer's disease. It seems evident that extracellular amyloid-β is not the right target in later stages of the condition, however.

Accumulation of amyloid β in the brain is regarded as a key initiator of Alzheimer's disease pathology. Processing of the amyloid precursor protein (APP) in the amyloidogenic pathway yields neurotoxic amyloid β species. In the non-amyloidogenic pathway, APP is processed by membrane-bound ADAM10, the main α-secretase in the nervous system. Here we present a new enzymatic approach for the potential treatment of Alzheimer's disease using a soluble form of ADAM10.

The ability of the soluble ADAM10 to shed overexpressed and endogenous APP was determined with an ADAM10 knockout cell line and a human neuroblastoma cell line, respectively. Using proteomic approaches, we identified soluble ADAM10 substrates. Finally, a truncated soluble ADAM10, based on the catalytic domain, was expressed in Escherichia coli for the first time, and its activity was evaluated.

The soluble enzyme hydrolyzes APP and releases the neuroprotective soluble APPα when exogenously added to cell cultures. The soluble ADAM10 inhibits the formation and aggregation of characteristic amyloid β extracellular neuronal aggregates. Our in vitro study demonstrates that exogenous treatment with a soluble variant of ADAM10 would shift the balance toward the non-amyloidogenic pathway, thus utilizing its natural neuroprotective effect and inhibiting the main neurotoxic amyloid β species. The potential of such a treatment for Alzheimer's disease needs to be further evaluated in vivo.

AGEs Produce Harmful Effects via Interaction with RAGE
https://www.fightaging.org/archives/2023/06/ages-produce-harmful-effects-via-interaction-with-rage/

Advanced glycation end-products (AGEs) are a threefold problem. Firstly, a few species of persistent AGEs can form lasting cross-links between structural molecules of the extracellular matrix that alter its tensile properties, such as a loss of elasticity. Human biochemistry is ill-suited to the task of removing these cross-links, particularly those based on glucosepane. Secondly, AGEs can bind to proteins and modify their function, acting as a form of damage that cells must clear. Thirdly, transient AGEs interact with the receptor for AGEs, RAGE, to produce chronic inflammation and cellular dysfunction. This is characteristic of the abnormal, high-sugar environment of type 2 diabetes, but also an issue to a lesser degree in the broader aged population.

Advanced glycation end-products (AGEs; e.g., glyoxal, methylglyoxal, or carboxymethyl-lysine) are heterogenous group of toxic compounds synthesized in the body through both exogenous and endogenous pathways. AGEs are known to covalently modify proteins bringing about loss of functional alteration in the proteins. AGEs also interact with their receptor, receptor for AGE (RAGE) and such interactions can influence different biological processes that include oxidative stress and apoptosis.

Previously, AGE-RAGE axis has long been considered to be the maligning factor for various human diseases including, diabetes, obesity, cardiovascular, aging, etc. Recent developments have revealed the involvement of AGE-RAGE axis in different pathological consequences associated with the onset of neurodegeneration including, disruption of blood brain barrier, neuroinflammation, remodeling of extracellular matrix, dysregulation of polyol pathway and antioxidant enzymes, etc.

In the present article, we attempted to describe a new avenue that AGE-RAGE axis culminates to different pathological consequences in brain and therefore, is a central instigating component to several neurodegenerative diseases (NGDs). We also invoke that specific inhibitors of TIR domains of TLR or RAGE receptors are crucial molecules for the therapeutic intervention of NGDs. Clinical perspectives have also been appropriately discussed.

Fat Infiltration of Muscle Correlates with Age-Related Cognitive Decline
https://www.fightaging.org/archives/2023/06/fat-infiltration-of-muscle-correlates-with-age-related-cognitive-decline/

Researchers here show that great fat infiltration of skeletal muscle tissue correlates well with the progressive loss of cognitive function that occurs with advancing age. It is well demonstrated that greater visceral fat mass accelerates the declines of aging, but researchers here suggest that fat deposition in skeletal muscle correlated with cognitive decline independently of the degree to which study participants were overweight. The underlying reasons as to why two people of the same overall adiposity may have different degrees of intramuscular fat deposition are not well understood, but this manifestation of aging correlates well with many aspects of age-related dysfunction, including chronic inflammation, metabolic syndrome, and other usual suspects. In a web of correlations, it can be challenging to identify cause and effect.

Obesity and loss of muscle mass are emerging as risk factors for dementia, but the role of adiposity infiltrating skeletal muscles is less clear. Skeletal muscle adiposity increases with older age. In 1,634 adults (69-79 years), we obtained thigh intermuscular adipose tissue (IMAT) via computerized tomography at Years 1 and 6, and mini-mental state exam (3MS) at Years 1, 3, 5, 8 and 10.

A linear mixed effects models tested the hypothesis that increased IMAT (Year 1-6) would be associated with 3MS decline (Year 5-10). Models were adjusted for traditional dementia risk factors at Year 1 (3MS, education, APOe4 allele, diabetes, hypertension, and physical activity), with interactions between IMAT change by race or sex. To assess the influence of other muscle and adiposity characteristics, models accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass (all measured in Years 1 and 6). Models were also adjusted for cytokines related to adiposity: leptin, adiponectin, and interleukin-6.

Thigh IMAT increased by 4.85 cm^2 (Year 1-6) and 3MS declined by 3.20 points (Year 6-10). The association of IMAT increase with 3MS decline was statistically significant: an IMAT increase of 4.85 cm^2 corresponded to a 3MS decline of an additional 3.60 points, indicating a clinically important change. Interactions by race and sex were not significant. Clinicians should be aware that regional adiposity accumulating in the skeletal muscle may be an important, novel risk factor for cognitive decline independent of changes to muscle strength, body composition, and traditional dementia risk factors.

Evidence of Causality in the Relationship Between Excess Body Weight and Accelerated Progression of Aging
https://www.fightaging.org/archives/2023/06/evidence-of-causality-in-the-relationship-between-excess-body-weight-and-accelerated-progression-of-aging/

Excess visceral fat tissue produces a greater burden of senescent cells, so in that sense one might argue that it is literally causing accelerated aging. Generally researchers content themselves with pointing to the epidemiological data, in which being overweight correlates with greater incidence of age-related disease, greater lifetime medical costs, and a shorter life expectancy. Here, however, an effort is made to prove causation in human data: that the excess weight does in fact cause all of these problems.

Limited by the quality of evidence, possible potential reverse causality and residual confounding, observational studies have been almost unable to identify a causal association between being overweight and aging. In this regard, randomized controlled trials (RCTs) can be used to reveal cause and effect. However, RCTs are costly in terms of money, time and manpower. Instead, Mendelian randomization (MR) is a popular and effective method for causal inference in recent years. It takes genetic variation (single nucleotide polymorphism, SNP) as the instrumental variable to deduce the causal association between outcome and exposure, which can effectively avoid the confounding bias of traditional epidemiological studies.

We collected genetic variants associated with overweight, age proxy indicators (telomere length, frailty index, and facial aging, etc.), from genome-wide association studies datasets. Then we performed MR analyses to explore associations between overweight and age proxy indicators. MR analyses were primarily conducted using the inverse variance weighted method, followed by various sensitivity and validation analyses.

MR analyses indicated that there were significant associations of being overweight on telomere length, frailty index, and facial aging. Overweight status also had a significant negative causality with life expectancy. Moreover, the findings tend to favor causal links between body fat mass or body fat percentage on aging proxy indicators, but not body fat-free mass. In conclusion, this study provides evidence of the causality between overweight and accelerated aging (telomere length decreased, frailty index increased, facial aging increased) and lower life expectancy. Accordingly, the potential significance of weight control and treatment of overweight status in combating accelerated aging need to be emphasized.

Taurine Supplementation Slows Aging, Extends Life in Mice
https://www.fightaging.org/archives/2023/06/taurine-supplementation-slows-aging-extends-life-in-mice/

Taurine levels drop with age, and correlate with health in aged humans. Researchers here show evidence for taurine supplementation to improve health and extend life span in mice. While it isn't mentioned in this paper, if one takes a look around the literature on this topic, taurine may act on the pace of aging by increasing levels of the antioxidant enzyme glutathione, and has been shown to diminish oxidative stress. You may recall that supplementation with glutathione precursors has been shown to improve health in both old mice and old humans. Glutathione itself is harder to deliver directly, hence the more indirect strategies. The observed effects on health and life span may be due to improved mitochondrial function, reducing the dual impact of mitochondrial dysfunction: loss of ATP production needed to power cell processes on the one hand, and and excessive production of oxidative molecules that can damage molecular machinery elsewhere in the cell on the other.

Aging is associated with systemic changes in the concentrations of molecules such as metabolites. However, whether such changes are merely the consequence of aging or whether these molecules are drivers of aging remains largely unexplored. If these were blood-based drivers of aging, then restoring their concentration or functions to "youthful" levels could serve as an antiaging intervention. Taurine, a semiessential micronutrient, is one of the most abundant amino acids in humans and other eukaryotes. Earlier studies have shown that the concentration of taurine in blood correlates with health, but it is unknown whether blood taurine concentrations affect aging. To address this gap in knowledge, we measured the blood concentration of taurine during aging and investigated the effect of taurine supplementation on health span and life span in several species.

Blood concentration of taurine declines with age in mice, monkeys, and humans. To investigate whether this decline contributes to aging, we orally fed taurine or a control solution once daily to middle-aged wild-type female and male C57Bl/6J mice until the end of life. Taurine-fed mice of both sexes survived longer than the control mice. The median life span of taurine-treated mice increased by 10 to 12%, and life expectancy at 28 months increased by about 18 to 25%. A meaningful antiaging therapy should not only improve life span but also health span, the period of healthy living. We, therefore, investigated the health of taurine-fed middle-aged mice and found an improved functioning of bone, muscle, pancreas, brain, fat, gut, and immune system, indicating an overall increase in health span.

Investigations into the mechanism or mechanisms through which taurine supplementation improved the health span and life span revealed that taurine positively affected several hallmarks of aging. Taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammation. An association analysis of metabolite clinical risk factors in humans showed that lower taurine, hypotaurine, and N-acetyltaurine concentrations were associated with adverse health, such as increased abdominal obesity, hypertension, inflammation, and prevalence of type 2 diabetes. Moreover, we found that a bout of exercise increased the concentrations of taurine metabolites in blood, which might partially underlie the antiaging effects of exercise.

Targeting Pro-Inflammatory Cytokine IL-17 to Slow Skin Aging
https://www.fightaging.org/archives/2023/06/targeting-pro-inflammatory-cytokine-il-17-to-slow-skin-aging/

Researchers here report that a few cell types in aged skin begin to generate large amounts of IL-17, an inflammatory signal molecule. While the obvious suspect here is cellular senescence, as we know that senescent cells accumulate with age and energetically secrete pro-inflammatory signal molecules, this data suggests that this may not be the case, at least for this particular signal molecule in this particular tissue. The researchers show that blocking IL-17 slows the manifestations of skin aging. The challenge in this sort of approach is that inflammatory signal molecules are needed for the normal immune response to function correctly. The treatment of autoimmune conditions via blockade of various inflammatory signals has meaningful side-effects that include suppression of necessary immune responses. This is less of a concern if treatments target only the skin, but we should hope that researchers can identify more targeted, subtle ways to eliminate only excess inflammatory signaling in the rest of the aging body.

During aging, tissue-specific alterations in the stem cell niche synergize with stem cell-intrinsic changes to contribute to the development of age-associated traits. Aging has been proposed to drive a tissue-dependent proinflammatory microenvironment that perturbs adult stem cell behavior. Infiltration of immune cells into the stem cell niche, or a transcriptional switch of stem cells, contributes to this proinflammatory environment that negatively feeds back to their own fitness. Here we have characterized the effects of the proinflammatory cytokine IL-17 on skin aging.

Our results show that elevated IL-17 signaling, secreted by aged dermal CD4+ T-helper cells, γδ T cells, and innate lymphoid cells, orchestrated many of the age-associated tissue dysfunctions by exertion of pleiotropic effects. IL-17-mediated signaling is heavily linked to the development of chronic inflammatory and autoimmune diseases. In the skin, these diseases include psoriasis, pemphigus, and alopecia areata. Even if none of the clinical signs of these diseases are common with physiological aging, they share an increased aberrant IL-17-based signaling that impedes correct skin function.

Our results strongly suggest that, intriguingly, the local environment of the aged skin resembles a low-level but persistent state of chronic inflammation, with deficient permeability and impaired wound healing that is reminiscent of what occurs in serious skin diseases such as psoriasis. Consequently, anti-IL-17 therapies, already approved for treatment of psoriasis, might be repositioned to other age-associated ailments such as excessive skin dryness or difficulty in repairing damaged skin in the elderly.