Fight Aging!

The market has been in the doldrums and it has been a tough year for fundraising, both for non-profits and biotech startups. The conferences have exhibited more of an academic focus as companies tightened belts and postponed investment rounds, while investors stayed home. Not that this halts the flow of hype for some projects, and nor has it slowed media commentary on the longevity industry as it presently stands. A few of the articles in that commmentary are even interesting to read! The field has grown and is more mature now than has ever been the case. Biotech of all forms is a challenging field with a high failure rate, but the biotechnology of treating aging looks to become a vast industry in the years ahead. The first signs of tiers in the industry are beginning to emerge, as some groups pull further ahead than others.

But I have talked less this past year about the community and spent more time sampling the firehose flow of research papers from the aging research field. So I thought that I would try something different for this year's retrospective. Rather than grouping the output by mechanism of aging, a very Strategies of Engineered Negligible Senescence (SENS) way of looking at the world that appeals to me, this year I'll instead try grouping by age-related condition, skipping over all of the research that was in too early a stage or too mechanism-focused to discuss application to a specific condition. That also meant skipping over some interesting commentary on epigenetic clocks, but we shall see whether or not the result is as useful as past years. One of the interesting outcomes is that it becomes easy to see that a great deal of research into age-related disease is focused on neurodegenerative conditions, perhaps reflecting the budget priorities of the NIA.

Philanthropy, Advocacy, Lobbying, and Non-Profits

In the long run, people will live for a very, very long time, but for now advocacy remains largely focused on the question of how to increase funding for aging research and development programs, under the assumption that this is the best way to speed up progress towards therapies available in the clinic. Venture capitalists have pointed out the likely impressive financials for a drug capable of treating aging, intending it to attract the interest of investors. The Dublin Longevity Declaration called for more research funding. XPRIZE launched the $101M XPRIZE Healthspan initiative to encourage more translational research and clinical application of approaches to slow aging. The Impetus Grants project continues to make efficient, useful grants to researchers focused on mechanisms and treatment of aging. The Amaranth Foundation continues to do the much same, but with a broader purview of solving bottlenecks in aging research.

The LEV Foundation is the present focus of Aubrey de Grey, and the foundation's initial projects are large animal studies testing combinations of rejuvenation therapies. The foundation is presently soliciting philanthropic donations for the next set of studies. SENS Research Foundation gave small-scale, per-project crowdfunding conducted via Experiment a try, and their 2023 annual report is worth reading, as always. If you want to help speed progress towards therapies to reverse aging, there are plenty of options that don't involve working in a laboratory. A number of people in academia and industry are creating new organizations now, such as the Phaedon Institute.

On the political lobbying side of the house, the US now has a congressional caucus for longevity science, and we shall see where that goes. Some politicians like to get out in front of potential future flows of campaign donations, whenever it seems likely that a heavily regulated activity will see an influx of funding. Nonetheless, in the bigger picture, lobbying efforts for industry and research remain at a very early stage, even given that the economic argument to put in front of politicians is a compelling one.

On the regulatory front, companies are not expecting a path for approval to treat aging rather than specific diseases of aging to emerge at any time soon, even given progress made by the developers of veterinary therapies to slow aging. Even if it emerges, the regulatory path to approval will remain challenging and expensive. All developers pick a disease and aim at that goal. Nonetheless, there is the feeling that the regulatory landscape will inevitably shift to permit treatment of aging - it is just a matter of time. Meanwhile, off-label use of therapies that may modestly slow or reverse aging in humans, such as rapamyin and the senolytic dasatinib and quercetin combination, is starting to become large enough to come to the attention of the media and public.

Life Extension and Improved Function in Animal Models

A number of studies demonstrate slowed aging, extended life, or improved function in animal models. Some of these are a more interesting, some of these less interesting. The shorter the life span of the model, the less exciting the result, as a rule. Researchers still work with short-lived species despite this point because it is less expensive to do so. Quite a few research researchers were worthy of mention this past year. intermittent gene therapy reprogramming in aged mice doubles remaining life span. This year, researchers published a claim for the longest-lived lab rat, resulting from a study of transfusion of young rat plasma into old rats. Upregulation of ghrelin pathway activation produced a modest increase in mouse life span, supporting evidence for the importance of hunger in the beneficial response to calorie restriction. PI3K inhibition via alpelisib, taurine supplementation, long-term hypoxia, and menin upregulation in the hypothalamus have also been shown to modestly extend life in mice. Neoagarotetraose supplementation improves the gut microbiome and extends life in mice.

Plasma transfer from young individuals lowers epigenetic age and mortality in rats. Heterochronic parabiosis, joining the circulatory systems of an old and young mouse, produces a modest extension of life in the older mouse. Reduced APRT expression extends life in killifish, mostly likely via calorie restriction mimetic effects. As a reminder that lifespan in mice and other short-lived species is very sensitive to environmental factors, and we should probably be skeptical of any effect size smaller than a 10% extension of life in this species, researchers demonstrated that female odors slow development and extend life in female mice by 8%-9%. To round off the mouse news with an interesting negative result, the Interventions Testing Program found that fisetin, despite clearing senescent cells in mice, does not extend mouse life span. Puzzling!

For very short-lived laboratory species, such as flies and worms, there have also been new demonstrations. Increased expression of a few electron transport chain proteins can meaningfully improve mitochondrial function in aged flies. The induction of hunger independently of calorie intake via optogenetic techniques can extend life in flies. A DEC2 mutation both reduces sleep and extends life in flies. Upregulation of adh-1 in nematodes extended life by reducing glycerol and glyceraldehyde levels. Suppression of transposable element activity, mild mitochondrial inhibition and neuron-specific mTORC1 inhibition also extends life in nematodes. Finally in this list, ATG4B overexpression to improve autophagy increases fly life span.

Comparative Biology of Aging

It remains unclear as to whether it will be possible in the near term to translate any specific species differences into therapies to improve human capabilities. Is autophagy important in species life span differences? It is hard to say, given that upregulation of autophagy doesn't do that much in individuals of a given species. How about transposable element activity as a driver of species longevity? There is certainly increasing interest in the role of transposons in aging. There is also a great deal of ongoing study of other species in the context of their longevity, negligible degeneration over much of the course of life, increased resilience, and regenerative capacity. We might look at the following selection: long-lived rockfish, buffalofish, and bowhead whales; whales are in general interesting for their resistance to cancer; jellyfish can be highly regenerative; the naked mole-rat is ever popular, a species that does not exhibit demographic aging; continued efforts to understand the role of senescent cells in salamander and zebrafish regeneration; bivalves present a wide range of life spans in similar near neighbor species, a good test-bed for theories.

To what degree do genetic differences contribute to pace of aging? Between species, clearly everything, though there is presently little understanding as to which of the countless differences are actually important. A small step in the direction of finding out was achieved by engineering mice to have the naked mole-rat hyaluronan synthase 2 gene, producing a slight extension of life. Similarly, examining differences in autophagy genes suggests it is important in species life span - which is interesting, as within a species, upregulation of autophagy doesn't appear to do all that much for life span. Another small step was an investigation of gene duplications, in search of longevity-associated genes that might be duplicated in longer-lived species, indicating that mechanisms they are involved in might be important in species life span. Immune system differences may be important, but this is a very complex, very large, and poorly explored area of research. Additionally, researchers have found that CD44 expression correlates with species longevity. Looking beyond genetics to epigenetics, epigenetic drift occurs more slowly in long-lived species.

Long-lived mammals exhibit a downregulated methionine metabolism, and are thus gaining some of the benefits of calorie restriction derived from methioine sensing observed in short-lived species without needing to eat less. Long-lived (and usually physically larger) species also exhibit a diverse range of effective anti-cancer mechanisms that are of great interest to the cancer research community. Relatedly, blind mole rats have an interesting mechanism of replicative senescence.

A Selection of Articles on the Topic of Aging

Sometimes I write rather than comment on research news, but again there was less of this in the past year. I largely focused on self-experimentation and conference reports:

• A Proposal to Accelerate Progress Towards Human Rejuvenation
• Request for Startups in the Rejuvenation Biotechnology Space, 2023 Edition
• Three Years of Gut Microbiome Data for Flagellin Immunization and Fecal Microbiota Transplantation
• How to Run a Comparatively Simple Self-Experiment to Assess the Impact of Taurine Supplementation on Measures of Aging
• Will Success in Reversing Aging Shape the Regulatory System to Accommodate It?
• Notes from the 2023 Age-Related Disease Therapeutics Summit
• All Too Short Comments on the 10th Aging Research and Drug Discovery (ARDD) Meeting

Alzheimer's Disease and Other Neurogenerative Conditions

It remains unclear as to how in detail Alzheimer's emerges from underlying mechanisms of aging. The same goes for other neurodegenerative conditions, and may go some way towards explaining the lack of progress towards effective treatments. Even absent treatments, the risk of dementia has declined year by year in recent decades, and the evidence points to improved vascular health as the underlying cause. Certainly, the state of frailty correlates with cognitive decline, as does cardiovascular aging, while vascular endothelial dysfunction is strongly implicated in Alzheimer's disease, and control of hypertension is shown to reduce dementia risk.

Researchers have over the years implicated many specific issues as contributing to neurodegeneration. The burden of white matter hyperintensities, a form of structural damage to brain tissue, correlates with cognitive decline, but to what degree is it driven by amyloid and thus secondary to Alzheimer's processes? Inflammation in the brain is ever a popular area of study. Added visceral fat and fat infiltration of muscle, both causative of inflammation, correlate with cognitive decline. The decline in clearance of cerebrospinal fluid through the glymphatic system, or through other pathways, allows waste products to build up in the brain, also provoking inflammatory reactions. Senescent cells throughout the body can provide harmful signaling that encourages dysfunction in the aging brain, but the senescence of glial cells and senescence of astrocytes in the brain may be more important. Age-related hearing loss has been shown to contribute to neurodegeneration in a number of different studies, as has impaired vision. The relationships may be bidirectional! The growing somatic mosiacism present in every tissue is implicated in brain aging, as is the activation of transposons.

Researchers are finding that while the gut microbiome changes with age in every individual, those changes are distinctly different in Parkinson's disease and Alzheimer's disease patients. Other studies show correlation between gut microbiome configuration and risk of neurogenerative conditions. Alzheimer's symptoms can be produced in rats by transplanting the gut microbiome from Alzheimer's patients. The aged gut microbiome can produce a metabolite that directly harms the dopaminergenic neurons that are lost in Parkinsons' patients. In general, cognitive impairment correlates with an altered gut microbiome. Parkinson's disease may have a bacterial origin, and the intestines may also be a source of amyloid-β in the early stages of Alzheimer's disease. Researchers have developed models for the way in which the gut microbiome contributes to Alzheimer's, and are considering ways to alter the microbiome as a potential source of treatments for neurogenerative conditions. Relatedly, intermittent fasting reduces pathology in a mouse model of Alzheimer's disease.

Alzheimer's is a complex condition of many layers, with many links between, both to and from aspects of aging. There may be subtypes of Alzheimer's disease that exhibit important differences in mechanisms, muddying the waters. Researchers are increasingly considering a central role for neuroinflammation in the development of Alzheimer's, a state that may be influenced by dysfunction in T cells outside the brain. Greater neuroinflammation correlates with greater exhibition of neuropsychiatric symptoms in Alzheimer's patients. Earlier viral infection correlates with later dementia risk, and there a growing interest in the question of whether Alzheimer's disease is a consequence of infection-driven inflammation, whether largely viruses or largely bacteria that are found in the brain. The exhaustion of T cells resulting from persistent infection may be a relevant factor here. Herpes zoster vaccination reduces Alzheimer's risk, as is the case for other vaccines, at least in some study populations. Additionally, mitochondrial dysfunction is clearly a feature of neurodegenerative conditions. In Parkinson's disease, damaged mitochondrial DNA may spread between neurons, carrying dysfuntion with it.

The amyloid cascade hypothesis remains dominant in the scientific community, with optimism for the future of therapies to clear amyloid, given emerging evidence for anti-amyloid immunotherapies to slow progression of early stage Alzheimer's. Few other interventions have managed this, but blarcamesine is one of them, and we may at some point find out whether or not senolytics are another. initial results were published from the first senolytic trial for Alzheimer's disease - but there is too little data to draw any conclusion. There is nonetheless plenty of room for minority hypotheses, such as a role for fructose metabolism. Introducing amyloid-specific regulatory T cells has reduced amyloid burden in a mouse model of Alzheimer's disease. Researchers are coming up with novel hypotheses as to how amyloid is causing harm, such as via dysregulation of lysosomal function. Amyloid-β aggregation appears accelerated by demyelination of nerves. VCAM1 and APOE affect amyloid-β burden via microglial clearance efficiency. Immunotherapies to clear amyloid-β are a going concern nowadays, but like all immunotherapies, the side-effects are not to be taken lightly. Further, these therapies are not what we might call cures, having very limited effects on the progression of the condition.

Leakage of the blood-brain barrier is another mechanism by which inflammation can be generated in the brain, as inappropriate cells and molecules cross over into the central nervous system. Age-related changes in the gut microbiome may be a contributing mechanism of this leakage. Researchers are trying to find ways to repair the blood-brain barrier and reduce leakage. There may be other paths of communication by which the immune system outside the brain can drive inflammation in the immune system within the brain.

In other news, tau aggregation may drive neuroinflammation by provoking transposable element activation and cellular senescence, two related states. TDP-43 aggregation and tau aggregation may interact via shared mechanisms. TDP-43 aggregation is one of the more recently discovered forms of protein aggregation in the brain, and has been shown to inhibit regeneration of axons. Microglia undergo changes in aging, and exhibit distinct transcriptomic changes in Alzheimer's disease patients. Inflammatory behavior and senescence in microglia are thought to be important, and impaired autophagy (a popular topic!) may play a role. Other contributions emerge from accumulation of lipofuscin, and the APOEε4 variant, known to influence inflammation, and perhaps the gut microbiome. Once senescent and dysfunction, microglia can harm the brain by lactate production, not just via more direct forms of inflammation. Astrocytes, similarly, also become inflammatory in the aging brain and contribute to neurodegeneration in this way. Further, border-associated macrophages at the edges of the brain may also change their behavior with aging to contribute to neuroinflammation.

Delving into the development of therapies, measures of cognitive function have been improved in aged mice via GlyNAC supplementation, reducing oxidative stress and improving mitochondrial function, via overexpression of TFEB in muscle tissues, and via upregulation of RSG14 in the visual cortex. In old humans, a program to stimulate the olfactory system produced some gains in measures of cognitive performance. Glycogen phosphorylase inhibition via small molecule therapy also improves cognitive function in aged mice. Calorie restriction slows the loss of memory function in old rats. Resistance exercise slows the onset of pathology in mouse models of Alzheimer's disease. Platelet-derived PF4 may be an important mechanism in a number of interventions shown to reduce neuroinflammation. Researchers have tried using hematopoietic stem cell transplantation to treat mouse models of Alzheimer's disease, also with the aim of reducing neuroinflammation. A senolytic vaccine targeting SAGP, a characteristic of senescent cells, has been shown to reduce pathology in a mouse model of Alzheimer's disease. USP30 inhibition halts progression of pathology in a mouse model of Parkinson's disease. Epigenetic reprogramming has been proposed as a treatment for Alzheimer's disease, though there is clearly a great deal of work remaining between this proposal and the reality of a clinical trial.

To deal with protein aggregation, researchers are considering ways to upregulate cell maintenance mechanisms focused on clearance of aberrant proteins. Trying to inhibit formation of amyloid oligomers is also on the table, as are efforts to inhibit phosphorylation of tau. Delivery of soluable ADAM10 inhibits amyloid-β aggregation. In Parkinson's disease, detection of misfolded α-synuclein can identify the earliest stages of the condition. Meanwhile, researchers are working on ways to inhibit that misfolding and aggregation. Icariin supplementation has been shown to be neuroprotective, reducing cell death in the brains of mice.

Inhibition of glycolysis has been proposed to slow the progression of neurodegeneration. More drastically, is it possible that tissue engineering can be applied to parts of the brain, producing new tissues to replace the old? Mitochondrial function declines with age in the brain, and SIRT3 upregulation is considered a possible way to slow this process and consequent neurodegeneration. Other researchers have shown that a tyrosine kinase inhibitor, possibly a senolytic, produces modest benefits in early Alzheimer's patients. Transplantation of stem cell-derived neurons remains a goal in the treatment of Parkinson's disease, with every more sophisticated cell therapies entering clinical trials. Researchers continue to find ways to refine this approach, such as by transplanting regulatory T cells alongside the neurons. It has been shown that transplanted young glial progentior outcompete native aged glial cells in the brain, offering a way to replace dysfunctional cells.

Neurogenesis decreases with age. This is the result of declining neural stem cell activity, but the fine details are somewhat more complex than just a declining supply of immature neurons. One of the approaches to boost neurogenesis is to upregulate BDNF expression, which can be engineered to some degree by fasting and exercise. Senolytic therapies have been shown to improve neurogenesis in aged killifish. Further, mesenchymal stem cell therapy and upregulation of miR-181a-5p expression have been shown to improve neurogenesis and cognitive function in old mice.

Synaptic ultrastructure changes in older individuals and this may induce impaired memory function. Synaptic dysfunction precedes the death of neurons in Parkinson's patients. Axons are damaged in Alzheimer's disease. Synapses may be inappropriately pruned by overactive microglia, and P2Y6R inhibition is an approach to damp down this maladaptive response to an inflammatory environment. Researchers have also tried minocycline treatment and PU.1 inhibition (via a number of approaches) to reduce microglial activation. Clearing microglia from the brain entirely and allowing them to repopulate from progenitor cells is also viable. Upregulation of klotho is another possible approach, demonstrated to improve cognitive function in old non-human primates, as is intermittent fasting. Attempting to upregulate mitochondrial quality control is another avenue. There is clearly a wide variety of research in its early stages underway at the moment.

Amyloidosis Apart from Alzheimer's

There are twenty or so other forms of amyloid, solid deposits resulting from protein misfolding, beyond the very well studied amyloid-β involved in Alzheimer's disease. All are likely to be problematic, and medin is an amyloid with recent evidence indicating that it causes harm. Cellular senescence is likely a contributing factor in the production of medin amyloidosis. For the better studied transthyretin amyloidosis, there is at least the existence of a treatment approved by regulators, and other therapies are under active development and heading into clinical trials. Interestingly, researchers have noted that this condition can spontaneously reverse via immune clearance of transthyretin amyloid. It may be possible to extract patient antibodies as a basis for immunotherapies.

Atherosclerosis and Other Cardiovascular Aging

On a positive note, even without a therapy capable of reversing atherosclerosis, risk of death from heart attack resulting from rupture of atherosclerotic plaque has fallen considerably in the last few decades. Cyclarity is developing a means to bind and clear 7-ketocholesterol and thereby reduce the impact of the toxic atherosclerotic plaque environment on macrophage cells, hoping to shift the balance away from plaque growth. The company is progressing towards clinical trials. Repair Biotechnologies works on clearance of localized excesses of cholesterol more generally via gene therapy to introduce protein machinery into cells capable of this task.

Looking at recent thoughts on other contributions to atherosclerosis: mitochondrial dysfunction; inflammatory signaling is clearly important, such as that produced by macrophages in visceral fat; a high fat diet isn't as direct a contribution as one might imagine, but streptococcus presence in the gut microbiome correlates with plaque burden; ex-T regulatory cells contribute to inflammation in the plaque environment. Researchers are investigating the contribution of lipoprotein(a) to atherogenesis, and trials have started on a therapy to lower levels of lipoprotein(a) in the bloodstream. TREM2 expression influences the dysfunction of macrophages in the development of atherosclerotic lesions.

The decline of the vasculature is characterized by chronic inflammation and endothelial dysfunction. Much of that inflammation arises from the innate immune system. Some of this endothelial dysfunction may arise from CD44 expression. The aging of the vasculature correlates with loss of physical function. Particularly damaged vasculature can form an aneurysm, a physical consequence of many underlying degenerative mechanisms. Angiogenesis declines with age, reducing capillary density, and cellular senescence in the endothelium may be involved in this. This loss of angiogenesis produces loss of capabilities, such as loss of regenerative capacity. It is possible that a better understanding of extracellular matrix aging will be needed to intervene effectively in this age-related decline.

The aging heart is damaged by protein aggregation in addition to the more usually considered mechanisms, such as increased numbers of senescent cells and growing mitochondrial dysfunction. Researchers have found that microbial DNA leaking from the aged intestines provokes harmful inflammation in the heart. In general, cellular stress signaling appears to contribute to ventricular fibrillation.

Looking at existing and proposed avenues for intervention: physical fitness correlates with a lower risk of atrial fibrillation and stroke; PKR inhibition slows vascular aging in mice; rapamycin can reverse diastolic dysfunction in aged mice; while many different approaches to transplantation of cells ands scaffold materials are under development to repair an aged, damaged heart. The longevity associated variant of BPIFB4 reduces heart disease severity, which has some groups thinking about how to turn this knowledge into a therapy. Delivery of extracellular vesicles derived from cardiac progenitor cells improved heart tissue in old mice. Inhibition of fatty acid oxidation improved regeneration in the aged heart. Clearing senescent cells is expected to improve heart regeneration, and delivery of senolytic nanoparticles to atherosclerotic plaque should help there. Suppression of oxidative stress may lead to better tissue maintenance and regeneration in the aging heart. Fisetin supplementation is demonstrated to be senolytic in mice (but not yet humans, robustly) and it improves vascular function in old mice. Adoptive transfer of regulatory T cells may also help treat atherosclerosis by dampening inflammation. FDPS inhibition can restore lost capacity for vascularization in aged tissues. Inhibition of microRNA-206 can suppress atherosclerosis development in mouse models. Finally for this section, semaglutide may reduce the impact of heart failure through mechanisms other than weight loss.

Age-Related Blindness and Presbyopia

A number of groups have worked on breaking cross-links in the lens of the eye to reverse presbyopia. Sadly, the most advanced of these options failed in phase II and the program was shut down. The first therapeutic application of reprogramming is likely to be in the eye. Researchers have shown that reprogramming restores vision in non-human primates with optic neuropathy. Senescent cells, on the other hand, contribute to the degeneration of retinal vasculature and consequent retinopathies.

Cancer

The cancer community is one of the more adventurous portions of the medical research field, for all that few of the adventures make it as far of the clinic. Some items from the past year follow, starting with the note that present approaches to cancer treatment produce an acceleration of biological age, as assessed by epigenetic clocks. This is likely due to an increased burden of senescent cells following therapy. Cellular senescence is a double-edge sword in the matter of cancer, initially protective, but later encouraging tumor growth. Some cancers induce cellular senescence to aid in that growth. Regardless, reducing the burden of senescent cells generated by cancer treatment is expected to improve patient outcomes, and periodically clearing senescent cells throughout life should reduce the risk of cancers that arise from persistent viral infection.

In other news, a meta-analysis sugests that aspirin use modestly reduces cancer mortality, another addition to the continued back and forth over whether and when aspirin use is beneficial. Engineered cancer cells can arouse an immune response, a mirror of the now widely employed CAR-T and other T cell therapies. Those CAR-T therapies can be combined with tumor-seeking bacteria for greater effect. Some researchers have proposed reprogramming cancer cells into antigen-presenting immune cells, to direct the immune system to destroy the tumor. Cancer cell replication can be disrupted by PCNA inhibition, at present the goal of small molecule development programs. Triggering the STING innate immune pathway can suppress metastasis by encouraging the immune system to attack metastatic cancer cells. Engineered macrophages lacking the ability to recognize the CD47 "don't eat me" marker are able to aggressively attack cancers. The gut microbiome appears to be characteristically different in people with precanceous colon polyps, suggesting a path to early detection and prevention.

Epigenetic and Genetic Damage in Aging

Researchers are building new models of epigenetic damage to better understand its role in aging. They are also attempting to further support earlier work suggesting that repair of DNA double strand breaks produces epigenetic changes characteristic of aging. They have produced a mouse lineage in which DNA double strand breaks occur more frequently in non-active areas of the genome, and the resulting accelerated aging argues for the role of this process in aging. Changes in DNA structure make transcription more error-prone, a novel way in which epigenetic change can affect function. Accelerated epigenetic age correlates with cardiovascular risk and aging of the gut microbiome, while centenarians exhibit slower epigenetic aging.

Epigenetic change and mutational damage interact with one another in aging, in ways yet to be fully mapped. Somatic mosiacism is considered important in aging, but researchers are still struggling to produce compelling direct links between this form of spreading mutational damage and specific age-related conditions.

Fibrotic Diseases

The interplay of mechanisms underlying fibrosis is complex and incompletely understood, one of the reasons why it is remains presently largely irreversible. Simple answers may or may not exist, and there is certainly still a role for expanding our knowledge of the underlying biochemistry. Still, if there is one important line item to focus on, senescent cells seem likely to be that line item. Senescent cells can produce lung fibrosis when transplanted into mice, and thus senolytic therapies to clear senescent cells may be a useful approach to the problem. Other avenues for the development of therapies typically involve attempts to disrupt potentially pro-fibrotic regulatory pathways, such as via VGLL3 inhibition.

Hearing Loss

There are many potential contributing causes to the age-related loss of sensory hair cells in the inner ear, or the loss of their connections to the brain. Mitochondrial dysfunction for example, and the related sterile inflammation of aging in the inner ear. Frailty correlates with hearing loss. A range of approaches are underway to attempt regeneration of hair cells, including reprogramming of supporting cells, currently a popular tpoic. Hair cells can, it seems, repair themselves to some degree, so it may be possible to adjust the regulation of that process instead.

Hair Aging

Hair follicles are very complex structures, little mini-organs of many different cell types. This is one of the reasons why there is still no good answer as to which of the many relevant mechanisms are important in the aging of hair. Researchers have implicated impairment in melanocyte stem cell migration in hair graying.

Immunosenescence and Inflammaging, the Aging Immune System

The only way to improve vaccination in the old is to reduce immune dysfunction, and the only way to do that properly is to target the mechanisms of aging that cause that dsyfunction. Many contributing mechanisms feed into the immunosenescence and chronic inflammation of aging, and it remains entirely unclear as to which of them are more or less important: mitochondrial dysfunction, particularly in T cell exhaustion; reduced levels of serum klotho; the accumulation of age-associated B cells; toll-like receptor sensing of molecular damage, leading to maladaptive inflammation; thymic involution; hematopoietic aging leading to increased myeloid cell production; impaired germinal center activity; and the alterations in mitochondrial calcium metabolism that appear important in generating inflammaging.

Nonetheless, many different mechanisms means many different potential avenues for the development of therapies to change the dysfunction of the aged immune system. A few from this past year follow. CASIN treatment produces lasting improvements in hematopoiesis and immune function following a single treatment. Netrin-1 upregulation gives a boost to bone marrow niche cells, also improving hematopoiesis as a result. MicroRNA-7 is a promising target for suppression of maladaptive inflammatory activity. Improving mitochondrial function via delivery of the peptide MOTs-c tends to reduce inflammatory signaling. Inhibition of IL-1 signaling can improve hematopoietic and immune function in aged mice. Inhibition of miR-141-3p reduces age-related inflammation in mice. Interfering in the STING pathway in selective ways may also prove to be a useful approach to excessive age-related inflammation. Senolytic therapies may be a viable strategy to improve late life immune function. Urolithin A supplementation improves hematopoiesis in mice.

Regrowth of the thymus remains a much desired goal. The thymus atrophies by middle age, and low thymic function correlates with a sizable increase in late life mortality. While thymus structure is more plastic to lifestyle interventions than suspected, more than good health practices are needed. The new company Thymmune Therapeutics intends to mass produce cells that can home to the thymus, offering the potential for regeneration and renewed T cell production. Another research team improved on a FOXN1-TAT fusion protein approach, allowing intravenous delivery with uptake in the thymus to enourage growth of active tissue. Still others are looking at recellularization of donor thymus tissue.

Intestinal and Gut Microbiome Aging

The gut microbiome ages in ways that contribute to inflammation and degenerative aging, such as via the production of fatty acids that increase neuroinflammation, or valeric acid to boost inflammatory cytokine expression. Pigs are now being put forward as a model to investigate these links. Centenarians and other long-lived individuals appear to have uniquely beneficial gut microbiomes, and are thus becoming a useful source of comparative data.

Reversing age-related harmful changes in the gut microbiome is becoming an important area of research, even if some research stops at probiotics and prebiotics. Probiotics and prebiotics in their present form are essentially ineffective in this context. Fecal microbiota transplant, on the other hand, is shown to rejuvenate the gut microbiome and improve muscle and skin function, among other health measures, in mice. Researchers are considering its application in human medicine, for example to slow cognitive decline, among other possibilities. Time restricted feeding may also help to reverse age-related changes in the microbiome. Researchers are also considering genetic engineering of gut microbes as a form of advanced probiotic therapy.

Intestinal barrier dysfunction is a feature of aging in many species. Intestinal inflammation increases with age, likely in a bidirectional relationship with barrier leakage. Senescent cells and inflammatory signaling in general are involved in reduced intestinal tissue function, while long-term exercise and physical fitness reduces markers of senescence in intestinal tissue. Looking at intestinal barrier cells, ribosomal stress appears with aging and dysfunction, offering another possible avenue of investigation.

The Aging Kidney and Urinary System

Kidney disease, or even loss of kidney function leading into chronic kidney disease, appears to fairly directly contribute to forms of neurodegeneration such as Alzheimer's disease. Of the contributions to declining kidney function, mitochondrial dysfunction appears important, and mitochondrial transplantation is proposed as a treatment for kidney damage. As for all tissues, there is also a sizable role for age-related chronic inflammation. Changes in the gut microbiome may affect the kidney by contributing to this inflammation. The rest of the urinary system receives comparatively little attention in the context of aging, but researchers have proposed D-mannose treatment as way to improve bladder function by suppressing cellular senescence.

The Aging Liver

Non-alcoholic fatty liver disease (NAFLD) isn't widely thought of as an age-related condition, but it absolutely is. The mechanisms of aging make it ever easier to suffer this condition at a given weight as the years go by. Resolvin D2 treatment affects production of monocytes and macrophages, and has been shown to slow liver aging in mice.

Muscle Aging Leading to Sarcopenia and Frailty

Sarcopenia is a complex condition with many possible contributing causes that drive the loss of muscle mass and strength that leads to frailty. Decline in neuromuscular junctions and innervation of muscle seems important, and researchers have examined the role of Schwann cells in this degeneration. Mitochondrial dysfunction is one contributing cause thought to be important. Obesity raises the risk of frailty. Increased remnant cholesterol level in the bloodstream, increased CAP2 expression, and increased serum galectin-3 also correlate with frailty risk. Aged muscles exhibit a disruption of the timing of gene expression during maintenance and regeneration, a contribution to declining function.

The production of treatments for sarcopenia is very much an active area of development. Some researchers argue for adapting existing treatments for osteoporosis, on the grounds that targeted underlying mechanisms may be shared. In the category of potentially bad ideas, reversine appears to allow muscle cells to escape cellular senescence and continue function and replication. Clearance of senescent cells, on the other hand, has fewer associated concerns, and improves muscle growth and regeneration in old mice. Minicircle has run an informal trial outside the US of a gene therapy to upregulate follistatin and provoke muscle growth. Calorie restriction improves muscle stem cell activity and muscle quality in old age, which may go some way to explaining the slowing of sarcopenia observed in animal models subjected to calorie restriction. Another possible reason why calorie restriction may have this effect is via lowered dietary phosphate intake. MANF upregulation in macrophages of the innate immune system and angtiotensin (1-7) protein therapy can improve muscle regeneration in old mice. NT-3 gene therapy can improve muscle function in old mice, while ATF4 knockout slows the loss of strength and endurance with age. Similar, PGC1α4 overexpression reduces sarcopenia and metabolic disease in mice. Inhibiting VPS-34 expression in neuromuscular junctions slows the age-related loss of motor function in nematodes and mice.

Osteoarthritis and Degenerative Disc Disease

Extracellular matrix stiffening contributes to osteorthritis and cartilage degeneration. Excess visceral fat generates inflammatory signaling that contributes to osteoarthritis. Researchers have tested an anti-inflammatory cell therapy that appears to provoke regeneration in mice and humans. Extracellular vesicles can also be used to modulate inflammation in this and other contexts. The use of scaffold material to encourage bone and cartilage regrowth is an area of active development. FGF18 treatment expands stem cell populations in joint cartilage, recoverying structure and reducing osteoarthritis.

Cellular senescence appears important in the aging of bone tissue, particularly the presence of senescent mesenchymal stem cells. Ceria nanoparticles have been shown to reduce the impact of senescent cells in osteoarthritic joints. On this topic of senescent cells, more than a decade after researchers showed that osteoarthritis patients taking bisphosphantes exhibited a five year life extension versus controls, the research community is still debating whether or not zoledronate, a commonly used bisphosphone, is a senolytic drug to any meaningful degree.

Cellular senescence is also implicated in the onset and progression of degenerative disc disease. Exosomes have been shown to reduce inflammation in the same way as first generation stem cell therapies, and so are a potential treatment.

Osteoporosis

There is a correlation between gut microbiome aging and loss of bone density. Senescent cells contribute to the aging of bone, a topic that is increasingly explored these days. Researchers have shown in mice that local clearance of senescent cells isn't as effective as global clearance in improving osteoporosis, much as expected. Most therapies for osteoporosis try to remove the inbalance between osteoblast and osteoclast activity. KDM5C inhibition suppressed osteoclast activity to reduce bone density. Scaffold materials aimed at accelerating bone regeneration following injury may have some application to aged bone, however. The same is true of gene therapy to upregulate VEGF and Runx2, which speeds bone regeneration. Disabling notch signaling in skeletal stem cells has been shown to improve bone density in mice.

Skin Aging

Skin is negatively impacted in many ways by the growing presence of senescent cells with aging, particularly senescent fibroblasts, and that may include even the earliest examples of skin aging, as young as the 20s and 30s. Senotherapeutics are certainly high on the list of potential future therapies to treat skin aging. Skin heals more reluctantly with age, and many individual mechanisms contribute to this decline. Implanting hair follicle cells can remodel scar tissue, however. Other mechanisms relevant to skin aging include increased levels of pro-inflammatory IL-17.

The skin is an interesting target for gene therapies, given its accessibility versus the challenges inherent in delivery of gene therapies to deeper locations in the body. One team has developed a LNP-mRNA approach to increase collagen expresson in aging skin. Another delivered reprogramming factors via AAV to ensure the generation of new hair follicles and sweat glands during wound healing. Relatedly, HOXA3 upregulation via gene therapy accelerates wound healing in old mice.

Aging of Teeth and Gums

Researchers continue to work on regeneration of teeth and important components of teeth, such as enamel and dental pulp. Meanwhile, it has been shown that senescent cells contribute to chronic periodontitis, which can in turn provoke harmful activation of microglia in the brain. The bacterial involved in gingivitis can enter the bloodstream and cause harm elsewhere in the body, such as impairing already poor regeneration in the heart.

Type 2 Diabetes and Other Metabolic Dysfunction

Senescent cells are thought to contribute to type 2 diabetes. Clearing senescent cells has been shown to treat type 2 diabetes and more broadly reduce inflammatory metabolic dysfunction in aged mice.

Looking Forward to 2024

And that was that! To some degree the distribution of conditions reflects my own biases regarding what is interesting, but one still gets a sense of what the research community devotes its time to in the context of aging. Looking forward, there are signs that the market and biotech industry will become more energetic in the year ahead, and funding more readily available. That will set the stage for the next few years of human clinical trials, generating initial data for a wide range of novel therapies that have been under development in recent years. Interesting times lie before us, as ever more people realize that treating aging as a medical condition is both viable and imminent, and more large, instititional sources of funding turn their attention to this endeavor. Think about how you can help!

The ovaries, like the thymus, are interesting for their comparatively early exhibition of age-related degeneration. Is there anything useful that can be learned about aging more generally by looking at the portions of the body that experience aging more rapidly? That remains to be seen. Here, researchers investigate NAD+ metabolism in the ovaries versus other tissues, noting that CD38, an enzyme that removes NAD+, is more active earlier in life. Approaches to maintain NAD+ levels slow ovarian aging, including knocking out CD38.

Delayed childbearing is prevalent worldwide, and ovarian senescence occurs earlier than most of the other organs in females. Ovarian function decreased dramatically in middle age, as shown by a decrease in oocyte quality and ovarian reserve. We hypothesized that middle-aged mice may be useful for investigating the molecular mechanisms underlying ovarian senescence. Our study showed the transcriptome changes that occur in the ovaries of middle-aged mice when many other organs showed no aging-related gene changes. In particular, gene transcripts in aging-related pathways, including the senescence-associated secretory phenotype (SASP), cell cycle, inflammation, and DNA repair, were misregulated in the ovary but not in multiple other organs when comparing middle-aged with young mice. Indeed, increased expression of aging markers, namely, p16 and p21, and inflammation-related factors was observed in the ovary but not in other organs from middle-aged mice. Our findings are consistent with a report classifying the aging-associated alterations in gene expression patterns of different tissues into four stages with ovarian aging occurring in 6-month-old to 12-month-old mice, which is earlier than for most of the other organs.

Importantly, the current study showed that the expression of inflammation-related genes rapidly increased in the middle-aged ovary, accompanied by activation of the NAD+ metabolizing enzyme CD38, whereas other key enzymes for NAD+ generation and metabolism were not changed in the ovaries from middle-aged mice. The activation of CD38 and inflammation-related transcripts was not observed in other organs. A previous study showed that CD38 levels increased in the liver, adipose tissue, spleen, and skeletal muscle in aged (approximately 18-month-old) mice, indicating that the increases in CD38 expression during middle age are likely a key event during ovarian senescence. We and several groups have reported that ovarian NAD+ levels decline during aging, whereas boosting NAD+ by supplementation with NAD+ precursors, such as nicotinamide riboside or nicotinamide mononucleotide, increased ovarian NAD+ levels and delayed ovarian aging by improving mitochondrial function. The present work found that deletion of CD38 prevented ovarian NAD+ decline, extended ovarian lifespan and resulted in increased litter sizes in aged mice. Importantly, increased ovarian follicle reserve was found in aged Cd38-/- mice compared with wild-type mice. Consistent with these findings, higher levels of serum anti-Mullerian hormone and decreased cell DNA damage and apoptosis were observed in the ovarian follicles of Cd38-/- mice than in those of age-matched wild-type mice.

Link: https://doi.org/10.1038/s43587-023-00532-9

Finding out exactly how some species can regenerate lost body parts without loss of function may provide means to enhance human regeneration, and possibly also tissue maintenance in old age. It is too early to say whether gains are possible in the near future, or whether introducing new capacities into human biochemistry in this way will prove to be a very hard task. Most research into exceptional regenerative capabilities is focused on salamanders and zebrafish, with some work going into the basis for unusual mammalian regeneration such as that exhibited by MRL mice and African spiny mice. These are not the only highly regenerative species, however, and here researchers discuss the biochemistry of regeneration in a species of small jellyfish.

Blastema formation is a crucial process that provides a cellular source for regenerating tissues and organs. While bilaterians have diversified blastema formation methods, its mechanisms in non-bilaterians remain poorly understood. Cnidarian jellyfish, or medusae, represent early-branching metazoans that exhibit complex morphology and possess defined appendage structures highlighted by tentacles with stinging cells (nematocytes). Here, we investigate the mechanisms of tentacle regeneration, using the hydrozoan jellyfish Cladonema pacificum.

We show that proliferative cells accumulate at the tentacle amputation site and form a blastema composed of cells with stem cell morphology. Experiments indicate that most repair-specific proliferative cells (RSPCs) in the blastema are distinct from resident stem cells. We further demonstrate that resident stem cells control nematogenesis and tentacle elongation during both homeostasis and regeneration as homeostatic stem cells, while RSPCs preferentially differentiate into epithelial cells in the newly formed tentacle, analogous to lineage-restricted stem/progenitor cells observed in salamander limbs. Taken together, our findings propose a regeneration mechanism that utilizes both resident homeostatic stem cells (RHSCs) and RSPCs, which in conjunction efficiently enable functional appendage regeneration, and provide novel insight into the diversification of blastema formation across animal evolution.

Link: https://doi.org/10.1371/journal.pbio.3002435

Bloodless, heartless calculations of the value of your life are constantly taking place behind the curtains that society politely draws over some of the uglier realities of the human condition. Interactions with insurance companies might be the most visible signs of these calculations, but this is the tip of the iceberg. Humans assign value instinctively; to value is to be human. We don't just value objects, we value our lives, we value the lives of others. Based on an analysis of our actions, i.e. revealed preferences, one can estimate monetary equivalents to those life valuations and how they shift with time and circumstances. These estimates are produced constantly, and widely used in policy and industry circles, whether or not we might agree with them.

For all that it makes many people uncomfortable, this is an interesting topic, and one that can help in understanding why it is that the powers that be behave as they do in circumstances involving aging, medical research, medical regulation, centralized control of medical services, entitlements, and so forth. It is, I suspect, considerably easier to harness technological progress in order to reduce the cost of intervening to save a life or improve a life than it is to change human nature such that life and quality of life is valued more highly. We do not live in a perfect world, but we can at least work to make it better!

Valuing life over the life cycle

The COVID-19 pandemic has been associated with considerable economic and personal tolls. Two of the motivations often invoked to justify these interventions have been (i) the collective duty to protect society's most vulnerable members, and (ii) the consequences of pandemic-driven excess demand for medical care. The allocation of scarce medical resources in situations of excess demand for life support raised the specter of uncomfortable medical triage decisions between saving one person against another.

These considerations highlight the fundamental questions of (i) how to value longevity in general and how to adjust this value to account for (ii) the personal characteristics such as age, health, labor market and financial statuses, as well as (iii) the characteristics of the changes in death risk (e.g. magnitude, beneficial vs detrimental, permanent vs temporary, longevity mean vs variance). Indeed, the substantial costs to society of COVID-19 measures should be contrasted with the presumably large economic value of those lives saved by intervention. Moreover, the reallocation of such consequential financial and medical resources to the pandemic raises the issue of the long-term arbitrage of addressing a single illness at the potential expense of others. Put more bluntly, the delicate question of which lives should be prioritized - contemporary COVID-19 infected vs other current or future illnesses, young vs old, healthy vs unhealthy, rich vs poor - was brutally unearthed by the pandemic.

Addressing the first question of life value measurement involves proxying the (non-marketed) value of longevity through a theoretical (shadow) price. A natural candidate is the marginal rate of substitution (MRS) between additional life/mortality and wealth which, at the optimum, will capture the relative price of longevity. A second related alternative is the maximal willingness to pay (WTP) or the minimal willingness to accept compensation (WTA) for changes in life expectancy. The Value of a Statistical Life (VSL) is an infra-marginal approximation to the MRS that sums the willingness across agents to calculate an aggregate WTP or WTA to save someone, i.e. an unidentified (statistical) member of the community. Personalized life values can be assessed from the market value of an agent's foregone net revenues such as in the Human Capital (HK) value. Despite its usefulness in wrongful death litigation, the HK value is arguably less relevant for non-working (e.g. retired or disabled) agents, and therefore imperfectly applicable for society's more vulnerable members. Identified values can alternatively be recovered from the agent-specific MRS, WTP and WTA. An extreme example, potentially useful in both litigation and terminal care decisions, is a person's two Gunpoint (GPV) values: her willingness to pay to prevent and to receive compensation to accept imminent and certain death which gauges a specific person's willingness to save or lose her own life.

Secondly, adjusting identified life values for personal characteristics involves charting how ageing processes (e.g. the life cycles of wages, morbidity, and mortality risks, and finite biological longevity bounds), quality of life (e.g. health status, mix between market activities such as consumption and non-market ones, such as leisure) and disposable resources (financial wealth, labor income) affect an agent's shadow price of longevity. Third, since life values are to be inferred from changes in death risk exposure, the distributional characteristics of these changes are relevant. Indeed, whether the changes correspond to small or large, temporary or permanent increases or decreases in mortality risk and whether those changes affect the mean and/or the variance of longevity will alter the individual and societal willingness measures, and therefore the degree of substitution between personalized lives. For example, how do we compare the possibly large contemporary beneficial gains of intervention on the survival outcomes of currently infected persons versus the possibly small, but long-term detrimental increases in the risk of dying of agents whose interventions have been postponed is certainly relevant to both groups and to society as a whole.

In the model of Revealed Preferences presented in this paper, ageing is associated with (i) lower WTP/WTA per given change in death intensity, but (ii) higher willingness per given change in expected longevity. Indeed, the combined influence of falling wages, increased morbidity and mortality risks exposures and eroding remaining horizon imply falling net total wealth. Moreover, increasing mortality risks induces lower marginal (and therefore continuation) utility, although the mortality effects are dampened by age. Finally, the longevity returns of changes in survival fall in age, i.e. elders require much larger mortality changes to attain a given change in expected longevity. The combination of the three factors induces a lower willingness for changes in survival risk, but a higher willingness for expected longevity changes for older agents. The WTP to avoid certain imminent death falls from 1.75 M$ at 25 to 1.15 M$ at 65, whereas the WTA to accept death is unsurprisingly higher and falls from 4.13 M$ at 25 to 1.92 M$ at 65. Conversely, the WTP/WTA associated with changes in expected longevity increase in age, although the effects of ageing are weaker. The WTP per additional life-year through one-shot changes thus increases from 211 K$ at age 25 to 220 K$ at age 65.

T cells of the adaptive immune system do find their way into the brain to some degree, even given the existence of the blood-brain barrier that separates the brain from the vasculature. Researchers here report on an effort to engineer regulatory T cells to recognize amyloid-β, associated with the onset of Alzheimer's disease. In an animal model of Alzheimer's disease, mice engineered to generate amyloid-β aggregates, these engineered regulatory T cells reduced the resulting pathology by migrating into the brain and dampening the maladaptive inflammatory responses characteristic of neurodegenerative conditions.

Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCRAβ).

TCRAβ-Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCRAb identified from Aβ reactive effector T cells. Adoptive transfer of TCRAβ-Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes.

TCRAβ-Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCRAβ-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18F-fluorodeoxyglucose radiolabeled TCRAβ-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions.

Link: https://doi.org/10.1186/s13024-023-00692-7

Researchers here demonstrate that administration of angiotensin (1-7) protein to injured muscles in mice provokes improved regeneration of muscle tissue. Protein therapies are an expensive proposition at this point in time, so the usual approach for research of this nature is to look for a small molecule that upregulates expression of the desired protein. That said, gene therapies are looking ever more promising for any use case in which the objective is to increase levels of a circulating protein. Only a small number of cells, such as subcutaneous fat cells, need to be transfected via an injected therapy in order to produce a factory to generate that protein. That is a feasible goal if using presently available, well-established gene therapy technologies.

Skeletal muscle possesses regenerative potential via satellite cells, compromised in muscular dystrophies leading to fibrosis and fat infiltration. Angiotensin II (Ang-II) is commonly associated with pathological states. In contrast, Angiotensin (1-7) [Ang-(1-7)] counters Ang-II, acting via the Mas receptor. While Ang-II affects skeletal muscle regeneration, the influence of Ang-(1-7) remains to be elucidated. Therefore, this study aims to investigate the role of Ang-(1-7) in skeletal muscle regeneration.

C2C12 muscle cells were differentiated in the absence or presence of 10 nM of Ang-(1-7). The diameter of myotubes and protein levels of myogenin and myosin heavy chain (MHC) were determined. C57BL/6 wild-type male mice (16-18 weeks old) were randomly assigned to injury-vehicle, injury-Ang-(1-7), and control groups. Ang-(1-7) was administered via osmotic pumps, and muscle injury was induced by injecting barium chloride to assess muscle regeneration through histological analyses. Moreover, embryonic myosin (eMHC) and myogenin protein levels were evaluated.

C2C12 myotubes incubated with Ang-(1-7) showed larger diameters than the untreated group and increased myogenin and MHC protein levels during differentiation. Ang-(1-7) administration enhances regeneration by promoting a larger diameter of new muscle fibers. Furthermore, higher numbers of eMHC (+) fibers were observed in the injured-Ang-(1-7), which also had a larger diameter. Moreover, eMHC and myogenin protein levels were elevated, supporting enhanced regeneration due to Ang-(1-7) administration. Ang-(1-7) effectively promotes differentiation in vitro and improves muscle regeneration in the context of injuries, with potential implications for treating muscle-related disorders.

Link: https://doi.org/10.4081/ejtm.2023.12037

Taurine is a semi-essential amino acid. Dietary taurine supplementation has been shown to modestly slow aging in mice, though as for all such interventions there is always the question of whether it will prove to be less useful in humans, and also whether these results in mice will be disproved by the much more rigorous Interventions Testing Program (ITP), once that group gets around to assessing taurine supplementation. Few of the numerous interventions thought to modestly slow aging in mice on the basis of earlier research actually held up once subjected to the ITP degree of experimental rigor.

Speculatively, taurine may produce its benefits by affecting levels of the antioxidant glutathione. More research is needed on this topic, but if confirmed it would make taurine supplementation more interesting given the benefits produced in a human trial of supplementation with glutathione precursors. The benefits observed in that trial were large for a supplementation approach, and might improve on exercise - though one has to mention that the trial was small, and that benefits to patients tend to diminish in size as trial populations increase.

In today's open access review, researchers discuss what is known of the effects of taurine supplementation on metabolism. As one might imagine, effects are broad and varied, and little to nothing is known of the relative importance any specific effect when it comes to a potential contribution to slowed of aging. This is par for the course: the research community knows far too little of the fine details of cell metabolism and its adjustment in the context of aging. In the bigger picture this line of research is only interesting because taurine is cheap and readily available. This is generally true for any intervention that produces benefits that are in the same ballpark as those resulting from exercise. As soon as one proposes that years of research must be conducted on top of that, well, people should exercise more than they do, and there are far more useful programs that could be conducted with that funding.

Flattening the biological age curve by improving metabolic health: to taurine or not to taurine, that's the question

Taurine is not used by the body for protein synthesis and exists in higher concentrations in energy-demanding organs, such as the brain, retina, heart, pancreas, and skeletal muscles, but its abundance almost invariably reduces as animals and humans age. Interestingly, blood taurine levels can also be increased, at least temporarily, after a short period of exercise, with some authors suggested that taurine may play a causal role in explaining why exercise is beneficial to human metabolic health by mediating atheroprotection. At the organ function level, taurine has also been reported to improve bone, retinal, and brain health in animal studies; and furthermore, in small human studies, improvements in glycemic control, exercise endurance and myocardial function after taurine supplementation have been reported.

The mechanisms by which taurine may improve cellular and organ function or health in general are likely multiple, and not necessarily restricted to its direct actions. Specifically, some of the long-term benefits of taurine are believed to be mediated through its interactions with gut microbiome and bile acid conjugation, both of which are currently believed to play a pivotal role in maintaining human health. For instance, at least one of taurine's conjugated bile acids has been shown to stimulate colonic secretion of glucagon-like-peptide 1 (GLP-1) through activation of the Takeda-G protein-coupled-receptor 5. Taurine is also needed to conjugate fatty acids to form N-acyl taurines in the liver, which have been shown to mediate release of GLP-1. The association between GLP-1 release and taurine supplementation has potential important clinical implications as the use of GLP-1 receptor agonists is now widely accepted as an effective metabolic therapy for patients with diabetes mellitus and people who are overweight. Furthermore, both taurine and taurine-conjugated bile acids (e.g., tauroursodeoxycholic acid - TUDCA) may directly activate insulin receptors (IRs) by binding to docking sites not related to the insulin binding sites on the IRs, thereby improving glucose homeostasis and the other cellular functions related to IRs, including IRs in the brain.

Calorie restriction (CR) has been consistently shown to improve metabolic health and longevity in a wide range of animal species and taurine acts biologically as a CR mimetic. Mechanistically, CR could alter gut microbiome through which it would increase the intestinal levels of taurine and taurine-conjugated bile acids; and transplantation of microbiota from mice with CR to ad libitum fed mice triggered CR-like changes in levels of taurine and taurine conjugates in the mucosa of the ileum. Therefore, there is a strong scientific basis to support the hypothesis that taurine supplementation could improve long-term metabolic health, including optimizing blood glucose control and HbA1c levels, through multiple biologically plausible mechanisms. Because HbA1c has a dose-related positive relationship with long-term all-cause mortality, cardiovascular mortality, and cardiovascular events in both diabetic and non-diabetic individuals, determining whether taurine can improve long-term plasma glucose control, as reflected by HbA1c, has considerable clinical importance.

Specific to the heart, taurine and TUDCA have also been shown to offer some benefits, including improvements in myocardial contractility and exercise capacity of cardiovascular testing, tolerance to ischemia, and a reduction in QT interval, cardiac arrhythmias, blood pressure, trimethylamine N-oxide (TMAO) induced atherosclerosis, and blood lipid levels including the low-density-lipoprotein (LDL) concentration in both individuals with and without diabetes mellitus. Maintaining a long-term normal LDL level is associated with a decreased risk of coronary artery disease and stroke. A large prospective multinational observational study had indeed showed that a high excretion of taurine in the urine (implying a high dietary intake of taurine) had significantly lower body mass index, systolic and diastolic blood pressure, total cholesterol, and atherogenic index (defined as total cholesterol / high-density-lipoprotein [HDL]-cholesterol in this study) than those who had a lower urinary taurine excretion. Similarly, a recent observational study showed that having a low plasma taurine level was associated with an increased risk of developing metabolic syndrome within 5 years. Taken together, epidemiological data suggest that a low taurine intake may increase an individual's susceptibility to cardiovascular and metabolic diseases; and conversely, a high dietary taurine intake may play a pivotal role in maintaining both long-term cardiovascular and metabolic health.

A growing body of evidence points to a significant role for senescent cells in the aging of skin, including the work of some researchers who believe that changes that occur in skin over early adult life may be influenced by the presence of senescent cells. Skin is a large organ and its state of inflammation does influence the rest of the body. It remains to be seen as to whether presently available senolytic therapies can produce a meaningful effect on the burden of senescent cells in skin, and to what degree that will affect manifestations of skin aging in humans.

Skin aging is characterized by changes in its structural, cellular, and molecular components in both the epidermis and dermis. Dermal aging is distinguished by reduced dermal thickness, increased wrinkles, and a sagging appearance. Due to intrinsic or extrinsic factors, accumulation of excessive reactive oxygen species (ROS) triggers a series of aging events, including imbalanced extracellular matrix (ECM) homeostasis, accumulation of senescent fibroblasts, loss of cell identity, and chronic inflammation mediated by senescence-associated secretory phenotype (SASP).

These events are regulated by signaling pathways, such as nuclear factor erythroid 2-related factor 2 (Nrf2), mechanistic target of rapamycin (mTOR), transforming growth factor beta (TGF-β), and insulin-like growth factor 1 (IGF-1). Senescent fibroblasts can induce and accelerate age-related dysfunction of other skin cells and may even cause systemic inflammation. In this review, we summarize the role of dermal fibroblasts in cutaneous aging and inflammation. Moreover, the underlying mechanisms by which dermal fibroblasts influence cutaneous aging and inflammation are also discussed.

Link: https://doi.org/10.1111/acel.14054

The set of neurodegenerative diseases characterized by aggregation of altered tau protein are collectively known as tauopathies. Alzheimer's disease is the best known of these conditions. The later stage of Alzheimer's disease, in which cell death is widespread, is characterized by tau aggregation and chronic inflammation of brain tissue. As noted here, how exactly tau alteration and aggregation causes dysfunction is still an active area of research that may result in ways to sabotage the progression of tauopathies.

Tauopathies are characterized by the buildup of tau inside the brain. Alzheimer's disease is well known, but there are many other tauopathies, including frontotemporal lobar degeneration, progressive supranuclear palsy, and chronic traumatic encephalopathy. These diseases typically present as dementia, personality changes and/or movement problems. "A lot of fantastic research has been done to learn how toxic tau spreads from neuron to neuron in the brain, but very little is known about exactly how this toxic tau damages neurons, and that question is the motivation for our new paper. The toxic tau described here is actually released from neurons, so if we can figure out how to intercept it when it's floating around in the brain outside of neurons, using antibodies or other drugs, it might be possible to slow or halt progression of Alzheimer's disease and other tauopathies."

Researchers discovered that tau oligomers - assemblages of multiple tau proteins - can have dramatic effects on the normally smooth shape of neuronal nuclei. The oligomers cause the nuclei to fold in on themselves, or "invaginate," disrupting the genetic material contained within. The physical location and arrangement of genes affects how they work, so this unnatural rearrangement can have dire effects. "Our discovery that tau oligomers alter the shape of the nucleus drove us to the next step - testing the idea that changes in gene expression are caused by the nuclear shape change. That's exactly what we saw for many genes, and the biggest change is that the gene for tau itself increases its expression almost three-fold. So bad tau might cause more bad tau to be made by neurons - that would be like a snowball rolling downhill." The researchers found that patients with Alzheimer's disease had twice as many invaginated nuclei as people without the condition. Increases were also seen in lab mice used as models of Alzheimer's and another tauopathy.

Link: https://www.eurekalert.org/news-releases/1029540/a>

Senescent cells are created throughout the body at all stages of life, largely when somatic cells reach the Hayflick limit on replication. Senescent cells cease replication and begin to energetically produce pro-growth, pro-inflammatory factors, attracting the attention of the immune system and otherwise changing the behavior of surrounding cells. Cell stress and mutational damage can induce senescence, and in this case senescence is a mechanism that acts to limit the risk of cancer. Tissue injury also produces senescent cells, and here they help to coordinate the activities of the many different cell types that become involved in the complex process of regeneration.

In youth, senescent cells are promptly destroyed, either through programmed cell death mechanisms, or by attracting the attention of immune cells. In later life, the immune system becomes less efficient in its task of clearing senescent cells. This leads to a growing burden of lingering senescent cells. While the signals generated by senescent cells are useful in the short-term, when sustained over the long-term they become disruptive to tissue structure and function, contributing to the chronic inflammation of aging. Researchers are coming to see the inflammation of aging as an important mechanism in the aging of the brain and the onset of neurodegenerative conditions, and so attention is turning, slowly, to whether clearance of senescent cells is a viable treatment for Alzheimer's disease, Parkinson's disease, and other paths to dementia.

Cellular senescence in brain aging and cognitive decline

The mechanisms underlying brain aging have garnered significant attention due to the significant number of patients suffering from dementia and Alzheimer's disease (AD). The cost of managing these patients exceeds that of cancer and cardiovascular disease patients combined. Importantly, however, cognitive decline is observable in individuals without AD or overt neurodegenerative changes. Age-related mild cognitive impairment (MCI) and late-onset AD can be mechanistically explained by processes governing biological aging. Currently, 12 biological aging hallmarks have been identified: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, altered nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, altered intracellular communication, cellular senescence, disabled macroautophagy, chronic inflammation (i.e., inflammaging), and gut microbiome dysbiosis. The geroscience hypothesis posits that age-related diseases arise from the cumulative effects of these biological aging hallmarks and that targeting them constitutes an avenue to ameliorate age-related diseases.

Cellular senescence describes a state of cell cycle arrest accompanied by characteristic morphological, cellular, and molecular changes. Studies using pharmacological targeting of senescent cells (SCs), transplanting SCs, and transgenic mouse models have demonstrated a causal relationship between SC accumulation and age-related tissue dysfunction, with addition of SCs being shown to accelerate aging phenotypes on the one hand and clearance being shown to alleviate them on the other. In the brain, SCs become more abundant with aging in mice, which is associated with cognitive decline, and their depletion mitigates neuroinflammation and delays cognitive decline.

This review explores the association between cellular senescence and age-related cognitive decline. We also discuss how cellular senescence may underlie cognitive decline in different patient populations that exhibit a premature brain aging phenotype. These patients include cancer survivors, traumatic brain injury (TBI) patients, obese individuals, obstructive sleep apnea (OSA) patients, and chronic kidney disease (CKD) patients. Understanding the role of senescence in cognitive decline is essential, especially considering the rapidly evolving field of senotherapeutics. Targeting SCs could mitigate early brain aging and reduce a significant burden on patients, healthcare systems, and society.

Osteoporosis is the loss of bone strength and density, while sarcopenia is the loss of muscle mass and strength. Both of these are near universal in the aging population, the only question being when they rise to the level of frailty. Researchers have noted mechanistic connections between these two conditions, and some data suggests that osteoporosis treatments can improve sarcopenia. Is there a path leading from current osteoporosis medications to therapies that can slow the progression of sarcopenia? That would likely require more dedicated research and development programs than are currently taking place, and it is unclear as to whether the outcome would be better than a continuation of present independent efforts to find therapies to treat sarcopenia.

Sarcopenia is a progressive and systemic skeletal muscle disorder associated with aging that usually occurs with age in the elderly. Sarcopenia currently lacks effective pharmacological treatment modalities. Multiple pharmacological intervention modalities are available for osteoporosis, a comprehensive disease characterized by decreased systemic bone mass, degradation of bone microarchitecture, and increased bone fragility. Several recent studies have shown an extremely strong correlation between sarcopenia and osteoporosis, leading to the concept of "osteosarcopenia". Therefore, it is possible to alleviate sarcopenia simultaneously by improving osteoporosis.

There are still no drugs for sarcopenia that can be effectively treated, and as the aging society progresses, it is crucial to find a treatment for sarcopenia. Current studies have shown conflicting results between anti-osteoporosis treatment and improvement of sarcopenia, with some drugs relying on a common pathway between the bone and muscle to improve sarcopenia alongside anti-osteoporosis treatment, such as denosumab and tibolone. Multiple mechanisms could explain the improvement in sarcopenia after anti-osteoporosis treatment.

Current evidence suggests that denosumab binds to RANKL and antagonizes the negative regulatory effect of RANKL on myocytes, while tibolone binds to oestrogen receptors in muscle and directly increases muscle anabolism. Furthermore, in addition to the common pathway, it does not mean that bone is negligible, through the effect of the paracrine bone factors on skeletal muscle. In conclusion, the current study suggests that anti-osteoporotic therapy offers a lasting and easy to use program for patients with sarcopenia in general.

Link: https://doi.org/10.1097/MS9.0000000000001352

GLP-1 receptor agonists such as semaglutide are suddenly a popular topic in the pharmaceutical industry. They alter metabolism to produce weight loss and improve the dysregulation that is characteristic of type 2 diabetes. Like any newly popular drug category, GLP-1 receptor agonists will now be assessed for their ability to produce marginal benefits in all sorts of conditions, from cancer to heart failure. Given that excess visceral fat is harmful, it is plausible that any marginal benefits will emerge largely or entirely due to weight loss in initially overweight patients. With that in mind, researchers here produce data in mice to argue that, at least in the case of heart failure, there are other mechanisms involved.

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes.

In a mouse model of HFpEF that was caused by advanced aging, female sex, obesity, and type 2 diabetes mellitus, semaglutide, compared with weight loss induced by pair feeding, improved the cardiometabolic profile, cardiac structure, and cardiac function. Mechanistically, transcriptomic, and proteomic analyses revealed that semaglutide improved left ventricular cytoskeleton function and endothelial function and restores protective immune responses in visceral adipose tissue.

Strikingly, treatment with semaglutide induced a wide array of favorable cardiometabolic effects beyond the effect of weight loss by pair feeding. Glucagon-like peptide-1 receptor agonists may therefore represent an important novel therapeutic option for treatment of HFpEF, especially when obesity-related.

Link: https://doi.org/10.1016/j.jacbts.2023.05.012

Today I'll point out an opinion piece on how to get drugs to treat aging into the clinic as fast as possible. This is a moderately conservative viewpoint, focused on what will most rapidly produce the necessary regulatory changes to allow approval of new therapies specifically for the treatment of aging. At present regulators will only approve therapies to treat specific diseases of aging. The present focus of the industry is to produce treatments for specific age-related disease based on underlying technologies that target one or more mechanisms of aging, conforming to the present regulatory regime. The author makes the fair point that if one is focused on treating a given disease, then that is likely going to be at the expense of treating aging generally; that a therapy will be optimized to the specific disease rather than to the broader landscape of aging, and worse for it.

That said, I think that the basically sensible outline of lobbying, regulatory change, and industry and patient advocate activities laid out in the opinion piece are only likely to happen at a rapid pace in the US (or EU) once some other jurisdiction is very publicly offering therapies that successfully treat aging in some clear, measurable way. That is typically how the FDA operates, in any case, as illustrated by the history of first generation stem cell therapies, which were widely available via medical tourism for years before the FDA finally relented somewhat under pressure. Thus the best thing that could be done to accelerate the availability of therapies to treat aging may well be to make them available via medical tourism, and accumulate compelling human data while doing so.

Longevity biotech: a different strategy

It may be possible to treat an age-related disease by targeting a mechanism of aging and I think some companies will eventually achieve that. However, the treatment would be optimised for treating the disease; and not necessarily for slowing down aging. Running clinical trials to get any drug approved for an indication is by itself extremely difficult. And the best way to increase the chances of success is to optimise every detail. It may be dosage, formulation, biomarkers, protocol, duration or anything in between. From an investment perspective, given the scientific and historical risks, a drug that targets a specific pathway or mechanism of aging to treat a disease has no superior value than any other drug. Unless that drug can slow down aging. And it is probable that at least some of the drugs from all the longevity biotech startups that are currently active could do that.

You only get good at what you do. Not at what you say you do, not at what you think you're doing and definitely not at what you hope you will one day do. If a company is developing drugs that target a mechanism involved in the aging process to treat a disease, that's what they are doing. So that's what they are getting good at. And that's what they will eventually achieve. However, if a company aims at slowing down the aging process and extend healthy lifespan, that's what the they should do. And that's what they will eventually achieve. So maybe it's worth considering a different product strategy: assume the regulatory risk, target aging itself and go for preventative instead of curative studies.

The challenges are indeed extremely difficult but fundamentally simple: (1) Identify drugs that can potentially slow down the aging process at a molecular and cellular level that are safe, affordable and easy to distribute. (2) Understand how to run rigorous longevity clinical trials in a reasonable time at low cost. (3) Collaborate with regulators to find new pathways to market for geroprotectors. It is essential to overcome the agreed pessimism and skepticism towards regulatory agencies and their willingness to challenge the status quo. Current health care systems cannot survive the growth of the aging population so I'm positive we can work collaboratively with regulatory agencies like the FDA and EMA to cautiously explore responsible ways to evolve our healthcare system towards more preventative medicine

The longevity space will differentiate itself from traditional biotech and thrive (trillions of dollars pouring in every year) if and only if a company manages to commercialise a product that has been clinically proven to slow down the aging process and extend healthy lifespan. For that, a different approach should be considered. It may be fundamentally different than the traditional biotech playbook: spin-out a biotech company around a novel discovery, gather enough pre-clinical data to raise capital for running real world clinical trials or sell the intellectual property to another pharmaceutical or biotech company. Instead of being about how can this reach the market; it's about how can a market be created as soon as possoble. And the way to do that is by targeting aging itself preventatively instead of curatively and assuming the regulatory risk.

Researchers here report on a gene therapy to upregulate RGS14 expression in an area of the brain associated with object recognition, showing that it enhances function in both old and young mice. Given past studies of RSG14, this is an expected result. Interestingly, increased RSG14 expression appears to produce benefits via upregulation of BDNF expression, a change that is is known to increase neurogenesis. Neurogenesis is the creation of new neurons and their integration into existing neural networks, necessary for memory function, as well as for maintenance of the brain more generally. Increased neurogenesis in adult life has been shown to produce numerous benefits in animal studies, with no obvious downsides.

Memory deficit, which is often associated with aging and many psychiatric, neurological, and neurodegenerative diseases, has been a challenging issue for treatment. Up till now, all potential drug candidates have failed to produce satisfactory effects. Therefore, in the search for a solution, we found that a treatment with the gene corresponding to the RGS14414 protein in visual area V2, a brain area connected with brain circuits of the ventral stream and the medial temporal lobe, which is crucial for object recognition memory (ORM), can induce enhancement of ORM.

In this study, we demonstrated that the same treatment with RGS14414 in visual area V2, which is relatively unaffected in neurodegenerative diseases such as Alzheimer's disease, produced long-lasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer's disease. Furthermore, we found that the prevention of memory deficits was mediated through the upregulation of neuronal arborization and spine density, as well as an increase in brain-derived neurotrophic factor (BDNF). A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer's disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits.

These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer's disease. Therefore, our findings of RGS14414 gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.

Link: https://doi.org/10.4103/1673-5374.389301

This paper makes the reasonable argument that means of modestly slowing aging will emerge from ways to reverse age-related changes in the varied microbial populations making up the gut microbiome. The gut microbiome changes with age, in ways that provoke chronic inflammation while also diminishing the supply of metabolites necessary for tissue function. Given the evidence generated from human and animal studies over the past decade, it is reasonable to think that the gut microbiome has as much influence on the course of long-term health as lifestyle choices relating to diet and exercise.

Aging is a complex natural physiological progression, which involves the irreversible deterioration of body cells, tissues, and organs with age, leading to enhanced risk of disease and ultimately death. The intestinal microbiota has a significant role in sustaining host dynamic balance, and the study of bidirectional communication networks such as the brain-gut axis provides important directions for human disease research. Moreover, the intestinal microbiota is intimately linked to aging.

Both the intestinal microbiota and aging are sophisticated subjects. The human intestinal microbiota undergoes significant changes during aging, and it is closely related to aging. However, the causal debate between intestinal microbiota and aging continues, and the analysis results indicate that they co-evolve and are mutually causal. The study of aging through the gut microbiota is a promising direction, whether it is to target the intestinal microbiota for intervention or to explore the underlying mechanisms of aging.

Interventions to delay aging primarily aim at aging drivers. Several animal studies have confirmed that aging can be delayed by fecal microbiota transplantation (FMT), probiotics, diet, and other regulation of the gut microbiota. However, the specific microbial characteristics related to delayed aging and maintenance of youth still need to be combined with several related experimental results for professional summary analysis.

Link: https://doi.org/10.3389/fmicb.2023.1268142

Atherosclerosis is the name given to the growth of fatty lesions in blood vessel walls, narrowing and weakening blood vessels, and eventually rupturing to cause a heart attack or stroke. This is the primary cause of human mortality. Many approaches have been demonstrated to slow the progression of atherosclerosis in the most commonly used mouse models, in which atherosclerosis is rapidly induced by a combination of high fat diet and the disabling of genes, such as APOE and LDLR, that are important to maintain normal blood cholesterol levels and cholesterol transport. Very few approaches have been shown to produce a reduction in the size of atherosclerotic lesions once they are established, however.

In today's open access paper, researchers demonstrate that a small molecule capable of provoking increased autophagy in a number of cell types relevant to atherosclerosis can meaningfully slow development of lesions in APOE-knockout mice. This is reasonable. Dysfunction in both (a) the endothelial cells lining blood vessels and (b) the macrophages responsible for clearing cholesterol from blood vessel walls is important in atherosclerosis. Increased operation of autophagy tends to help cells resist stresses that would otherwise disable them, kill them, or change their behavior for the worse, such as by inducing a senescent state. It should be expected to adjust the tipping points for formation and growth of atherosclerotic lesions. It most likely won't do anything to reverse existing lesions, however. Few approaches can, and if upregulation of autophagy was one of them, then exercise would be able to modestly reverse established atherosclerosis - which is not the case.

3,4-dimethoxychalcone induces autophagy and reduces neointimal hyperplasia and aortic lesions in mouse models of atherosclerosis

In the past, we showed that autophagy inducers can prevent or mitigate cardiovascular diseases, including myocardium infarction and heart failure. Due to their galenic properties and reduced cost, small molecules are particularly interesting for the prevention or treatment of cardiovascular diseases. Thus, high nutritional spermidine uptake is associated with reduced cardiovascular morbidity and mortality in humans and spermidine supplementation reduces the severity of atherosclerosis in mice. Spermidine acts against normal cardiac aging, as well as against high-salt diet-induced cardiac insufficiency. The copper-chelating agent triethylenetetramine (TETA) improves cardiovascular function and can induce the regression of pressure overload-induced cardiac hypertrophy. Another autophagy inducer, 4,4'-dimethoxychalcone (4,4'-DC) prevents myocardial necrosis after ligation of the left coronary artery. Furthermore, another, structurally related chalcone, 3,4-dimethoxychalcone (3,4-DC), prevents myocardial necrosis and induces autophagy in multiple mouse organs.

Atherosclerosis is the most prevalent aging-associated cardiovascular disease, providing the pathogenic substratum of most cases of myocardial infarction, stroke, aortic aneurysm, and arterial occlusion affecting internal organs or the femoral artery. The etiology of atherosclerosis appears complex but involves an important dysfunction of innate and cognate immune effectors, with macrophage-mediated inflammatory responses and the formation of foam cells (macrophages exhibiting the accumulation of lipid droplets in their cytoplasm) as prominent elements of the disease process. Given the anti-inflammatory effects of autophagy and the important anti-atherosclerotic role of lipophagy (a subtype of autophagy causing the removal of lipid droplets), we wondered whether the administration of pharmacological autophagy inducers might protect against the development of atherosclerosis.

Based on these premises, we attempted to identify the best strategy to prevent atherosclerosis by searching for agents among the aforementioned compounds that would induce autophagy in all cardiovascular disease-relevant cell types, i.e., cardiomyocytes, endothelial cells, and macrophages. As we report here, 3,4-DC stood out as a broad autophagy inducer. In a series of in vivo experiments involving two distinct mouse models of atherosclerosis, we obtained preclinical evidence indicating that 3,4-DC can efficiently slow the onset of this condition.

The immune system is made up of many different cell types. Further, distinct populations within those types exhibit a varied range of behaviors. The molecular damage and resulting cellular dysfunction of aging produces complex changes in the immune system, as is the case for all of the complex biological systems of the body and brain. Aging leads to a reduced ability to defend against pathogens and increased chronic inflammation, but understanding exactly how observed changes in cell behavior lead to that outcome remains a work in progress. Here, researchers use a large set of study data to investigate associations between the size of specific immune cell populations and human mortality.

Age-related immunosenescence is characterized by changes in immune cell subsets and is associated with mortality. In this study, we found that T cells and natural killer (NK) cells with low expression of CD56 were inversely associated with mortality while neutrophils were positively associated with mortality. In addition, we found myeloid dendritic cells to be nominally associated with a reduced odds of mortality, and CD4+ effector memory T cells and IgD- memory B cells to be nominally associated with increased mortality odds.

Several previous studies have shown a positive association between neutrophils and mortality and our study confirmed these previous findings. The number of neutrophils are preserved in older adults though their phagocytic ability is impaired. Furthermore, since neutrophils are pro-inflammatory, higher numbers of neutrophils in older adults may increase the odds of mortality. NK cells cytotoxicity and IFN-γ production decreases in old age, and low cytotoxicity is associated with increased morbidity and mortality. NK LO cells have significantly higher cytotoxicity than NK Hi cells. Hence, the observed inverse association with mortality was consistent with the biological activity of this NK cell subtype.

A higher percentage of myeloid subset of dendritic cells was associated with reduced mortality, which was consistent with previous studies showing that dendritic cells mediate antitumor immune responses, and were used in immunotherapies and vaccinations that resulted in improved survival of cancer patients. The absolute count of T cells decreases with age, and this decrease especially affects naïve subset (Tn). This alters the T cell repertoire, compromising their ability to mediate effective immune responses, and thus increasing the odds of mortality. The inverse association seen for total T cells in this study was in line with a previous study on hemodialysis patients.

As immunosenescence is characterized by accumulation of memory and effector T cells, a positive association between CD4+ effector memory T subset and mortality was consistent with the known distribution of this immune subset in older adults. Of note, we have previously shown that CMV seropositivity and not age was the predominant determinant of CD4+ effector memory T levels suggesting that the association between some of the immune cell subsets and mortality may be primarily driven by environmental exposures as compared to age-related processes.

Link: https://doi.org/10.3389/fimmu.2023.1280144

Extension of life in short-lived species via manipulation of aspects of metabolism using supplements and small molecules tends to be larger than that in long-lived species. So a 40% extension of life in flies is not as interesting as it would be in mice, for example. Nonetheless, few approaches have been shown to extend life span in flies to this degree. So this may be a strategy that will modestly improve measures of health in humans.

Phytochemicals are increasingly recognized in the field of healthy aging as potential therapeutics against various aging-related diseases. Nutmeg, derived from the Myristica fragrans tree, is an example. Nutmeg has been extensively studied and proven to possess antioxidant properties that protect against aging and alleviate serious diseases such as cancer, heart disease, and liver disease. However, the specific active ingredient in nutmeg responsible for these health benefits has not been identified thus far.

In this study, we present evidence that Nectandrin B (NecB), a bioactive lignan compound isolated from nutmeg, significantly extended the lifespan of the fruit fly Drosophila melanogaster by as much as 42.6% compared to the control group. NecB also improved age-related symptoms including locomotive deterioration, body weight gain, eye degeneration, and neurodegeneration in aging D. melanogaster. This result represents the most substantial improvement in lifespan observed in animal experiments to date, suggesting that NecB may hold promise as a potential therapeutic agent for promoting longevity and addressing age-related degeneration.

Link: https://doi.org/10.18632/aging.205234

The big disadvantage of the geroprotective approach to aging, which is essentially to undertake the long-term use of supplements and small molecule drugs to alter metabolism in ways that slow aging over years and decades, is that distinct supplements and small molecules and adjustments tend to combine in unexpected ways. Short of testing every combination in laboratory species, something that Brian Kennedy's team has been working on, one can never know the outcome of combining a treatment. Based on presentations and interviews given by Kennedy in the last few years, the result of combining two geroprotectors that individually modestly slow aging is often instead a modest reduction in healthspan or life span.

This is one of the many reasons as to why I favor the development of therapies to repair the underlying cell and tissue damage of aging, treatments that can be applied once for lasting benefit, and which produce actual rejuvenation, a reversing of the progression of aging. These therapies would not need to be continuously applied, and instead be used very intermittently. We should expect such a repair therapy that targets one form of damage to have little interaction with other repair-based therapies that targeting other forms of damage. Every such therapy should hence provide an incremental benefit. Demonstrating that to be the case is in fact the present focus of the LEV Foundation.

Exercise, or rather the maintenance of physical fitness, is an intervention that modestly slows aging, and, like geroprotectors, an intervention that has to be kept up continuously over time. As it turns out, exercise is subject to the same sorts of issue when combined with geroprotectors as is the case for combinations of those geroprotectors. Some geroprotectors are thought or demonstrated to interfere with the benefits produced by exercise. It is possible that some combinations of exercise and geroprotector produce a net loss rather than a net gain for long-term health. This is food for thought.

Geroprotector drugs and exercise: friends or foes on healthy longevity?

Functional parameters such as cardiorespiratory fitness (CRF), daily steps, gait speed, and skeletal muscle mass, strength, and power predict the risk of morbidity and mortality in humans. Exercise has wide-reaching systemic effects impacting nearly every tissue and intervenes on multiple biological pathways that become impaired with age, including senescence, proteostasis, mitochondrial function/quality, nutrient signaling, DNA damage, and inflammation. Through repeated exercise, these cellular and molecular changes facilitate increasing CRF, muscle mass, strength, and power while also decreasing established risk factors for cardiometabolic diseases and thereby lowering the risk of type 2 diabetes mellitus (T2DM), dementia, Alzheimer's, cardiovascular disease (CVD), atherosclerosis, frailty, and improving cancer survival/remission. Despite extensive research and commercial investment, a pharmacological agent that captures the numerous pleotropic health benefits of exercise has yet to be identified; thus, efforts to increase adherence to regular exercise continues.

Increased adherence to exercise over a lifetime has remarkable health benefits. At the musculoskeletal level, lifelong exercise delays age-related declines in functional metrics while extending a more youthful molecular phenotype later in life. However, with increasing age, sedentary behavior and cardiometabolic risk factors (hyperglycemia, hyperlipidemia, etc.) may contribute to delayed or diminished whole body and skeletal muscle adaptive potential to exercise, which is often referred to as anabolic resistance. Many of the proposed cellular and biological hallmarks of aging are implicated in blunting the responsiveness of skeleteal muscle to a bout of exercise. However, consistent exercise can still elicit robust adaptations in older adults. One year of endurance training can improve CRF by ~ 5 ml kg-1 min-1 in previously untrained 65-year-old or older individuals. Importantly, in healthy individuals, a 3.5-ml kg-1 min-1 greater CRF was associated with a 11% reduction in all-cause mortality.

Intervening on conserved underlying mechanisms of aging before the development of disease could postpone the onset, slow the progression, or perhaps ameliorate multi-morbidity and extend healthy longevity. Numerous dietary, lifestyle, pharmacological, and genetic approaches have identified that lifespan is modifiable in model systems. The mTOR inhibitor rapamycin is the most ubiquitous intervention thus far to extend lifespan in diverse species. The glucose-lowering medications metformin, sodium-glucose transporter 2 inhibitors (SGLT2i), acarbose, senolytics, and estrogenic agonists (17 estradiol) have also been demonstrated to extend lifespan.

Positive results from preclinical models have spurred large-scale public interest in gerotherapeutics, prompting some self-motivated individuals to take one or more putative geroprotective drugs and supplements off-label with the idea of further extending healthy longevity. Several telehealth companies have begun supplying these proposed geroprotectors to thousands of people across the globe. Importantly, it remains unclear whether the benefits of these pharmacologic approaches observed in pre-clinical models or in-patient populations extend to individuals free from overt disease who may also engage in other bona fide health-extending interventions such as exercise. Current dogma suggests combining geroprotectors with concurrent exercise blunts hallmarks of exercise that are associated with healthy longevity. Frequent (daily) dosing of leading geroprotectors blunts clinically relevant improvements to cardiorespiratory fitness, muscle size/strength/power, and insulin sensitivity.

Here find a high-level look at the work of Rejuvenate Bio, a gene therapy company aiming to manipulating aging metabolism into a better shape. They have chosen to focus on the strategy of altering tissues to generate signal molecules known to be influential in the progression of aging. This is perhaps the easiest way forward for any gene therapy platform. Gene therapies are clearly the future, but at present it is somewhere between hard, expensive, and impossible to specifically target a gene therapy to most organs or cell types or tissues. If one can use one of the few established approaches, such as delivery of a gene therapy to the liver or injecting the vector directly into fat tissue, then one can turn cells into factories that manufacture and secrete the desired signal molecule. That signal molecule is then transported to the rest of the body.

While looking at previous lifespan and healthspan extension studies may seem an obvious place to start when seeking new gene therapies, the Rejuvenate Bio founders explain that there is more to it than just the results. "These studies are essentially long-term safety experiments where they showed durable safety, coupled with an ability to treat multiple different issues with the animal or at least prevent age related conditions. Our focus was on how to turn transgenic interventions into therapies that would be safe and relevant for human patients. That is where we started."

The team studied those successful genetic interventions and how to "therapize" them - selecting the genetic or transgenic interventions that best lent themselves to becoming a gene therapy. In the end, the company arrived at three key longevity genes with proven efficacy and validated safety profiles, each associated with either an upward or downward trajectory through age: FGF21, which regulates important metabolic and immune pathways; TGFβ-1, which is a known driver of fibrosis and several cancers; and α-klotho, which is associated with cognitive performance as well as protection against heart and kidney diseases.

The Rejuvenate Bio founders explain how the company's FGF21 gene therapy is delivered via a strain of adeno-associated virus that targets liver tissue. "Even if our FGF21 gene therapy is only infecting liver tissue, we can actually see systemic effects throughout the body. What we're doing is turning the liver into a therapeutic bio factory, and then overexpressing this key signaling protein that then goes out through the blood stream and does its work across the body." This approach has advantages over gene replacement therapies, as evidenced by the company's recent success targeting arrhythmogenic cardiomyopathy in mice. "Because we're utilizing a secreted protein for our delivery, we've shown that we're able to hit large amounts of the cardiac tissue. Compare that to these groups who are trying to get the gene therapy to infect every cardiomyocyte that they'd like to change. That's a key difference."

Link: https://longevity.technology/news/were-turning-aging-research-into-a-therapeutic-category/

Researchers here show that D-mannose treatment can upregulate autophagy in bladder and urinary tract epithelial cells, reducing inflammation and other cellular dysfunction. Like other approaches that increase autophagy, such as the use of mTOR inhibitors and calorie restriction, this appears to reduce the burden of cellular senescence over time in aged tissues. This likely results from a slowdown of the pace at which cells become senescent, allowing the immune system to catch up in its task of destroying lingering senescent cells. The end result of this improvement in tissue quality is a greater resistance to urinary tract infection. Normally, risk of such infections increases with age.

Aging poses a number of challenges to the body's well-being, one of the most important being an increased susceptibility to multiple diseases, including urinary tract infections (UTIs). Researchers have now shown that, compared to the younger counterpart, the aging urinary tract in animal models changes how it functions at the cellular level in ways that seem to favor the establishment and recurrence of UTIs. The researchers investigated a process called autophagy that all cells naturally use to clean up old or defective cellular materials by digesting and recycling them in structures called lysosomes. "We found that the recycling process naturally slows down as urothelial cells age. Older cells accumulate larger lysosomes that are less effective at degrading cellular materials, which leads to their toxic accumulation inside the cell."

Aged urothelial cells also accumulate more damaging reactive oxygen species (ROS) than younger tissues. "ROS are molecules that can harm tissues, and the redox response that normally neutralizes ROS in younger cells is dampened in aging urothelial cells. Consequently, an inflammatory process builds up, leading to cell death. Dead urothelial cells leave their location, exfoliating the bladder and disrupting its integrity, which further exacerbates age-related dysfunction."

Importantly, researchers also discovered that treating aged mice with D-Mannose, a natural sugar, restores autophagy and mitigates ROS and urothelial cell shedding, suggesting that mannose supplementation could counter age-associated human urothelial dysfunction. Researchers then compared bacterial UTIs in older animals versus younger animals. "We found that aged mice have more bacterial reservoirs in the urinary tract and are more prone to spontaneous recurrent UTI than younger mice, suggesting that the age-related dysfunction of the tissue could explain the higher recurrence of UTIs observed in older age. Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection. We suggest that mannose supplementation could counter age-associated urothelial dysfunction in addition to limiting recurring UTIs."

Link: https://www.bcm.edu/news/d-mannose-reduces-age-triggered-changes-in-urinary-tract-that-increase-susceptibility-to-utis

Inflammaging is a blanket term for the inappropriate inflammatory reaction of the immune system to the accumulation of molecular damage and other changes that take place with age. Constant, low-grade, unresolved inflammatory activation of the immune system is a feature of aging. It alters cell behavior for the worse and is disruptive to tissue structure and function. A number of different mechanisms contribute to forming and maintaining the state of inflammaging, such as pro-inflammatory signaling produced by ever-larger numbers of senescent cells, and innate immune recognition of mislocalized mitochondrial DNA that results from mitochondrial stress and dysfunction. It seems likely that progress in stopping inflammaging will only emerge from ways to address the mechanisms that cause aging, like those mentioned above. Clear the senescent cells, repair or replace the mitochondria, and so forth.

In today's open access review paper, researchers discuss inflammaging as a contribution to age-related hearing loss. Chronic inflammation and the problems that follow in its wake can be found throughout the body; one could point to dozens of papers much like this one, each focused on the consequences of chronic inflammation in a single organ or tissue. Controlling inflammaging, shutting it down while still preserving the normal, transient inflammatory response to infection and damage, is a very necessary goal in the treatment of aging as a medical condition.

Cochlear inflammaging: cellular and molecular players of the innate and adaptive immune system in age-related hearing loss

Age-related hearing loss (ARHL) is one of the most common health disorders in the aging population, affecting over a third of adults over age 65. Recently, dysregulation of the immune system has come into light as a major pathological driver of ARHL. The term "inflammaging" describes the low-grade, sterile, chronic inflammatory state in the body's tissues with age. Chronic inflammation plays a role in multiple systemic diseases such as diabetes, as well as neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, and retinal degeneration.

During aging, immune cells undergo senescence, a process in which they lose the ability both to mount the normal immune response and to resolve inflammation after acute insults. Increased systemic levels of inflammatory markers, including C-reactive protein, interleukin-6 (IL-6), and white blood cell counts, are observed in neurodegenerative processes and ARHL, suggesting that inflammation is a hallmark of the aging brain and inner ear. Newer studies are exploring the role of gut microbiota in inflammaging, noting how pro-inflammatory diets such as foods high in sugar correlate with systemic inflammatory markers and severity of hearing loss. Conversely, long-term exercise is thought to delay progression of neurodegenerative processes and ARHL through the dampening of inflammation. Inflammaging can impair neural and sensory networks through several interrelated processes, many of which have been well-characterized in neurodegenerative diseases. Similar mechanisms are now being elucidated in ARHL as well.

This brief review summarizes current research on the cellular and molecular components of the innate immune system in ARHL, including the role of inflammatory cytokines, chemokines, inflammasomes, the classical complement pathway, and macrophages, as well as the interactions of each of these players with inner ear sensory structures. It also discusses emerging research of the involvement of the adaptive immune system in ARHL which thus far has largely been overlooked. A better understanding of immunosenescence in ARHL can elucidate future therapeutic avenues for a very prevalent and debilitating condition that currently has no preventative medicines or molecular treatments that target its underlying pathology.

Researchers here report on their development of a means to target microglia in the brain with small interfering RNA (siRNA) to reduce PU.1 protein expression. PU.1 is implicated in the regulation of inflammation in microglia, and a number of groups are attempting to produce a basis for therapies. Chronic inflammation driven by microglia is a feature of aging and neurodegenerative conditions. Unresolved, constant inflammation is disruptive of tissue structure and function, and the brain is no exception. Inflammation is thought to be an important factor in the onset and progression of the most common forms of neurodegeneration, including Alzheimer's disease.

In a prior study researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer's disease-related neuroinflammation and pathology. The simplest way to test whether siRNA could therapeutically suppress PU.1 expression in microglia would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.

Instead the team had to optimize a lipid nanoparticle (LNP) to do the job. LNPs have four main components and by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Among the seven candidates, one the team named "MG-LNP" stood out for its especially high delivery efficiency and safety of a test RNA cargo. What works in a dish sometimes doesn't work in a living organism, so the team next tested their LNP formulations' effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia.

Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.

The final set of tests evaluated MG-LNP's performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25. In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.

Link: https://picower.mit.edu/news/nanoparticle-delivered-rna-reduces-neuroinflammation-lab-tests

Somewhere in the list of topics that are not given a great deal of thought outside the research community, there is the issue of how exactly one goes about measuring healthspan in mice, the length of life spent in good health. There is no standardization to speak of, and what is called healthspan in one study is typically assessed with a completely different set of measures from what is called healthspan in another study. Thus there are groups attempting to promote specific well-defined approaches to assessment of healthspan in animal models, in the hope that others adopt them in order to make data on the effects of interventions more comparable.

The population around the world is graying, and as many of these individuals will spend years suffering from the burdens of age associated diseases, understanding how to increase healthspan, defined as the period of life free from disease and disability, is an urgent priority of geroscience research. The lack of agreed-upon quantitative metrics for measuring healthspan in aging mice has slowed progress in identifying interventions that do not simply increase lifespan, but also healthspan.

Here, we define FAMY (Frailty-Adjusted Mouse Years) and GRAIL (Gauging Robust Aging when Increasing Lifespan) as new summary statistics for quantifying healthspan in mice. FAMY is based entirely on a widely utilized clinical frailty index, while GRAIL incorporates frailty, widely utilized healthspan assays, and information about the hallmarks of aging. Both metrics are conceptually similar to quality-adjusted life years (QALY), a widely-utilized measure of disease burden in humans, and can be readily calculated from data acquired during longitudinal and cross-sectional studies of mouse aging.

We find that interventions generally thought to promote health, including calorie restriction, robustly improve healthspan as measured by FAMY and GRAIL. Finally, we show that use of GRAIL provides new insights, and identify dietary restriction of protein or isoleucine as an intervention that promotes healthspan but not longevity in female HET3 mice. We suggest that the routine integration of these measures into studies of aging in mice will allow the identification and development of interventions that promote healthy aging even in the absence of increased lifespan.

Link: https://doi.org/10.1101/2023.11.07.566044

We live in the world in which the regulatory costs imposed on the development of new medicine are enormous. This leads to centralization and regulatory capture. Only the largest entities, the Big Pharma companies, have the funds needed to satisfy the demands of regulators. These companies exist in synergy with the regulators, guiding the regulators (and the politicians backing them) to ensure that (a) their revenue streams are large and stable, and (b) there are fewer challenges to those revenue streams. Big Pharma entities are easily viewed through a cynical lens because their "treating the world, improving lives" rhetoric is far distant from their financial motivations as public companies, and their leadership has helped to produce a world in which medicine is more expensive and worse than would otherwise be the case.

But this is the view one has to adopt when developing a new medical technology with the intent of improving the human condition. A drug has to be truly amazing in order to reshape the system around it, and most do not reach that level. A drug that slows aging by a couple of years probably doesn't reach that threshold. One that modestly and rapidly reverses many age-related conditions may do so. We'll see! If a drug is merely a good, but cannot be shown to have a reasonable expectation of large profits, then it will never be widely used, as no Big Pharma entity will champion it though the vast expenses of regulatory approval, or during the subsequent machinations of adoption by physicians and payers. A drug can exist, but the complex and ugly systems of centralized healthcare can absolutely refuse to pay for it. Further, if a drug isn't patented, it will be ignored - there is no way to generate enough profit to justify championing it.

The post I'll point out today, from partners of a longevity-focused venture fund, builds a toy financial model as a refinement of the intuitive point that any drug capable of slowing or reversing aging will be enormously valuable, and therefore likely highly desirable to the pharmaceutical industry. One only has to look at the costs imposed by aging and age-related disease to see that. But one still has to build some form of model that takes account of the varied financial motivations of the regulators, Big Pharma, and the payers, and the way in which their decision makers look at drug value in order to be able to say, yes, it is likely to see adoption and use. The model here produces big numbers at the end of the exercise, which in one sense is expected.

The more interesting question is what it would take for the leadership of the various highly conservative organizations in pharma and medicine to believe that a new drug is actually worth that much, and act accordingly. Because these drugs already exist. Rapamycin to slow aging and the senolytic dasatinib and quercertin combination to reverse aging by clearing senescent cells are both backed by compelling animal data, and only lack similarly compelling human data. But one would think that based on (a) the compelling animal data and (b) models predicting enormous numbers for future drug profits, that someone would be attempting to commercialize, while being a great deal more aggressive in moving forward with that commercialization than is presently the case. New rapalogs and senolytics have their developers, but this part of the industry looks a lot like business as usual, and not a gold rush. So one might suspect that the powers that be in Big Pharma don't yet believe that this is real.

$200 Billion in Revenue: How an Aging Drug Will Conquer Pharma

An aging drug is a drug that has been rigorously shown to increase healthy lifespan in people, with emphasis on the ability of such an intervention to extend quality of life. It could allow older adults to enjoy a higher quality of life, for longer. The economics of delivering such value to human health at scale are unprecedented - we found that a drug approved and labeled for aging would conservatively have a peak global market size in the range of $150-$200 billion annually. This size is ~4x the peak projected annual revenue of GLP-1 receptor agonists at $50 billion by 2030, ~6x the peak projected revenue of America's soon-to-be best-selling drug, Keytruda (PD-1 cancer immunotherapy) at $30 billion annually by 2028, ~10x current bestseller Humira's peak annual revenue (anti-TNF) at $21.2 billion in 2022, and ~15x the peak annual revenue of enormous blockbuster Lipitor (a statin) at $13 billion in 2013.

It's also promising that the clinical trial to get this drug approved for aging and age-related disease on the label could potentially be as short as 3-6 years in length and cost $50-$100 million, within an order of magnitude of most Phase III clinical trials. Furthermore, just in the past month, we learned it was possible to get a drug approved and labeled for healthy lifespan extension in dogs by the FDA. In this piece, we walk through an estimate of the market potential of an aging drug.

To build a financial model for an aging drug, we need to answer: 1) How big is the market? 2) Who will pay for it? 3) What is the price of the drug? 4) What does adoption look like? The total addressable market (TAM) for an aging drug refers to the entire potential customer base that could generate revenue for the drug, encompassing all individuals who might benefit from or be interested in using it. We based our foundational TAM size on the total number of adults aged 65 or older in the US from the 2017 US census data. To know how much a drug is worth, we need to start with understanding who will pay for it. In the US, the majority of prescription medication costs are paid for by commercial health insurers and Medicare Part D. There is the potential for direct to consumer (DTC) brands to obtain a significant slice of this pie, however. If a drug designed to slow down the aging process receives FDA approval, it could initially pursue a DTC route, especially before long-term health outcomes and economics research can show financial benefits for insurers and other payers.

To predict the price of an aging drug, we estimated the monthly list price for a cash-pay model and the monthly net price for a reimbursement model. The list price is what the manufacturer sets for a drug before negotiations or discounts, which might reflect DTC market prices. In reality, a consumer pays something closer to the net price after discounts and rebates, determined via negotiations between pharma industry stakeholders. Currently, the reduction from the monthly list price ranges between 40-60%. What does adoption over time look like? For the maximum penetration rate (percentage of the TAM captured), we considered the following patient adherence numbers to approximate a range of 25% to 50%: half of all American adults get the flu vaccine every year; patient adherence to chronic medications is about 50%; patient adherence to cardiovascular medication (treatment dependent) ranges from 25-50%; in one study, of 400,000 people eligible to take statins, about 20% were chronically taking them. What is the adoption of an aging drug over time? Assuming a 25% penetration rate, the numbers range from 0.006% in 2030 to 25% in 2045. Assuming a 50% penetration rate the numbers range from 0.012% in 2030 to 50% in 2045.

The approval of a drug targeting the aging process could lead to a seismic shift in healthcare. The potential long-term healthcare savings are vast, as was with statins, which significantly reduced expenditure for inpatient care from hospitalization. With the potential to yield conservatively up to $200 billion annually, a company that owned only this drug would be more valuable than the top two big pharma companies (J&J and Pfizer) in terms of revenue... combined. We believe that this drug has the potential to become the largest product in human history.

Over the past decade or so, researchers have demonstrated that it is possible to use existing organs as bioreactors to host organoids derived from other organ tissues. Functional liver tissue can be grown in lymph nodes, as can thymus tissue. Here, researchers show that thyroid organoids can be grown in the spleen. This is intended to help patients who have undergone thyroidectomy, but will this capability also be useful in the context of the aging of the thyroid gland? Interestingly, the aging of the thyroid is poorly understood in comparison to the interaction of aging with larger organs such as liver, kidney, or heart. The thyroid produces important hormones, and those levels change with age, but it is unclear as to whether this is a dysfunction or a compensatory response.

Patients undergoing total thyroidectomy typically require lifelong oral levothyroxine sodium (L-T4) treatment. While effective in maintaining basic serum hormone levels, this treatment falls short in restoring the dynamic responsive regulatory capacity of triiodothyronine (T3), essential for critical physiologic regulatory functions. Clinical data indicates that T3 deficiency can elevate the risk of hypertension, cardiac dysfunction, and other metabolic or mental health conditions.

Researchers have proposed an innovative solution to thyroid transplantation challenges by growing the thyroid in the spleen. Leveraging the spleen's unique properties, characterized by a loose structure and rich blood supply, the team explored a new strategy for thyroid regeneration. Intrasplenic thyroid transplantation was performed without compromising the structure and function of the spleen. Mice with total thyroidectomy were transplanted with thyroid glands in the spleen, featuring intact follicles and reconstructed vascular networks. This approach successfully recapitulated the angio-follicular unit (AFU), leading to the full restoration of hormone levels in mice.

Furthermore, studies have demonstrated that this method is more effective in responding to physiological signals than hormone replacement therapy. Moreover, long-term evaluation of the effects with that of hormone replacement therapy proved that the regenerated thyroid glands in the spleen completely restored the physiological homeostasis in the mice after total thyroidectomy without any negative side effects, indicating significant potential for clinical applications.

Link: https://www.eurekalert.org/news-releases/1010873

Atherosclerotic plaques emerge from the dysfunction of macrophage cells tasked with clearing excess LDL particles and cholesterol from blood vessel walls. Once a plaque is established, however, it becomes a complex mess of maladaptive processes that interact with one another to contribute to further plaque growth, instability, and rupture. This includes an inflammatory feedback loop that draws in more macrophages to become overwhelmed and add their mass to the growing plaque, but also the involvement and transformation of other cell types in the blood vessel wall.

Cardiovascular diseases (CVDs), such as coronary artery disease (CAD), are the leading global causes of mortality and morbidity. The pathological hallmark of CAD is atherosclerosis, a chronic build-up of plaque inside arterial walls, which can lead to thrombus formation and myocardial infarction (MI) or stroke. This process involves a complex interplay of both immune and vascular cell types and cell state transitions along a continuum. In response to injury of the inner vessel wall layer, contractile smooth muscle cells (SMCs) transition to a more proliferative and migratory state and endothelial cells to a mesenchymal state in early and advanced atherosclerosis. Thus, a thorough assessment of cell heterogeneity and plasticity within the vessel wall is paramount to uncover new knowledge regarding atherosclerosis development and progression.

This study generates a comprehensive single-cell transcriptomic atlas of human atherosclerosis including 118,578 high-quality cells from atherosclerotic coronary and carotid arteries. By performing systematic benchmarking of integration methods, we mitigated data overcorrection while separating major cell lineages. Notably, we define cell subtypes that have not been previously identified from individual human atherosclerosis scRNA-seq studies.

Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.

Link: https://doi.org/10.1016/j.celrep.2023.113380

The blood-brain barrier is a layer of specialized cells wrapping blood vessels that pass through the brain. Only certain molecules and cells are admitted. The metabolism of the brain is thus isolated from that of the rest of the body. In particular, the immune system of the brain is quite different from that of the rest of the body. Unfortunately, this isolation is a vulnerability when, like all biological systems, the blood-brain barrier begins to break down and leak. The leakage of inappropriate molecules and cells into the brain provokes inflammation and dysfunction, and this is likely a contributing factor in the development of neurodegenerative conditions.

What are the mechanisms leading to blood-brain barrier dysfunction? Researchers here focus on two specific topics, first the disruption of circadian rhythm observed to occur with aging, and secondly age-related changes to the gut microbiome. Circadian rhythm is a regulatory process in cell behavior and signaling that has many aspects, and that is becomes less well orchestrated with age is a whole topic in and of itself. The connections between this and any given dysfunction of aging are usually subtle. The gut microbiome is a little more straightforward, in that pro-inflammatory microbes increase with number, while those microbes producing useful metabolites are diminished in number. Chronic, unresolved inflammation is disruptive to tissues throughout the body, and likely contributes to blood-brain barrier dysfunction.

Targeting the blood-brain barrier to delay aging-accompanied neurological diseases by modulating gut microbiota, circadian rhythms, and their interplays

Aging is an uncontrolled biological process that poses challenges to human health and becomes a social problem that can't be ignored. Aging is regarded as a common risk factor for various human diseases and by reducing sensory, motor, circadian rhythms, and cognitive functions, aging affects the brain morphologically and functionally, resulting in neurological diseases. Importantly, circadian rhythms disruption, characterized by phase shifts and reduced expression of many genes and proteins involved in circadian rhythms greatly impacts aging and longevity in many ways. Disturbances in the circadian rhythms induce disorders of cognitive function, metabolism, mental function, motor control, alertness, blood-brain barrier (BBB) damage, and sleep/wake cycles.

A prospective cohort study of 72,242 participants further supported that disturbances of circadian rhythm are a risk factor for the development of common neurodegenerative and psychiatric disorders. Interestingly, the amount and function of different microbial species fluctuate over time during aging, leading to gut microbiota dysbiosis. The gut microbiota continuously exchanges nutrients, genetic material, and metabolites with the host throughout its life cycle which regulates the homeostasis in the host, including brain function and blood-brain barrier (BBB) integrity. In individuals with neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and multiple sclerosis (MS), circadian rhythm disturbances and gut microbiota dysbiosis are common symptoms. Accumulating data suggest that either circadian rhythms or gut dysbiosis contribute to aging-accompanied neurological diseases (AAND). Notably, the disruption of the circadian system can alter microbiome communities and perturb host metabolism, energy homeostasis, and inflammatory pathways, and gut microbiota can regulate host circadian rhythms and metabolism as a transducer of dietary cues. Genetic defects of a biological clock, timing or restriction of food availability, and light/dark phase changes can significantly affect microbial oscillations, leading to a reduction in microbial abundance and species. In addition, gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and bile acids (BA), can alter circadian rhythms, indicating that circadian rhythms and gut microbiota can affect each other, and their interplays can induce subsequent effects.

The BBB provides nutrients to the central nervous system (CNS), maintains homeostasis, and regulates its communication with the periphery, forming a protective barrier for the CNS. The changes and destruction of the structure and functional components of the BBB could occur naturally with the aging process. Aging itself may worsen the disruption of different components of the BBB, thus accelerating the progression of brain damage and an ever-increasing global aging population has stimulated the exploration of the relationship between AAND and BBB, to prevent or delay the prevalence of AAND.

Therefore, there is an urgent need to further investigate the role of the BBB in AAND and the underlying mechanisms of BBB damage induced by aging-accompanied circadian rhythms disruption and dysbiosis of gut microbiota which play important roles in regulating BBB integrity. Further elucidation of the interplay of gut microbiota with circadian rhythms could also shed light on the systemic regulatory mechanisms of aging and the BBB. Here, in this review, we first describe how BBB, circadian rhythms, and gut microbiota are altered during the aging process and how these alterations are exacerbated in AAND. We then discuss the effect of the interplay between circadian rhythms disruption and dysbiosis of gut microbiota on BBB integrity. We then discuss and propose potential mechanisms underlying BBB damage induced by dysregulated circadian rhythms and gut microbiota, which could serve as the basis for developing potential interventions to protect the BBB in the aging population through targeting the BBB by exploiting its links with gut microbiota and circadian rhythms for treating AAND.

Given that the Interventions Testing Program found that fisetin supplementation did not extend life in mice, it is interesting to see that other researchers are still demonstrating that this intervention clears senescent cells and, as a direct consequence, improves function in older mice. Fisetin is something of a puzzle in this respect, and the Mayo Clinic needs to hurry up and publish useful data from their ongoing phase 2 human trials of fisetin supplementation.

Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture.

In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on-2 weeks off-1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16INK4A-positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from controls but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress.

Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction.

Link: https://doi.org/10.1111/acel.14060

There has been some thought given to whether Alzheimer's disease is a collection of fairly distinct subtypes, with different origins and different dominant processes of pathology. The evidence for subtypes of Alzheimer's disease is suggestive, as noted in this article. It remains to be seen as to what the research community will do with all of this data, but it is possible that some therapies are not as bad as originally thought, if analysis were restricted to only one subtype of Alzheimer's disease.

Proteins floating in the cerebrospinal fluid (CSF) might do more than diagnose Alzheimer's disease (AD) - they may identify different subtypes. Of the 3,863 proteins measured, 1,058 were either more or less abundant in people with AD. Researches clustered these by whether they were upregulated or downregulated in sync, then used gene ontology to identify biological pathways associated with each cluster. Proteomic profiles suggested five subtypes based on cellular processes predicted to be dysfunctional: the three previously identified - neuronal hyperplasticity, innate immune activation, and blood-brain barrier (BBB) dysregulation - and two new ones, dubbed choroid plexus dysfunction and RNA dysregulation.

Among the 419 people with AD, 137 fell into the neuronal hyperplasticity subtype. Upregulation of proteins involved in synapse assembly, axon guidance, and neurogenesis and gliogenesis suggested overactive neuron signaling and possibly an overabundance of neurons. Indeed, MRI scans showed the least atrophy in this subtype. Only the hippocampus and temporal and parietal lobes shrank. Prevalence of the TREM2 R47H variant was highest in this group. This hypofunctional TREM2 hobbles microglial pruning of synapses in mouse models of amyloidosis and was recently linked to cortical synapse growth. This subtype represented the mildest disease, with people living nine years, on average, after being clinically diagnosed with dementia.

Fifty-six people fit the BBB dysfunction criteria, having blood proteins, such as albumin, fibrinogens, and plasminogen, show up in the CSF. In contrast, there was a dearth of proteins made by brain vascular cells that typically leach into the CSF, such as platelet-derived growth factor receptor β and the cell adhesion proteins cadherin and laminin, suggesting disrupted brain tissue around blood vessels. Along these lines, people with the BBB dysfunction subtype had more microbleeds on MRI than people in other subtypes. In contrast, microglia may be overactive in the second of the three previously identified subtypes, innate immune activation. Among the 124 people in this group, complement components, regulators of cytokine production, and microglial proteins were overrepresented. Researchers saw severe and widespread cortical atrophy in this group, perhaps because microglia prune synapses too vigorously, she speculated. People with this subtype progressed the quickest from mild cognitive impairment to dementia.

As for the two new subtypes, molecules from the extracellular matrix and the choroid plexus (CP), including transthyretin, wound up in the CSF of 78 people with the CP subtype. MRI scans showed that the CP, a network of extracellular matrix and blood vessels, was enlarged. Large CPs associate with inflammation and cortical atrophy in multiple sclerosis, and in this fourth AD subtype, researchers detected elevated cytokines and severe, widespread cortical thinning. The other new subtype, RNA dysregulation, comprised just 24 people. They had high levels of chaperones and RNA-binding proteins in their CSF. Intriguingly, they had little of the microtubule-binding protein stathmin-2 (STMN2). Correct splicing and translation of STMN2 requires the RNA-binding protein TDP-43, best known for its role in frontotemporal dementia. This RNA dysregulation subtype seems the most aggressive. People had the most total tau and neurofilament light in their CSF, both signs of neuron damage, and they died soonest, about 5.5 years on average, after a clinical dementia diagnosis.

Link: https://www.alzforum.org/news/research-news/and-then-there-were-five-csf-proteomics-defines-alzheimers-subtypes

The gut microbiome changes with age. Pro-inflammatory microbial populations grow in size at the expense of populations that produce beneficial metabolites. As researchers produce increasingly large databases of the composition of the gut microbiome across ages and populations, they are also mapping a growing number of specific connections between microbial species and aspects of aging. Some of this work shows causation, but most human data can only show correlations between aspects of the gut microbiome and aspects of aging.

In today's open access paper, the authors focused on finding links between the gut microbiome and the function of the kidney. Declining kidney function is clearly important in degenerative aging, affecting organs throughout the body. If changes in the gut microbiome can accelerate kidney aging, then this will contribute to aging in much of the rest of the body as well.

Age-dependent changes in the gut microbiota and serum metabolome correlate with renal function and human aging

Several cross-sectional studies have identified gut microbiota changes that occur with aging. Studies using 16S rRNA gene amplicon sequencing have indicated an association between diet-driven microbiota alterations and health decline in aging individuals and highlighted the presence of a core microbiota of prevalent, symbiotic bacterial taxa dominated by the families Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae, with a progressive reduction in the abundance of these core taxa with age. In recent years, deep shotgun sequencing studies have reported a trend toward an increase in the abundances of Escherichia and Streptococcus with age, while the abundances of Faecalibacterium and Ruminococcus were reported to exhibit a decreasing trend. Notably, compared to that in other age groups, the gut microbiota of healthy centenarians is enriched with bacteria with a potential for degradation of xenobiotics and biosynthesis of short-chain fatty acids. However, whether specific interactions between the serum metabolome and gut microbiota are related to an age-dependent decline in renal function remains largely unexplored.

Based on residents from a Chinese longevity county, with long-living individuals (nonagenarians and centenarians) as healthy aging controls, this study aimed to examine the possible relationship between renal function and age-associated alterations in the human gut microbiota and serum metabolome using an integrated omics approach. Our results indicated that the effect of the gut microbiota on serum metabolites increased with age and that many age-associated gut microbes (E. coli, O. splanchnicus, and D. piger in particular) and serum metabolites, including markers of impaired renal function and bile acids, were highly correlated. The relationships between renal functions, serum metabolites, and the gut microbiota further indicated a possible impact of the gut microbiota in the aging process. Through mediation analyses, we revealed putative causal relationships among the gut microbiota (E. coli, O. splanchnicus, and D. piger), markers related to impaired renal function (p-cresol, N-phenylacetylglutamine, 2-oxindole, and 4-aminohippuric acid) and age.

Separately, feces of elderly individuals were transplanted into C57BL/6J mice. This fecal microbiota transplantation (FMT) experiment demonstrated that the feces of elderly individuals could influence markers related to impaired renal function in the serum. Thus, this study not only revealed changes in the serum metabolome and the gut microbiota in the process of aging but also indicated a route by which the gut microbiota affects aging indirectly through its effect on renal function via the production of metabolites associated with impaired renal function.

Researchers here report on their exploration of a way to adjust the production of monocytes in the bone marrow, cells that become macrophages of the innate immune system. This is chiefly interesting for the lasting effect that a single treatment appears to have on the progression of liver aging in mice, leading to reduced pathology connected to inflammation, such as fibrosis. Also interesting is that providing aged bone marrow to young mice accelerates this liver pathology, by altering the generation of macrophages in the direction that induces liver pathology. Fibrosis is the excessive generation of collagen structures in the extracellular matrix, disruptive to tissue structure and function, and presently hard to treat.

Aging is associated with nonresolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a proresolving ligand that acts through the G-protein-coupled receptor called GPR18. Unbiased RNA sequencing revealed increased Gpr18 expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice.

MA mice that lacked GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, increased monocyte-derived macrophages, and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly on the bone marrow to increase monocyte-macrophage progenitors.

A transplantation assay further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice. Transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, this study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.

Link: https://doi.org/10.1016/j.ajpath.2023.08.011

The dominant view of the evolution of aging is that it emerges from what is known as antagonistic pleiotropy, a term used to describe a mechanism that is initially helpful but later harmful. Mutations that help early life reproductive fitness will be selected even if they cause later harm, as a greater chance of earlier reproduction tends to win out over a greater chance of sustained reproduction over time. Natural selection thus tends to produce biological systems that invest little in long-term maintenance and sustainability. Aging is the result.

In 1957, evolutionary biologist George Williams proposed that genetic mutations that contribute to aging could be favored by natural selection if they are advantageous early in life in promoting earlier reproduction or the production of more offspring. Researchers have now tested the Williams hypothesis using genetic, reproductive, and death-registry information from 276,406 participants in the UK Biobank database. They found reproduction and lifespan to be genetically strongly negatively correlated, meaning that genetic mutations that promote reproduction tend to shorten lifespan.

In addition, individuals carrying mutations that predispose them to relatively high reproductive rates have lower probabilities of living to age 76 than those carrying mutations that predispose them to relatively low reproductive rates, according to the study. However, the authors caution that reproduction and lifespan are affected by both genes and the environment. And compared with environmental factors - including the impacts of contraception and abortion on reproduction and medical advances on lifespan - the genetic factors discussed in the study play a relatively minor role, according to the authors. "These results provide strong support for the Williams hypothesis that aging arises as a byproduct of natural selection for earlier and more reproduction. Natural selection cares little about how long we live after the completion of reproduction, because our fitness is largely set by the end of reproduction."

Link: https://www.eurekalert.org/news-releases/1010067

As illustrated by the last decade or so of research, any sufficiently complex set of biological data can be mined via machine learning to produce algorithms that report chronological age and incorporate some sensitivity to biological age. Biological data changes over time, and many of those changes are characteristic of age. The processes and dysfunctions of age touch on all mechanisms in the body, given time. The hypothetical perfect measure of biological age would accurately predict mortality risk, and be a comprehensive reflection of the burden of damage and dysfunction resulting from processes of aging. That may be impossible to achieve, but good enough clocks of biological aging will greatly speed progress towards therapies capable of treating aging.

Everyone suffers from the same processes of aging, and those processes tend to interact with one another, so if one pulls ahead, then it will make other accelerate as well. Nonetheless, the progression of aging is a stochastic process, a sequence of essentially random occurrences of damage, and random interactions between damaged components. There will be a distribution of outcomes even in identical bodies. Thus just as we see different people aging at different rates, we would expect that, in one individual, sometimes the state of dysfunction and damage will be worse in one tissue or organ, better in another.

In today's open access paper, researchers demonstrate that this is in fact the case. They do so by using data on circulating proteins that are generated by specific tissues, and which can be obtained from a blood sample. Given that data, machine learning approaches derive aging clock algorithms that are specific to those tissues. The results show that a fraction of people exhibit accelerated aging in one organ. As for all newly created clocks, it is entirely unclear as to which specific underlying processes of aging drive the observed changes and outcomes, but nonetheless one might hope that the existence of aging clocks will help to improve outcomes in research, medicine, and lifestyle choices.

Organ aging signatures in the plasma proteome track health and disease

While many methods to measure molecular aging in humans have been developed, most of them provide just a single measure of aging for the whole body. This is difficult to interpret given the complexity of human aging trajectories. Some recent methods have used clinical chemistry markers which include some markers of organ function. However, many of these markers have low organ specificity, making them difficult to interpret for organ-specific aging. Methods to measure brain aging have used MRI-based brain volume and functional connectivity measurements, which are costly and do not provide molecular insights, or have required tissue samples, which prevents their application in living persons. Building off the wealth of literature and clinical practice that uses certain organ-specific plasma proteins to noninvasively assess aspects of organ health, such as alanine transaminase for liver damage, we hypothesized that comprehensive quantification of organ-specific proteins in plasma could enable minimally invasive assessment and tracking of human aging for any organ.

Animal studies show aging varies between individuals as well as between organs within an individual, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan.

We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181, the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations, and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

Delerium is not an often discussed topic in the context of aging research, but it is an age-related occurrence, usually presenting in the old, particularly those suffering neurodegenerative conditions. Researchers here argue that the aged gut microbiome contributes meaningfully to risk of episodes of delerium. The balance of populations in the gut microbiome changes with age in detrimental ways, such as an increase in pro-inflammatory microbial species and a loss of those microbes that generate beneficial metabolites. It is now known that Alzheimer's and Parkinson's patients exhibit a distinctly different gut microbiome from similarly aged individuals without evident neurodegenerative conditions.

Delirium is a clinical syndrome characterized by an acute change in attention, awareness, and cognition with fluctuating course, frequently observed in older patients during hospitalization for acute medical illness or after surgery. Its pathogenesis is multifactorial and still not completely understood, but there is general consensus on the fact that it results from the interaction between an underlying predisposition, such as neurodegenerative diseases, and an acute stressor acting as a trigger, such as infection or anesthesia.

Alterations in brain insulin sensitivity and metabolic function, increased blood-brain barrier permeability, neurotransmitter imbalances, abnormal microglial activation and neuroinflammation have all been involved in the pathophysiology of delirium. Interestingly, all these mechanisms can be regulated by the gut microbiota, as demonstrated in experimental studies investigating the microbiota-gut-brain axis in dementia. Aging is also associated with profound changes in gut microbiota composition and functions, which can influence several aspects of disease pathophysiology in the host. This review provides an overview of the emerging evidence linking age-related gut microbiota dysbiosis with delirium, opening new perspectives for the microbiota as a possible target of interventions aimed at delirium prevention and treatment.

Link: https://doi.org/10.20517/mrr.2023.15

For those who find use in such things, HALD is an interesting tool for exploration of the literature surrounding particular genes, proteins, lipids, and other molecules. The authors mined the literature and determined relationships between these various items, as well as their roles as biomarkers. At the high level, the life sciences find themselves afloat on a sea of data. It costs little to generate ever more data, and much more to try to analyze it, so the pace at which databases grow is somewhat faster than the pace at which various groups are organizing, analyzing, and obtaining useful insights from that data.

Human aging is a natural and inevitable biological process that leads to an increased risk of aging-related diseases. Developing anti-aging therapies for aging-related diseases requires a comprehensive understanding of the mechanisms and effects of aging and longevity from a multi-modal and multi-faceted perspective. However, most of the relevant knowledge is scattered in the biomedical literature, the volume of which reached 36 million in PubMed.

Currently, there are some publicly online databases related to human aging and longevity. However, to the best of our knowledge, these databases are all manually curated, making it difficult to incorporate comprehensive knowledge of human aging and longevity. It is also difficult to obtain the latest biomedical knowledge from manually curated databases as their services are out of maintenance or not updated in time. In addition, although human nucleic acids information is generally involved in these studies, knowledge of other important organic compounds like carbohydrates, lipids, and proteins is not yet fully integrated.

Here, we presented HALD, a text mining-based human aging and longevity dataset of the biomedical knowledge graph from all published literature related to human aging and longevity in PubMed. HALD integrated multiple state-of-the-art natural language processing (NLP) techniques to improve the accuracy and coverage of the knowledge graph for precision gerontology and geroscience analyses. Up to September 2023, HALD had contained 12,227 entities in 10 types (gene, RNA, protein, carbohydrate, lipid, peptide, pharmaceutical preparations, toxin, mutation, and disease), 115,522 relations, 1,855 aging biomarkers, and 525 longevity biomarkers from 339,918 biomedical articles in PubMed.

Link: https://doi.org/10.1038/s41597-023-02781-0

Klotho is a longevity-associated gene. Klotho functions within the cell, but a portion of the full protein is also released into the bloodstream. In humans, higher levels of circulating klotho correlate with lower incidence of age-related disease and mortality. In mice, interventions such as gene therapies that increase klotho levels have been shown to extend life, while reducing klotho levels shortens life. Klotho is thought to act within the kidney, where it is protective, slowing age-related decline of kidney function. Increased klotho levels produce cognitive improvement in mice and non-human primates, however, and higher levels in humans are associated with lesser degrees of cognitive decline in later life. This may be the case because kidney function is important to all organs, or it may be that klotho acts directly on the brain in some way yet to be rigorously determined. Some groups are pursuing delivery of klotho as a basis for therapies.

You might recall a recent discussion of circulating klotho protein in the bloodstream as a biomarker of the effectiveness of lifestyle interventions to modestly slow aging. Today's open access paper provides a counterpoint, in that it shows that while klotho levels and physical capabilities both decline with age, the degree of physical fitness at a given age doesn't appear to correlate with klotho levels. So, per these results, increasing one's physical fitness in later life wouldn't be expected to raise klotho levels. This is interesting, because circulating klotho has been shown to correlate with a number of parameters that one would expect to be helped by greater fitness. Levels of chronic inflammation, for example, are higher in people with less circulating klotho.

Relationship between klotho and physical function in healthy aging

Accumulating data suggests that the "anti-aging" protein Klotho may play a key role in the development of functional impairments. α-Klotho, hereby referred to as Klotho, is a large transmembrane glycoprotein that is predominantly expressed in the distal convoluted tubules of the kidneys. A landmark study found that Klotho-deficient mice exhibited a shortened lifespan and a premature aging phenotype that included functional impairments, such as severe muscle wasting, hypokinesis, an abnormal walking pattern, and decreased stride length. In support of these findings, experimental models have shown that Klotho is involved in several key processes that regulate skeletal muscle function, such as muscle regeneration, mitochondrial biogenesis, oxidative stress, and inflammation. Importantly, total circulating Klotho levels have been shown to decline with increasing age, and several epidemiological studies in older adults - all of which included those with chronic diseases - have revealed a strong association between lower Klotho levels and increased disability in activities of daily living, increased risk of frailty, lower performance in the short physical performance battery.

The majority of studies investigating the relationship between circulating Klotho and physical function focused solely on older adults and have included those with comorbidities. The problem is that it is currently unclear whether circulating levels of Klotho are associated with physical function in individuals without comorbidities, and whether they are also associated with impairments in physical function earlier in life. The present study therefore sought to examine the relationship between serum Klotho levels and physical function indices in a community-based cohort of healthy adults across various age categories. Elucidating this relationship enables us to examine the natural history of age-related declines in circulating Klotho and its relationship with physical function in the absence of any chronic disease. We hypothesized that serum Klotho levels are associated with higher measures of physical function in all age groups.

In this cross-sectional study, serum Klotho was measured in 80 adults. Participants (n = 20, 50% men per group) were chosen into four age groups: 20-34, 35-49, 50-64, and ≥ 65 years, and were further grouped based on performance (low vs. high) on grip strength and chair stand tests. Klotho levels were lower in the ≥ 65 years group and the 50-64 years group compared to 20-34 years. No differences were observed in Klotho between the low and high performers. The ≥ 65 years group walked a shorter distance during the 6-min walk test (6MWT) compared to 20-34 years. Klotho was correlated with age, body fat, and 6MWT distance. Klotho levels decline as early as the fifth decade of life, potentially before the onset of age-related impairment in exercise capacity.

The aging of hair is a priority for many, but in the grand scheme of things we might perhaps want to suffer that loss in preference to the decline of other bodily systems more essential to life. If that choice in priority of research and development is offered, at least. In fact, while a sizable and vocal industry focuses on the little that can be done today to satisfy the demand for an end to the aging of hair, research and development does occur, but not to the degree one might imagine, and is moving very slowly. The age-related disruption of hair growth and coloration processes is complex and incompletely understood. Even non-age-related conditions of alopecia have yet to be deciphered.

Hair follicles (HFs) are constituted by different cell types, including hair follicle stem cells (HFSCs), non-HFSC epithelial cells, immune cells, neurons, mesenchymal cells, adipocytes, and melanocytes. Other structures, such as sebaceous glands (SGs), blood vasculature, and arrector pili muscle (APM), are also important HF components. Generally, HF status depends on the hair cycle, which can be roughly divided into three stages, including anagen (the growing phase), catagen (the transition phase), and telogen (the resting phase). These phases are modulated by genes, age, microenvironment, diet, and psychological factors. HF homeostasis is disrupted due to aging, gene mutations, nutritional imbalance, hormonal dysregulation, the inflammatory microenvironment, etc., which will lead to various HF disorders such as hair aging. Although hair-related diseases are not life-threatening, they can significantly influence people's social activities and psychological wellbeing. Among these disorders, hair aging is manifested by hair graying, hair loss, hair thinning, hair follicle miniaturization (HFM), structural changes, lipid composition change, and curvature in the hair fiber. There are multiple causes of hair aging, including genetic defects, systemic diseases, ultraviolet (UV) radiation, nutritional imbalance, environmental pollution, and physical damage.

Hair aging is often accompanied by hair graying, hair loss, and hair thinning. The hair pigmentation process starts with melanocyte stem cells (McSCs), which differentiate into melanocytes to produce pigmentation units. During anagen, melanocytes go through mitosis and are activated, manifested by increasing dendricity. Through the dendrites, they can transfer melanosomes, which contain melanin. Hair graying happens when the pigmentation process is disrupted. For example, it was recently reported that McSCs could switch between transit-amplifying status and quiescence status and reside in a dynamic niche, indicating a potential role of McSC mobility in regulating cell stemness and hair graying. Hair loss, however, is mostly related to HFSC dysfunction and depletion. Physiologically, HFSCs are activated at anagen and stay quiescent at telogen. Whereas, in alopecia, HFSCs are depleted or remain in a quiescent status, leading to irreversible or reversible hair loss, respectively. HFSCs are regulated by intrinsic and extrinsic cues, such as Wnt and bone morphogenetic protein (BMP) signaling, as well as skin wounding. Hair thinning can be a transitional status before hair loss, frequently occurring with HFM, which is manifested by the reduction of the diameter of HFs and hair shaft.

Numerous theories exist about the primary mechanism underlying hair aging. The most well-known one is the thesis of oxidative stress, which accounts for multiple kinds of cell dysfunction such as mitochondrial damage and upregulated inflammatory signaling. Additionally, extensive research is being done on other possibilities, including hormone-induced premature hair aging, inflammation-predominant hair aging, and DNA damage-driven hair aging. The following sections will give detailed depictions of these concepts. In this review, we try to outline and update the signaling pathway underlying these hair aging hypotheses and provide insights into the current progress and limitations of hair aging research.

Link: https://doi.org/10.3389/fcell.2023.1278278

A number of large epidemiological studies demonstrate that particulate air pollution correlates with mortality and incidence of age-related disease, likely via mechanisms involving increased inflammation resulting from the interaction of particulates with lung tissue. While socioeconomic status interacts with both exposure to air pollution and life expectancy, it is nonetheless possible to disentangle these effects in some population studies. While the long-term trend is towards reduced air pollution, it seems likely that chronic inflammation will be controlled and its effects on tissues reversed via novel therapeutics on much the same timescale as meaningful control over particulate levels could be achieved.

Air pollution (AirPoll) accelerates human aging, as assessed by increased adult mortality and earlier onset of cardiovascular diseases, and dementia. Socio-economic strata (SES) of wealth and education have parallel differences of mortality and these diseases. Children from impoverished homes differ in brain development at birth and in risk of early fat excess and hypertension. To further enhance the healthspan, biogerontologists may consider a wider range of environmental exposures from gestation through later life morbidity that comprise the Gero-Exposome.

Experimental studies with rodents and nematodes document shared transcriptional responses to AirPoll. In rodents, AirPoll exposure activates gene systems for body-wide detoxification through Nrf2 and NFkB transcription factors that mediate multiple aging processes. Gestational environmental factors include maternal diet and exposure to AirPoll and cigarette smoke. Correspondingly, gestational exposure of mice to AirPoll increased adult body fat, impaired glucose clearance, and decreased adult neurogenesis in the hippocampus, a brain region damaged in dementia. Nematode larvae also respond to AirPoll with Alzheimer's relevant responses. These experimental approaches could identify interventions for expanded human health and longevity across SES gradients.

Link: https://doi.org/10.3389/fragi.2023.1273303

The latest results from the NIA Interventions Testing Program (ITP) were recently published. The ITP conducts the most rigorous of animal life span studies, frequently demonstrating that earlier promising results were incorrect. The most interesting outcome from this batch of different interventions is that fisetin, demonstrated to clear senescent cells in mice and improve health measures, did not extend life. In contrast, dasatinib and quercetin, the most well-studied senolytic, has been shown by other groups to extend life in mice, by 36% in one study. This is puzzling!

We might theorize that either fisetin at the senolytic doses used in the ITP study (more frequent dosing for a longer period of time than I might have chosen) produces meaningful harmful side-effects in comparison to less frequent dasatinib and quercetin dosing, or that an ITP-run life span study for dasatinib and quercetin treatment would show no benefit to life span. The former sounds more plausible than the latter, but the data is the data. The ITP researchers consider that the issue may be differences between mouse strains used in various fisetin studies, and this is also interesting if the case, that senescent cell burden and type might be different enough in different strains to produce quite different outcomes.

Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used

In genetically heterogeneous (UM-HET3) mice, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12%, while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8%. Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± standard error (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant.

Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.

Senescent cells have been reported as important mediators of the pathophysiology of aging, and senolytics like fisetin (Fis) may play important roles in mediating their effects. Past researchers treated naturally aged or progeroid mutant mice with Fis and found that it reduced cells with senescent markers; for example, C57BL/6 mice at 23 ± 1 months old were given Fis or vehicle for 5 days by oral gavage. Three days later, in inguinal fat, controls averaged 8% SA-β-gal+ cells, while Fis-treated fat had 2%. They also fed mice 500 ppm Fis from 19 months of age and found that the median lifespan was 27 months in controls and 30 months in Fis-treated, with 3 of 8 treated mice outliving all 8 controls.

We elected to use 600 ppm Fis, starting at 20 months of age, since senescent cells are present in potentially harmful quantities starting at that age in mice. We fed either continuously or for 3 days every 2 weeks. Fis, using the doses and route described here, did not significantly lower the amount of p16Ink4a mRNA in UM-HET3 mouse liver, kidney, or brain. p16Ink4a whole tissue mRNA is one marker of senescent cell burden, but it is not a fully sensitive marker of senescence, for example, it is also expressed in other cell types such as activated macrophages. We had hoped that Fis would deplete senescent cells and thus test the important idea that the removal of senescent cells would lead to longer lifespan, but the absence of an effect on p16Ink4a-positive cells and the lack of inflammatory p21Cip1+ cells in older UM-HET3 mice prevented us from addressing this question. Further studies to analyze the types and location of senescent cells that might increase with age in UM-HET3 mice and how they differ from other mouse models in regard to their upregulated senescent cell anti-apoptotic pathways (SCAPs), as well as the use of Fis and other senolytic agents by gavage, might help to clarify these issues.

Old tissues are dysfunctional in ways that young tissues are not. This has always been known in the context of organ transplants, but absent measures of aging and means to treat aging, there was little to be done about it and arguably more pressing logistical issues to focus on. Times change, however. A growing appreciation of the role of senescent cells in degenerative aging, and the ability to clear some fraction of these cells via senolytic therapies such as the dasatinib and quercetin combination, has given the research, medical, and industry communities involved in organ transplant a novel approach to improve the quality of transplanted organs and outcomes for patients.

Most organ transplantations involve supply from older donors to younger recipients. Aging cells can become senescent, a condition in which they stop multiplying and secrete chemicals that negatively affect neighboring cells. Senescent cells accumulate in older donor organs, and have the potential to compromise transplant outcomes.

A study found that in preclinical animal models, transplanting older organs can trigger senescence in younger recipients. They observed that young and middle-aged mice that received heart transplants from older mice had impaired physical capacity, with reduced running times and grip strengths. Middle-aged mice who received older hearts also showed increased anxiety-related behavior, impaired memory, and poorer learning performances.

Researchers found that these accelerated aging-related effects in younger recipients were driven by the release of senescence-associated factors and mitochondrial DNA from older transplants. Treating older donor mice with senolytics, or senescence-inhibiting drugs, before organ extraction reduced symptoms of senescence in the recipient mice.

Link: https://www.eurekalert.org/news-releases/1010194

Aspirin is probably a candidate for most well-studied drug in human patients, going by number of participants and sheer volume of data generated by studies. It is also a cautionary tale for those who expect clear answers to result from studies of modest, long-term effects in humans. The long-term benefits of aspirin, like most small molecule approaches to manipulation of metabolism, tend to appear in some studies and vanish in others. Effects may be positive in some classes of individual, negative in others, and it is not well understood how to differentiate between those groups. The meta-analysis here stands in opposition to the ASPREE study, for example, in which modestly increased mortality was found to correlate with aspirin use.

Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence 'for' and 'against' the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients

Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.

Link: https://doi.org/10.1038/s41416-023-02506-5

Regular moderate exercise remains one of the most beneficial interventions when it comes to slowing the progression of degenerative aging, if balancing effect size against volume of supporting data. This isn't where we'd like to be! Biotechnology is capable of so very much more, but progress is slow, and robust assessment of new therapies across large populations slower still. Exercise introduces sweeping changes in cellular biochemistry and the function of higher level systems in the body, which makes it an ongoing challenge for the research community to understand exactly how it produces benefits. As is usually the case, there is a disconnect between (a) the data that can be connected on cellular biochemistry and (b) an assessment of health parameters. Joining the dots between the high level and the low level is a sizable project with no end in sight.

Microglia are innate immune cells resident in the brain, analogous to macrophages elsewhere in the body. Like macrophages, microglia adopt polarizations, defined packages of behaviors. An M1 microglia is pro-inflammatory, focused on chasing down pathogens. An M2 microglia is anti-inflammatory, focused on aiding in tissue regeneration and clearance of metabolic waste. Polarization is a useful concept, but the underlying range of behaviors across individual cells is more an analogue continuum from pro-inflammatory to anti-inflammatory, and the same for other behaviors, than a binary choice. Still, polarization can be influenced, and researchers are interested in finding ways to change microglia behavior in order to suppress inflammatory signaling and encourage tissue regeneration. As noted in today's open access paper, that exercise can affect polarization may lead to regulatory mechanisms that can be adjusted by other means.

Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia

Lifestyle changes including increased physical activity is an effective strategy for delaying the progression of neurodegenerative disease. Several studies have proposed a possible link between exercise training and cognitive improvement. We trained mice to run at increasing speed over 8 weeks which represents a typical in vivo model of physical activity. The principal findings of our study are 1) Exercise training improves cognitive function in AlCl3/D-galactose-treated mice and aging mice by reducing neuronal loss and neuroinflammation, and 2) Elevated levels of lactate in the brain attenuate this neuroinflammation by acting as an "accelerator" for the "lactate timer" in microglia by promoting transition to a reparative phenotype through Histone H3 Kla. Our results provide an extension to the beneficial effects of exercise training beyond strengthening skeletal muscle, and further confirm that exercise training improves cognitive function and reverses neuronal loss in the brain of AD-like mice.

Other studies have attributed the beneficial effects of exercise to lactate. For example, lactate partially mediates the effect of physical exercise on neurogenesis in a MCT2-dependent manner. Subcutaneous injection of lactate lead to an increase in blood lactate levels similar to exercise and increases brain VEGF protein. These studies provide a preliminary link between exercise, lactate, and cognitive function. Although studies demonstrated an important role of lactate in physiological function in neurons and astrocytes, there has been little empirical investigation on microglia. Over the past thirty years, microglia are traditionally described as two states, resting and activated. The reactive gliosis observed in Alzheimer's disease histopathology reflects an abnormal morphology and proliferation of microglia. Once overactivated microglia release a wide range of inflammatory and bioactive molecules which impose negative impacts on neurons. Extensive activation of microglia was detected in our AD mice and may contribute to the observed cognitive impairment.

Both running training and exogenous lactate treatment inhibited the hyperactivation of microglia in AD-like mice and increased the number of anti-inflammatory/reparative microglia. In vitro experiments in microglia confirmed that lactate treatment significantly increases the expression of repair genes, indicating that lactate may promote a shift in balance from damaging to reparative microglia.

This review paper covers what is known of toll-like receptors in the development of age-related chronic inflammation, with a particular focus on toll-like receptor 4 (TLR4). A sizable number of researchers are focused on finding ways to suppress the constant overactivation of the immune system in later life by interfering in its regulation. Unfortunately, the sensing mechanisms involved are also required for normal immune function, so it is hard to envisage even sophisticated implementations of this strategy producing therapies that don't inhibit necessary immune functions, such as defense against pathogens and destruction of potentially cancerous cells. The better approach is to repair the underlying molecular damage and disarray that triggers toll-like sensors, such as the mitochondrial dysfunction that allows mislocalization of mitochondrial DNA into the cytoplasm where it is mistaken for bacterial DNA. This is not a sizable focus in the research and development community, alas.

Toll-like receptor (TLR) is a type of pattern recognition receptor (PRR) that plays a crucial role in the immune system. PRRs, predominantly expressed by innate immune cells such as dendritic cells, macrophages, monocytes, neutrophils, and epithelial cells, serve as sentinels of the body's defenses. They become activated upon detecting pathogen-associated molecular patterns (PAMPs), which are molecular signatures unique to external pathogens and distinct from host components, as well as damage-associated molecular patterns (DAMPs), encompassing molecules like heat shock proteins (HSPs) and plasma membrane components released due to cellular damage or death. PRR is a major factor in innate immunity and also plays a role initiating adaptive immunity through induce the maturation of dendritic cells and the release of inflammatory cytokines.

TLR activation serves as a defense mechanism for the host against infections and tissue damage, initiating a signaling cascade that leads to the secretion of various inflammatory cytokines and the activation of immune cells. Notably, TLR4, a pivotal member of the innate immune response, becomes activated by diverse ligands classified as PAMPs and DAMPs. However, excessive TLR4 activation disrupts immune homeostasis by sustaining pro-inflammatory cytokine and chemokine production, thus contributing to the onset and progression of various diseases, including Alzheimer's disease, cancer, osteoarthritis, and sepsis.

The aging process significantly impacts the immune system, fostering a bidirectional influence termed 'immunosenescence'. Cellular senescence triggers the release of senescence-associated secretory phenotype (SASP), which can induce inflammation, subsequently promoting the generation of damage-associated molecular patterns (DAMPs), and escalating the exposure and circulation of externally infiltrated pathogen-associated molecular patterns (PAMPs) due to barrier deterioration. Diverse factors heightened by the aging process result in aberrant immune system regulation through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), consequently affecting cardiovascular, metabolic, and age-related degenerative diseases. In this review, we delineate the role of TLR4, a pivotal component of the immune system, and its association with aging-related diseases, thereby shedding light on the significance of TLR4 signaling in disease research.

Link: https://doi.org/10.1186/s12979-023-00383-3

Researchers here report on a mechanism by which increased cellular stress in heart tissue can disrupt the regulation of the heartbeat, thus leading to arrhythmia and potentially fibrillation. The accumulated molecular damage of aging, of course, provides increased contributions to cell stress, whether from inflammatory signaling, mitochondrial dysfunction, increased presence of molecular waste, or other causes. When researchers characterize more of the ways in which regulatory pathways in cells can produce maladaptive reactions to this damage, they tend to then search for means to alter the response, rather than means to repair the underlying damage. More focus should go towards damage repair in the research community, but that that is largely not the way in which research and development progresses.

Ventricular fibrillation is the most frequent cause of sudden cardiac death. Although aging is an established risk factor for the development of cardiac arrhythmia, the mechanisms underlying this connection have been hard to pin down, hindering progress toward the development of specific treatments. With the development of an arrhythmia, the cardiac cycle speeds up and becomes irregular, with potentially life threatening consequences.

Working with animal models, researchers discovered a connection between the development of ventricular fibrillation and the activation of two key signaling proteins, the stress kinases p38γ and p38δ. This discovery opens the way to new possible intervention strategies for this condition. When the scientists examined the hearts of old mice, they found that the activation of p38γ and p38δ was increased. A similar increase in the activity of these enzymes was also observed in the hearts of mice with a genetic or pharmacologically induced predisposition to developing ventricular arrhythmias. Together, these results suggest that stress signaling via p38γ and p38δ likely plays an important role in the development of this condition.

The scientists found that p38γ and p38δ phosphorylate a receptor called ryanodine receptor 2 and another protein called SAP97, resulting in a mislocalization of the potassium ion channel Kv4.3. These molecular changes lead to premature ventricular activation and an increased susceptibility to ventricular fibrillation. The study findings identify a promising therapeutic target for the development of new strategies to prevent sustained ventricular fibrillation and provide protection against this serious condition.

Link: https://www.cnic.es/en/noticias/nature-cardiovascular-research-spanish-scientists-discover-promising-therapeutic-target

Veterinary medicine is typically less impeded by FDA regulatory costs than human medicine. A cynic would note that the publicity-related incentives operating on FDA staff and leadership are quite different in these two cases, with a great deal more attention given by the media to matters regarding human medicine. With the relative costs being what they are, a number of entrepreneurs in the longevity industry chose to work towards veterinary therapies targeting mechanisms of aging. One of those companies, Loyal, here reports on progress towards the FDA essentially agreeing to a regulatory framework for therapies targeting aging rather than specific diseases. On the human side of the house, you might recall that the primary analogous effort is the TAME trial and the lobbying surrounding it, a very expensive and slow-moving process that has yet to come to fruition.

Loyal's approach involves adjusting a mechanism of metabolism that operates differently in large dogs versus small dogs, and which may provide a meaningful contribution to the well-known lifespan differences between breeds of different sizes. This treatment is thus intended for large dogs only. The FDA may or may not be considering the details of the specific approach used to be an important factor in allowing treatment of aging in dogs. The regulators may or may not reject a similar path to approval for other approaches, such as implementations of SENS-style repair of molecular damage. It remains to be seen as to whether a following company will be able to point to Loyal's regulatory progress and expect the FDA to approve a different treatment intended to slow or reverse aging in dogs, or other animals, without picking a specific disease to focus on. Still, that is the goal!

FDA Center for Veterinary Medicine agrees Loyal's data supports reasonable expectation of effectiveness for large dog lifespan extension

Loyal was only a few months old and about five people when we decided to begin by targeting the abnormally short lifespan of large breed dogs with a drug program we code-named LOY-001. LOY-001 extends lifespan in part by reducing IGF-1 to levels seen in smaller-breed dogs. The IGF-1 axis is one of the most well-studied longevity pathways. In model organisms from C. elegans to mice, reducing IGF-1 extends healthy lifespan, and increasing IGF-1 shortens healthy lifespan. In humans, certain centenarians have been shown to have genetically lower levels of IGF-1.

Today, I'm so proud to announce that Loyal has earned what we believe to be the FDA's first-ever formal acceptance that a drug can be developed and approved to extend lifespan. In regulatory parlance, we have completed the technical effectiveness portion of our conditional approval application for LOY-001's use in large dog lifespan extension. As there was no established regulatory path for a lifespan extension drug, we had to design from scratch a scientifically strong and logistically feasible way to demonstrate efficacy of an aging drug. This process took more than four years, resulting in the 2,300+ page technical section now approved by the FDA. It included interventional studies of LOY-001 in an FDA-accepted model of canine aging and an observational (no-drug) study of 451 dogs.

Our interventional studies with LOY-001 showed that the drug improved clinically-relevant aging parameters. We assessed these in laboratory studies using a dog model that represents accelerated aging. We then correlated those results with quality of life scores in the observational study, as independently measured by dog owners, and health outcomes as measured by veterinarians. This was key to show that the biological benefits of the drug are linked to clinically relevant outcomes. From our data, the FDA believes LOY-001 is likely to be effective for large dog lifespan extension in the real world. Once we satisfactorily complete safety and manufacturing sections and other requirements, vets will be able to prescribe LOY-001 to extend the lifespan of large dogs while we complete the confirmatory pivotal lifespan extension study in parallel.

Researchers here note an interesting project, the production of self-assembling, mobile clumps of cells propelled by cilia, formed from lung epithelium. These mobile bodies can encourage growth in nerve cells, at least in vitro. How exactly that happens remains to be determined, but the usual mechanism is via release of pro-growth factors, either directly, or encapsulated in extracellular vesicles. Whether this is a useful basis for future regenerative therapies remains to be seen; one might imagine concerns attending the introduction of large numbers of these epithelial cell bodies into other tissues. The full paper is nonetheless an interesting read.

Researchers had previously developed tiny robots using clumps of embryonic frog cells. But the medical applications of these 'xenobots' were limited, because they weren't derived from human cells and because they had to be manually carved into the desired shape. The researchers have now developed self-assembling 'anthrobots' made of human cells and are investigating their therapeutic potential using human tissue grown in the laboratory.

The researchers grew spheroids of human tracheal skin cells in a gel for two weeks, before removing the clusters and growing them for one week in a less viscous solution. This caused tiny hairs on the cells called cilia to move to the outside of the spheroids instead of the inside. These cilia acted as oars, and the researchers found that the resulting anthrobots - each containing a few hundred cells - often swam in one of several patterns. Some swam in straight lines, others swam in circles or arcs, and some moved chaotically.

To test the anthrobots' therapeutic potential, researchers placed several into a small dish. There, the anthrobots fused together to form a 'superbot', which the researchers placed on a layer of neural tissue that had been scratched. Within three days, the sheet of neurons had completely healed under the superbot. This was surprising because the anthrobot cells were able to perform this repair function without requiring any genetic modification. Going forward, researchers think anthrobots made from a person's own tissue could be used to clear arteries, break up mucus or deliver drugs, with or without genetic engineering.

Link: https://doi.org/10.1038/d41586-023-03777-x

If you're familiar with discussion of veganism as a lifestyle choice, nothing in this material will all that surprising. Vegans tend towards lower calorie intake and the benefits resulting from that, and that may be the dominant effect when looking at commonly measured health metrics in vegan study participants. It would be interesting to see more comparison studies in which the vegans were held to the same calorie intake as the omnivore control participants, but, alas, that is logistically harder and thus not the approach chosen by most study organizers.

Although it's well-known that eating less meat improves cardiovascular health, diet studies are often hampered by factors such as genetic differences, upbringing and lifestyle choices. By studying identical twins, however, the researchers were able to control for genetics and limit the other factors, as the twins grew up in the same households and reported similar lifestyles. The trial, conducted from May to July 2022, consisted of 22 pairs of identical twins for a total of 44 participants. The study authors selected healthy participants without cardiovascular disease from the Stanford Twin Registry - a database of fraternal and identical twins who have agreed to participate in research studies - and matched one twin from each pair with either a vegan or omnivore diet.

The authors found the most improvement over the first four weeks of the diet change. The participants with a vegan diet had significantly lower low-density lipoprotein cholesterol (LDL-C) levels, insulin, and body weight - all of which are associated with improved cardiovascular health - than the omnivore participants. At three time points - at the beginning of the trial, at four weeks and at eight weeks - researchers weighed the participants and drew their blood. The average baseline LDL-C level for the vegans was 110.7 mg/dL and 118.5 mg/dL for the omnivore participants; it dropped to 95.5 for vegans and 116.1 for omnivores at the end of the study. The optimal healthy LDL-C level is less than 100.

Because the participants already had healthy LDL-C levels, there was less room for improvement. Researchers speculated that participants who had higher baseline levels would show greater change. The vegan participants also showed about a 20% drop in fasting insulin - higher insulin level is a risk factor for developing diabetes. The vegans also lost an average of 4.2 more pounds than the omnivores.

Link: https://med.stanford.edu/news/all-news/2023/11/twin-diet-vegan-cardiovascular.html

The heart is one of the least regenerative organs, and what limited ability it has to recover from injury is further diminished by age. This is of particular concern in the context of recovery from a heart attack, which leaves regions of scar tissue rather than functional tissue, weakening the heart. The best approach to this problem is to prevent heart attacks from occurring in the first place, which would have to be achieved by in some way halting and reversing the underlying processes of atherosclerosis and the growth of fatty lesions in the vasculature. There is enthusiasm for this goal in academia and industry, at least in principle, but very little concrete progress in departing from the futile focus on lowering LDL-cholesterol in the bloodstream, which can only modestly slow the progression of atherosclerosis, not reverse it.

Thus, a sizable fraction of the regenerative medicine community is interested in finding ways to provoke greater regeneration in heart tissue, largely with the primary goal of helping heart attack survivors to regain at least some lost function. Today's open access paper is a discussion of the role of oxidative stress and cellular senescence in the age-related loss of regenerative capacity in heart tissue, with particular attention given to the function of progenitor cells in the heart responsible for regeneration. Researchers are looking for ways to reprogram the behavior of these cells, to reduce the impact of senescence, and it may be that oxidative signaling is a place to start.

Targeting the redox system for cardiovascular regeneration in aging

Lifespan has nearly doubled over the recent seven decades, but the final years of life come often with aging-associated diseases, most prominently cardiovascular disease (CVD) featured by progressive deterioration of cardiovascular structure and function. Aging imposes extensive changes on cardiovascular tissues that lead them toward a pathological state including hypertrophy, left ventricular dysfunction, arterial stiffness, and vascular dysfunction. Extrinsic factors, such as environment and lifestyle, and intrinsic processes, such as oxidative stress and inflammation, exacerbate DNA damage response, metabolic remodeling, and epigenetic drift, and thereby promote cellular aging in the cardiovascular system. These irreversible changes progressively impair the ability of cells to proliferate, which is critical to replace damaged cells that naturally accumulate in aged cardiac and vascular tissues.

During the recent decade, it is increasingly understood that the accumulation of the non-proliferating cells, so-called "senescent cells," declines mammalian tissues and organ function. According to the emerging "adult stem cell senescence theory of aging," stem cells and/or progenitor cells harboring in the heart and blood vessels or circulating progenitor cells, which replenish either preexisting senescent stem cells or specialized cardiomyocytes (CMs) and endothelial cells (ECs), become exhausted and lose their stemness during aging. The aging/senescence milieu suppresses endogenous regenerative and reparative mechanisms in the adult stem cells and progenitor cells, and also limits the success of cell-based regenerative therapies that aimed at repairing injured and dysfunctional tissues and restoring a youthful phenotype in the cardiovascular system. In a middle-size human study involving 119 humans with cardiovascular disease (32-86 years), more than 50% of tissue-specific cardiac progenitor cells (CPCs) exhibited the senescence phenotype.

Reactive oxygen species (ROS) have been viewed as pathological molecules that undermine normal cellular pathways by increasing oxidative stress. The cardiovascular system is principally vulnerable to reactive oxygen species (ROS) induced oxidative damage due to its high metabolic demand and low antioxidant defense capacity in aging. Single-cell RNA-Seq analysis of mouse aged cardiovascular ECs reveals transcriptomic reprogramming, including upregulation of ROS metabolic process in these cells. Not only in aged arterial ECs, single-nucleus RNA-Seq verify that oxidative responses are enriched in aged CMs in both primate and human hearts. These studies and beyond have demonstrated that these aged cardiac and arterial tissues exhibit a higher level of senescence-associated β-galactosidase staining and expression of pro-senescence genes including IL1β, IL17, and Type-I interferon (IFN-α). The relentless ROS production can also cause oxidative stress in cellular components, leading to cardiovascular stem/progenitor cell senescence and impaired proliferation and differentiation.

A mounting body of evidence underscores the significance of targeting redox machinery to restore stem cell self-renewal and enhance their differentiation potential into youthful cardiovascular lineages. Hence, the redox machinery holds promise as a target for optimizing cardiovascular regenerative therapies. In this context, we delve into the current understanding of redox homeostasis in regulating stem cell function and reprogramming processes that impact the regenerative potential of the cardiovascular system. Furthermore, we offer insights into the recent translational and clinical implications of redox-targeting compounds aimed at enhancing current regenerative therapies for aging cardiovascular tissues.

The first small human clinical trial of the senolytic therapy of dasatinib and quercetin targeted idiopathic pulmonary fibrosis, showing some benefit to patients. Later trials for kidney disease demonstrated that this treatment does remove a fraction of lingering senescent cells in human tissues in much the same way as it does in mice. Senescent cells accumulate with age in tissues throughout the body, the burden of these cells resulting from a growing gap between pace of creation and pace of clearance by the immune system. Researchers are coming to see a prominent role for senescent cells in all fibrotic conditions, in which excess extracellular matrix is produced, disrupting tissue structure and function. Compelling evidence in animal studies demonstrates reversal of fibrosis following senolytic treatment, a goal that is presently hard to achieve for human patients using existing interventions, those presently widely available in the clinic.

Pulmonary fibrosis (PF) is a chronic, progressive, devastating, and irreversible interstitial lung disease, with a median survival of 2 to 3 years after diagnosis. The present comprehension of the pathogenesis of PF entails the repetitive injury of alveolar epithelial cells (AECs) due to various risk factors, such as environmental exposure, viral infections, genetic predisposition, oxidative stress, and immunological factors. This injury subsequently results in the abnormal activation of AECs and dysregulated epithelial repair processes. The dysregulated epithelial cell secretes multiple cytokines and growth factors and interacts with endothelial, mesenchymal, and immune cells via multiple signaling mechanisms to trigger fibroblast and myofibroblast activation and promote extracellular matrix deposition, ultimately leading to the destruction of lung function, diminished exercise tolerance, and a decreased quality of life.

The existing epidemiological data from various data sources indicate that the average age of patients with PF is estimated to be over 65 years, and the incidence increases with age. Furthermore, individuals aged 70 and above have a risk of developing PF that is seven times higher than those in their 40s. Therefore, PF is now considered an age-related lung disease. Among the hallmarks of aging, cellular senescence serves as the primary driver behind tissue and organ aging, as well as an independent risk factor for PF progression. Age-related disturbances were increasingly observed in epithelial cells and fibroblasts in PF lungs compared to age-matched cells in normal lungs. Physiologically, alveolar epithelial type II (ATII) cells, serving as progenitor cells of the alveoli, differentiate into alveolar type 1 (ATI) cells in response to injury. Utilizing organoid cultures, single-cell transcriptomics, and lineage tracing, it has been discovered that ATII cells differentiate into ATI cells and acquire a transitional state known as pre-alveolar type 1 cell during the process of maturation. This transitional state exhibits regulation by TP53 signaling, making it susceptible to DNA damage and undergoing transient senescence.

However, there are at least two harmful consequences of persistent senescence. On the one hand, telomere wear and mitochondrial dysfunction lead to permanent cell-cycle arrest, which in turn causes stem cell/progenitor cell-renewal dysfunction and the loss of self-repair and regeneration abilities. On the other hand, senescent cells produce pro-inflammatory, pro-fibrotic, and stroma-remodeling cytokines such as IL-6, TGF-β, and several matrix metalloproteinases collectively known as the senescence-associated secretory phenotype (SASP), which can activate myofibroblast and scar formation. In fact, some components of SASP appear to enhance the growth arrest of exposed adjacent cells in a paracrine manner, further driving senescence, leading to low-grade chronic inflammation, and increasing susceptibility to pulmonary fibrosis.

A comprehensive understanding of how senescence promotes the occurrence and progression of PF can provide new insights into the further treatment of age-related diseases. This review presents compelling recent evidence indicating that cellular senescence is a significant driving factor in age-related lung diseases such as PF. It systematically summarizes the causes of cellular senescence in PF and the signaling pathways regulating different types of cellular senescence and also provides potential therapeutic strategies for targeting cellular senescence to improve PF. These strategies include targeting the clearance of senescent cells, intervening in senescence-related signaling pathways, and inhibiting the secretion of SASP.

Link: https://doi.org/10.3390/ijms242216410

The peripheral nervous system is far more capable of self-repair than the central nervous system. Nonetheless, nerve damage typically results in far less functional regeneration than is the case for other tissues. The research community is thus interested in finding ways to enhance existing repair processes. Here, researchers investigate a portion of the regulatory mechanisms that control the activity of Schwann cells in nerve repair, in search of targets for drug development programs aimed at enhancing regeneration of nerve damage, both in the peripheral nervous system, and also potentially in the central nervous system.

The peripheral nervous system is made up of all the nerves that branch out from the brain and spinal cord to give us sensation throughout our bodies. There are many cell types in peripheral nerves, here researchers focus on understanding neurons, which transmit information throughout the nervous system, and Schwann cells, which protect healthy neurons and repair damaged ones. The peripheral nervous system's ability to repair damage is remarkable considering that the central nervous system - made up of the brain and spinal cord - is not able to repair damage. Yet, the mechanisms that orchestrate this feat have remained poorly understood.

To unravel how Schwann cells differentiate to begin repairing peripheral nerve damage, the researchers looked at mouse models of Charcot Marie Tooth disease (CMT), a type of hereditary neuropathy. In mice with CMT, the researchers noticed that the Schwann cells completing repairs had high levels of Mitf in their nuclei - where the genetic instructions for how to be a Schwann cell and how to conduct repairs are stored. Upon investigation of this relationship between Mitf and Schwann cells, they found that Mitf was in the cytoplasm of Schwann cells until sensing neuronal damage. Damage then prompted Mitf to relocate from the cytoplasm of the cell to the nucleus, where it would direct the Schwann cell to make repairs.

To validate the importance of Mitf in creating repair Schwann cells, the researchers removed Mitf altogether. In cases of both trauma and CMT, nerve repair was arrested in the absence of Mitf - demonstrating that Mitf is required for peripheral nerve repair and regeneration. "Harnessing Schwann cell repair programs has great potential in treating chronic diseases. It's possible that with targeted therapeutics, we can prompt more Schwann cells to repair peripheral nerve damage and push those repairs to completion in chronic cases. Furthermore, now that we have a better grasp on the repair mechanisms, we can see if it's possible to initiate repairs in the brain stem and spinal cord, too."

Link: https://www.salk.edu/news-release/repairing-nerve-cells-after-injury-and-in-chronic-disease/

One of the characteristics of neurodegenerative conditions such as Alzheimer's disease is the inflammatory activation and dysfunction of microglia. These are cells of the innate immune system distinct to the brain, analogous to macrophages elsewhere in the body. They undertake a similar portfolio of tasks, including chasing down pathogens, destroying errant cells, cleaning up waste and debris such as toxic aggregated proteins found outside cells, and aiding in tissue maintenance and repair. When microglia are in an inflammatory state, they are less inclined to aid in tissue maintenance and clearance of harmful metabolic waste. Further, changes in the signaling environment and other aspects of aging can interfere in the capacity of these cells to clear debris and waste even when they inclined to do so.

In today's research materials, researchers describe some of the mechanisms that regulate clearance of misfolded, aggregated amyloid-β. Aggregation of amyloid-β is a feature of the early stages of Alzheimer's disease, and is thought to cause the onset of later inflammation and tau aggregation. Alzheimer's may thus be a consequence of an age-related failure of the balance between formation and clearance of amyloid-β aggregates. Increased production of amyloid-β may play a role, in its capacity as an antimicrobial peptide in response to infections, and so may reduced drainage of cerebrospinal fluid from the brain, but much of the focus is on reduced clearance by microglia. It is thought that ways to restore the clearance activities of microglia may slow or reverse Alzheimer's disease in its early stages.

Scientists Unveil Promising Target for Alzheimer's Disease Treatment

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects over 50 million people worldwide. A key pathological hallmark of the disease is the accumulation of amyloid-beta (Aβ) plaques in the brain, which leads to progressive decline in cognitive function. Microglia, resident immune cells of the brain, are thought to play a vital role in the clearance of Aβ plaques, a function that is impaired in AD.

The research team sought to investigate how microglia control Aβ clearance and how they become dysfunctional in AD. Through their elegant study, the team discovered that VCAM1, a cell surface protein on microglia, mediates microglial migration towards Aβ and promotes microglial clearance of Aβ. The team also discovered that another protein found in Aβ plaques, APOE, acts in conjunction with VCAM1 to mobilize microglia to Aβ plaques. The team further found that stimulating the "VCAM1-APOE" pathway reduced AD pathology in a mouse model of AD. These findings suggest that proper VCAM1 functioning is critical for microglial migration and clearance of Aβ.

The team also examined VCAM1-expressing microglia in the brain tissue of AD patients. Interestingly, AD patients exhibited elevated levels of soluble VCAM1 in the cerebrospinal fluid, which suggested dysregulated VCAM1-APOE signaling. This observation correlates with reduced clearance of Aβ by microglia. Collectively, the findings of the study implicate VCAM1-APOE signaling in the pathogenesis of AD and identify VCAM1 as a promising target for AD therapy.

The VCAM1-ApoE pathway directs microglial chemotaxis and alleviates Alzheimer's disease pathology

In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial damage-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration.

Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1-ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1-ApoE-dependent microglial functions ameliorates AD pathology.

Here, researchers review present efforts to develop drugs to treat sarcopenia, the age-related loss of muscle mass and strength that occurs in every individual, leading to eventual frailty. As a snapshot of the research and development community, it is representative of efforts across age-related disease generally, in that the primary focus falls on more easily developed options that cannot possibly produce results larger than those resulting from exercise, particular resistance exercise. This is the unfortunate outcome of the present medical regulatory system, in which the costs of regulatory approval are made so high that concerns and incentives surrounding cost outweigh all other goals.

Sarcopenia is a challenging disease for drug development, and there is currently no clinically approved therapeutic. Outcomes in clinical trials depend on functional gains in muscle performance, rather than just increases in mass, while also being well tolerated with low side effects. Sarcopenia is also a complex multifactorial disorder, and the underlying mechanisms are not fully understood. This review focused on pre-clinical drug development for sarcopenia. Due to the lack of approved therapeutics and a large projected market value, there are a large number and variety of different compounds and target pathways/cellular mechanisms under investigation.

A large proportion of current research is focusing on natural compounds and extracts, due to their characterized biological activity and advantages for further drug development. Much research effort is also focusing on the role of non-coding RNAs in sarcopenia progression, which can provide targets for small molecules currently under development for inhibiting non-coding RNA biogenesis. A number of type 2 diabetes drugs, such as SGLT2 inhibitors, DPP-IV inhibitors, and GLP-1 analogs, are also being investigated for their effects on skeletal muscle mass in type 2 diabetes patients and animal models. It will be important to consider whether these drugs can also be effective in the context of pre-diabetes or normoglycemia.

Mitochondria have a pivotal role in maintaining muscle function and are known to become dysfunctional in aging. Mitochondria-targeting drugs also hold great promise for treating sarcopenia and may utilize recent advances in mitochondria drug delivery systems. Drug repositioning strategies are also providing clinically validated candidates with known pharmacokinetics in humans. These previously characterized drugs can also provide new insights into the molecular pathways regulating skeletal muscle atrophy. A wider adoption of cell-based screening systems, based on known master regulatory genes, such as PGC-1α, could accelerate throughput and increase the number of hits for further analysis. Overall, much effort is being focused on identifying drug candidates with promising pre-clinical therapeutic activity in sarcopenia models, which raises the probability of successful drug development for this debilitating and increasingly prevalent disease.

Link: https://doi.org/10.3390/cells12222608

Lower mitochondrial copy number, meaning fewer copies of mitochondrial DNA and thus presumably fewer mitochondria in a cell, is here shown to correlate with the presence of age-related macular degeneration in older individuals. Mitochondrial copy number is one approach to measuring the degree of mitochondrial dysfunction present in tissues. In the study here, it is assessed in blood samples, and is thus a measure of the health of immune cells, the degree to which they are impacted by processes of aging. Many aspects of aging tend to correlate with one another, as aging emerges from a web of various forms of damage and dysfunction that all influence one another, so one can't draw conclusions about the degree to which mitochondrial dysfunction contributes to the development of age-related macular degeneration based on this data.

Mitochondrial dysfunction is a common occurrence in the aging process and is observed in diseases such as age-related macular degeneration (AMD). Increased levels of reactive oxygen species lead to damaged mitochondrial DNA (mtDNA), resulting in dysfunctional mitochondria, and, consequently, mtDNA causes further harm in the retinal tissue. However, it is unclear whether the effects are locally restricted to the high-energy-demanding retinal pigment epithelium or are also systematically present. Therefore, we measured mtDNA copy number (mtDNA-CN) in peripheral blood using a qPCR approach in elderly participants with and without AMD from the AugUR study (n = 2,262).

We found significantly lower mtDNA-CN in the blood of participants with early (n = 453) and late (n = 170) AMD compared to AMD-free participants (n = 1630). In regression analyses, we found lower mtDNA-CN to be associated with late AMD when compared with AMD-free participants. Each reduction of mtDNA-CN by one standard deviation increased the risk for late AMD by 24%. This association was most pronounced in geographic atrophy (odds ratio = 1.76), which has limited treatment options. These findings provide new insights into the relationship between mtDNA-CN in blood and AMD, suggesting that it may serve as a more accessible biomarker than mtDNA-CN in the retina.

Link: https://doi.org/10.3390/ijms242216406

Klotho is a longevity-associated protein that operates both within the cell and also as a circulating signal protein. It is longevity-associated in the sense that upregulation increases life span and downregulation reduces life span in mice, but also in the sense that measured klotho levels correlate with health and life expectancy in human epidemiological studies. Klotho may largely operate by maintaining kidney function into late life, but researchers have found that it may also help brain cells resist the harmful effects of an aged environment.

In today's open access paper, the authors make the interesting point that while epigenetic clocks are receiving attention as a potential way to assess the effects of lifestyle interventions on health and aging, there is in fact a great deal more existing evidence for the use of klotho as a biomarker in this context. Klotho may be a good enough reflection of the state of fitness, diet, and metabolic health to be used as a way to test compliance with lifestyle change in studies, or to assess the degree to which a given lifestyle change is in fact improving long-term health in any given individual.

The Longevity Protein Klotho: A Promising Tool to Monitor Lifestyle Improvements

With the global population aging, the number of people with multiple chronic health conditions has been rising because medicine still focuses on treatment rather than prevention. It is estimated that one in three people in the world lives with two or more chronic diseases. One way to prevent and even reverse chronic diseases is through lifestyle changes through health promotion and education. This also helps delay the onset of geriatric syndrome (frailty, cognitive decline, and reduced performance in the activities of daily living scale). This is why a new discipline of medicine has emerged to specifically address this issue: lifestyle medicine.

The American College of Lifestyle Medicine (ACLM) promotes a science-based approach that integrates lifestyle factors to prevent and treat chronic conditions. There are six pillars of lifestyle medicine: nutrition, physical activity, stress management, restorative sleep, social connection, and avoidance of risky substances. The goal of this discipline is not only to prolong the lifespan but to increase the healthspan by reducing the morbidity span. A study estimated that adherence to four or five low-risk lifestyle factors (diet, physical activity, alcohol intake, etc.) at age 50 could extend life expectancy free of major chronic diseases (cancer, cardiovascular disease, or diabetes) by 7.6 years in men and 10.6 years in women when compared to people with no low-risk lifestyle factors

Healthspan is defined as longevity without diseases and is often associated with a higher quality of life. Healthy longevity is a World Health Organization (WHO) priority. Chronological age, the number of years a person has been alive, is a great predictor of disease prevalence and mortality risk but is unchangeable. On the other hand, biological age is variable and measures the accumulation of physiological damage in individuals, meaning that two individuals of the same chronological age can have different biological ages. Thus, a biological marker providing a quantifiable overall insight into the patient's current health status would be of great use.

A few longevity markers do currently exist, such as PhenoAge (algorithms to improve chronological age by adding 9 biomarkers found in routine blood tests) or GrimAge, which is an epigenetic clock that can evaluate the biological age of an individual using DNA methylation-based markers. These tests are reliable for determining biological age, but there is little literature linking them to healthspan potential and even less to each of the pillars of lifestyle medicine. A new biomarker, the longevity protein klotho, might become a game-changing tool for measuring metabolic health and predicting the potential for healthy longevity. This review introduces the klotho protein as a potential novel, cost-effective biomarker and integrative tool to quantify and monitor the health status of individuals adopting lifestyle behavioral changes and summarizes current knowledge on the extent of klotho regulation across the six pillars of lifestyle medicine.

Based on this narrative analysis, klotho is a very promising marker candidate for lifestyle medicine due to its potential involvement in the six pillars of lifestyle medicine. Although we have identified knowledge gaps that warrant further study (randomized trials) to better understand the use of klotho in monitoring the effect of a lifestyle change intervention, it has enormous potential to enable objective, quantitative, and rapid monitoring of the overall health and the healthspan of patients. Klotho could be used as a marker in clinical studies where it is difficult to control the entire patient environment. Klotho is easy to quantify and, in the case of age-related diseases, would be an excellent marker to follow, as some diseases show no perceptible symptoms for a long period of time.

Muscle tissue is metabolically active, and affects the operation of other organs. At this time, a good map of the important signals that pass between muscle and other tissues has yet to be created. Maintenance of muscle mass and function in later life clearly produces a more systemic benefit than simply postponing weakness and frailty, but the details of the biochemistry are not well understood. Thus researchers can perform muscle-specific interventions in animal models, such as the one noted here, show a slowing of cognitive aging to result from that intervention, but not have a good grasp of how exactly how the altered muscle tissue influences the brain in this case.

Over the last decade, growing evidence has suggested that the periphery contributes to the etiology of age-associated neurodegenerative diseases. Manipulation of skeletal muscle protein quality control pathways protects against the accumulation of aggregation-prone disease proteins in the invertebrate brain and retina. The mechanisms responsible for these benefits remain poorly understood, some of these effects are mediated by secreted factors that communicate metabolic and inflammatory signals between tissues. Although the source and identity of these neuroprotective circulating cytokines are unclear, several are known to be secreted from skeletal muscle, an unconventional endocrine organ that secretes a myriad of bioactive factors that induce metabolic changes in distant tissues such as liver, adipose tissue, and the central nervous system (CNS).

Skeletal muscle metabolism is regulated in part by transcription factor E-B (TFEB), a master regulator of the lysosomal-to-nucleus signaling that integrates cellular metabolism and lysosomal function. TFEB expression and function are strongly induced in skeletal muscle in response to interventions with neuroprotective effects against aging and neurodegenerative disease, including low nutrient conditions and exercise. TFEB controls muscle metabolic flexibility during exercise, inducing the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation.

Here, we report the generation of a transgenic mouse with enhanced muscle metabolism via lifelong overexpression of TFEB. The resulting enhanced TFEB signaling protects against the onset of age-associated mitochondrial dysfunction in aging skeletal muscle. Overexpression of TFEB in skeletal muscle significantly reduces hippocampal accumulation of neuropathological hallmarks and reduces neuroinflammation in a mouse model of tauopathy, despite no exogenous activation of the transgene in the CNS. Muscle TFEB overexpression ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the "healthy" aged CNS, preserving cognitive performance in aging mice. Our results implicate maintenance of skeletal muscle function in regulating mammalian CNS health, and suggest that skeletal muscle-originating factors may act as therapeutic targets against age-associated neurodegenerative diseases.

Link: https://doi.org/10.1016/j.celrep.2023.113436

The nematode worm species Caenorhabditis elegans widely used in the laboratory is far removed from human biochemistry, but nonetheless there is much that can be learned about cellular mechanisms relevant to the aging of mammals. Here researchers review what is known of the role of messenger RNA (mRNA) quality control mechanisms in the aging of nematodes. mRNA is produced from gene sequences in the process of transcription, but every operation in the cell is subject to some level of error and happenstance damage to molecular structure. Thus quality control systems must exist to ensure that broken mRNA molecules do not lead to harmful outcomes, such as the production of broken, toxic proteins.

Aging is accompanied by the gradual decline in cellular and organismal fitness. At the macromolecular level, impaired protein homeostasis (proteostasis) and genome integrity are key features of aging. The age-dependent deteriorative changes are interconnected with each other to decrease the lifespan and increase the incidence of age-associated diseases, which eventually lead to death. Similar to other species, C. elegans exhibits age-associated changes such as the reduction in genome stability, proteostasis, lipid homeostasis, and immunity. Recent studies have indicated that RNA quality also declines during aging in C. elegans.

Eukaryotes are equipped with homeostatic systems that are crucial for the maintenance of mRNA quality, which is regulated by diverse surveillance pathways. Misprocessed mRNAs need to be eliminated by these RNA surveillance pathways. Nonsense-mediated mRNA decay (NMD), no-go decay, nonstop decay, and ribosome-associated quality control (RQC) are crucial for mRNA and protein quality control. mRNA splicing, which is a major pre-mRNA processing event in eukaryotes, selects and joins exons that are separated by introns, thus enabling diverse gene expression. Changes in splicing occur during aging and may reflect the deteriorated transcriptome quality. Abnormal mRNA splicing underlies the generation of aberrant transcripts that disrupts the proteostasis by producing truncated proteins and causing ribosome stalling, followed by ribosome collision.

Here we review recent studies that report on the key functions of various factors that regulate mRNA surveillance and splicing in the longevity and aging of C. elegans. Our review provides crucial information regarding the conserved functions of mRNA quality control in aging, which may be potentially utilized as therapeutic targets of aging and age-associated diseases in humans.

Link: https://doi.org/10.14348/molcells.2023.0103

Biopharma Dealmakers is a research news publication used by biotech and pharmaceutical startups to promote themselves and explain their work, published in association with editorial commentaries on the present state of the industry, as well as on specific areas of focus in research and development. It is published by Nature, and the way in which his typically works, under the hood, is that the editors decide on areas of focus for each issue and then reach out to selected companies related to that area of focus in order to invite them to pay a modest amount for inclusion. Technically this is a form of advertising wherein the Nature staff assists the selected companies in writing articles to discuss their research and development programs. The intended audience of that advertising is made up of life science investors and Big Pharma - publicity is ever useful!

However, this is also one of the few ways in which busy company leaders can be induced to explain their work in a format accessible to laypeople, and which is freely available to readers of any affiliation. So it can be an interesting read for industry observers. The last issue of 2023 includes a section on the longevity industry, and coverage of a few of the companies targeting age-related disease and mechanisms of aging that are currently interested in launching new initiatives or raising significant funding in the near future: Bioviva Science; Deciduous Therapeutics, a senolytics company; NIBEC; Rejuveron Life Sciences; and Repair Biotechnologies, the company that I co-founded. A few selected quotes follow, but I encourage you to take a look at the whole issue.

Biopharma Dealmakers, Volume 17 Issue 4, December 2023

Biopharma Dealmakers - a Nature Research publication - brings together life scientists, biotech and pharmaceutical professionals, and investors from across the globe. Biopharma Dealmakers offers readers themed editorial features that provide insights into dealmaking and industry trends. Regular editorial content includes biopharma deal round-ups, financing news and a collection of 'business of science' articles from the Nature Research catalogue. Biopharma Dealmakers also includes profiles of companies looking to partner or seek investment that showcases their pipeline products, technologies, therapeutic focus and partnering strategies. In this issue: Top 20 biopharma deals of 2023. Live forever: approaches to reverse aging. What are the drivers behind CNS deal flow? Oligonucleotide therapies broaden their reach. Make way for gene editing.

Editorial: The quest to turn back the clock

Delaying aging, restoring youth, regenerative medicine... whatever term is used, research aiming to target fundamental mechanisms of aging to increase life expectancy and quality has flourished in recent years. Ten years ago, researchers wrote a review that described hallmarks of aging, including genomic instability, stem cell exhaustion, deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence. Among efforts to target these hallmarks with potential therapies, those focused on cellular senescence have been at the forefront of industry activity, with more than 20 companies established in the past decade. In this piece, we highlight some of the progress and challenges for a selection of these companies.

Repair Biotechnologies: Developing therapies to degrade free cholesterol

Cholesterol is largely manufactured in the liver and transported throughout the body via a system of carrier molecules such as low-density lipoprotein (LDL) particles. Inside cells, cholesterol is esterified to provide protection from the toxicity of free cholesterol. Local excesses can overwhelm this protective mechanism and cells have no internal mechanism for degrading cholesterol. "When your system of transport breaks down, which happens in obesity and aging, localized excesses of cholesterol form. Our data show that the consequent toxicity is an important cause of downstream damage and disease." No current therapeutics directly target free cholesterol. While lifestyle changes, statins, or PCSK9 inhibitors can dramatically reduce LDL cholesterol levels to lower risk of atherosclerosis and slow its progression, they do not significantly impact free-cholesterol excess or reverse the damage caused by free cholesterol. "Getting rid of excess free cholesterol was impossible until our approach to effectively target it."

Established therapies focused on lowering LDL cholesterol cannot meaningfully remove established plaques, but Repair's animal studies have shown a sizeable reversal of plaques following gene therapy mediated clearance of free cholesterol. The company is now finalizing its formulation and preclinical studies. Repair is also developing a therapy for NASH, which affects 3% to 6% of the US population, being more prevalent in patients with metabolic disease and obesity. It progresses from inflammation and fibrosis to cirrhosis in approximately 20% of cases and is associated with increased overall mortality. There is no US Food and Drug Administration (FDA)-approved therapy for NASH, and, like atherosclerosis, its progressive pathology is largely irreversible. Repair's gene therapy reduced liver-tissue free cholesterol in mouse models significantly after only a few days, rapidly reducing key serum markers of liver damage. Moreover, hallmarks of NASH pathology including liver inflammation, insulin resistance and, most importantly, liver fibrosis were all significantly reduced following an 8-week therapy.

Deciduous Therapeutics: Restoring immune surveillance to tackle age-related diseases

Researchers discovered that a subtype of cells that sit between the innate and adaptive immune system were dramatically dysfunctional where senescent cells were accumulating. They m showed in two different mouse models of disease that the number and function of these invariant natural killer T (iNKT) cells was significantly reduced in tissues with high levels of senescent cells. Initial work showed that a tool compound, alpha-galactosylceramide (αGalCer) could be used to activate iNKT cells and reduce senescent cells in adipose tissue, leading to durable improvements in blood glucose levels, insulin resistance and HbA1c levels in diet-induced obese mice.

Subsequently, to demonstrate the widespread utility of immune-based senolysis, the company applied the approach to a severe model of pulmonary fibrosis. In this study, a single treatment at the peak of disease resulted in the ablation of senescent cells in the lung and attenuation of key fibrotic and inflammatory markers, which ultimately resolved fibrosis. Deciduous Therapeutics has used computational assisted design to synthesise a suite of proprietary therapies that could be used in the clinic to re-activate tissue-resident iNKT cells. To date, the company's lead program has shown single-dose efficacy in resolving both metabolic and fibrotic diseases along with a favorable safety profile at doses significantly higher than the efficacious dose.

Chronic, unresolved inflammation is a feature of aging. It emerges from mitochondrial dysfunction and mislocalization of mitochondrial DNA, from visceral fat tissue, from senescent cells, and from a range of other maladaptive processes. Sustained inflammatory signaling is disruptive of cell and tissue function. In recent years, researchers have come to put a greater emphasis on the role of chronic inflammation in the onset and progression of Alzheimer's disease. While it remains the case that protein aggregation (of altered amyloid-β and tau) is the primary point of focus in Alzheimer's research and the development of treatments, inflammation does appear to have a central role in the pathology of the condition.

Earlier this year, scientists discovered that excessive brain inflammation is critical for disease initiation and can predict whether cognitively unimpaired elderly are at a higher risk of developing Alzheimer's symptoms. This earlier research hinted at the importance of neuroinflammation in the pathological cascade involving other key players in Alzheimer's pathology including amyloid beta and tau. Now new findings provide the first strong evidence that brain inflammation is also a direct cause of neuropsychiatric symptoms that often accompany Alzheimer's-associated dementias.

In the new study, the researchers worked with 109 elderly individuals, the majority of whom had no cognitive impairments. Most of those individuals were, however, positive for amyloid and tau. By measuring levels of neuroinflammation, amyloid beta, and tau via brain imaging and comparing the results with clinical assessments of neuropsychiatric symptom severity, the scientists discovered that microglial activation was strongly associated with a variety of neuropsychiatric symptoms, including disturbed sleep and agitation. While levels of amyloid and tau alone were predictive of neuropsychiatric symptoms, neuroinflammation seemed to have an added effect.

Neuroinflammation was most strongly associated with caregivers or family members reporting their loved one's rapid mood swings from calm to tears or anger, one of the common symptoms of the disease. Individuals whose caregivers showed higher levels of distress when caring for them had greater levels of brain inflammation. Taken together, the study adds to the growing evidence of the role of brain inflammation in the early stages of the disease progression, when symptoms like excess irritability tend to emerge. It also suggests that clinical trials targeting neuroinflammation as a preventive therapy for Alzheimer's could track neuropsychiatric symptoms as one way of measuring the treatment's effectiveness. Conversely, drugs specifically targeting neuroinflammation could potentially help reduce neuropsychiatric symptom severity and alleviate some of the psychological burden experienced by caregivers, thus improving patient support.

Link: https://www.upmc.com/media/news/112723-alzheimers-brain-inflammation

Epigenetic drift is a measure of age-related change in epigenetic marks that alter the structure of packaged DNA in the cell nucleus, and thus control gene expression by making regions accessible or inaccessible to the translation machinery that produces RNA from gene sequences. Regardless of whether epigenetic drift is a form of damage contributing to aging, or a reflection of stochastic molecular damage within cells and consequent disarray in signaling and environment, one would in either case expect it to scale with species life span. Longer-lived species must show a slower pace of change in measures of aging, it would be surprising to find a measure for which this was not the case.

Epigenetic drift or "disorder" increases across the mouse lifespan and is suggested to underlie epigenetic clock signals. While the role of epigenetic drift in determining maximum lifespan across species has been debated, robust tests of this hypothesis are lacking. Here, we test if epigenetic disorder at various levels of genomic resolution explains maximum lifespan across four mammal species. We show that epigenetic disorder increases with age in all species and at all levels of genomic resolution tested. The rate of disorder accumulation occurs faster in shorter lived species and corresponds to species adjusted maximum lifespan.

While the density of cytosine-phosphate-guanine dinucleotides ("CpGs") is negatively associated with the rate of age-associated disorder accumulation, it does not fully explain differences across species. Our findings support the hypothesis that the rate of epigenetic drift explains maximum lifespan and provide partial support for the hypothesis that CpG density buffers against epigenetic drift.

Link: https://doi.org/10.1038/s41467-023-43417-6

It is somewhat interesting to see a careful analysis of diet and life expectancy, using the sizable UK Biobank population, that does not contain any of the words "calorie", "weight", or "obesity". The effects of calorie intake on health over the long-term are sizable, even if we focus only on mechanisms associated with the gain of weight. Visceral fat is metabolically active, generates an increased burden of senescent cells, and contributes to the chronic inflammation of aging via a range of different mechanisms.

Thus one would assume that buried underneath this set of data on what it is that people eat is a more relevant and useful set of data that incorporates both dietary components and calorie intake, and which is only mentioned in passing in this paper. Certainly, it is the case that people who eat more processed and less healthy foods are usually consuming significantly more calories than the few who put in an effort to garden their diet, and are usually going to carry a greater burden of visceral fat.

Life expectancy can increase by up to 10 years following sustained shifts towards healthier diets in the United Kingdom

In this paper, we present a method for estimating changes in life expectancy following changes in food choices, considering correlation between mortality and food group intakes, and effect delay. Such estimates may be useful particularly for policy purposes and for underpinning both guidance and interventions for improving public health. Our results indicate that UK adults aged 40 years with median dietary patterns can expect to gain approximately 3 years in life expectancy from sustained changes to the longevity-associated dietary patterns. Importantly, the estimated gain in life expectancy is approximately a decade for those shifting from the unhealthiest to the longevity-associated dietary patterns. Overall, the bigger the changes made towards healthier dietary patterns, the larger the expected gains in life expectancy are.

Consuming less sugar-sweetened beverages and processed meats and eating more whole grains and nuts were estimated to result in the biggest improvements in life expectancy. Sensitivity analysis also adjusting for body mass index and energy consumption indicated that body mass index and energy consumption might partially mediate and/or confound a possible beneficial effect between life expectancy and whole grains, vegetables and fruits, and inversely for red meat and eggs. For white meat, associations were stronger when adjusting for energy intake and body mass index, while the situation was mixed for legumes. These estimates correspond well with meta-analyses on associations between intakes of food groups and mortality.

Unsurprisingly, predicted gains in life expectancy are lower when the dietary change is initiated at older ages, but these remain substantial. For example, we estimated that people at the age of 70 years could expect to benefit from about half of the life expectancy gain predicted for adults at the age of 40 years, equivalent to a gain in 1.5 years when optimizing median dietary patterns and 4-5 years for those shifting from the unhealthiest dietary patterns. The UK population currently has a life expectancy at birth of 83.6 years for females and 79.9 years for males, and a 3 year gain in life expectancy associated with changes from median to longevity-optimized dietary patterns from the age of 40 years. Life expectancies have steadily increased over time, and the observed increase is parallel to the changes in life expectancy observed in the United Kingdom over the past 15 years. A large shift towards healthy dietary patterns could contribute substantially to meeting the Sustainable Development Goal target 3.4 that aims to cut premature mortality by one-third.

Proteins can become modified in a wide range of ways via addition or removal of various motifs. This is a necessary part of our biochemistry, but some modifications are harmful rather than useful. The pattern of protein modifications present in cells changes with age, and some pathological modifications begin to appear more often. The underlying reasons for these changes are usually poorly understood, at least once stepping beyond the immediate causal chemical reactions, as cellular biochemistry is very complex. As researchers here demonstrate, given a problematic modified protein that exists outside cells, it is possible to target it for removal and thereby produce benefits.

At a molecular level, aging is thought to be underpinned by progressive biomolecular damage caused by degenerative protein modifications (DPMs), including oxidation, deamidation, glycation, and a range of other non-enzymatic structural changes. We now recognize that aging is a consequence of deleterious chemical processes that damage biomolecules and impair the homeostatic functions programmed by our genomes. The functional impact of DPMs depends on the mode of modification and the target molecule involved. For example, deamidation leads to the accumulation of isoaspartate residues that progressively disrupt protein integrity and alter biological activity. However, "gain of function" structural changes caused by DPMs may play equally important roles in human pathology. DPMs greatly increase the diversity of biomolecules present in body tissues, with a high probability of generating proteoforms capable of interacting with or binding to key biomolecules in novel ways.

Indeed, we recently reported that deamidation of the amino acid sequence NGR (Asn-Gly-Arg) in extracellular matrix (ECM) proteins results in "gain-of-function" conformational switching to isoDGR (isoAsp-Gly-Arg) motifs that can bind to integrins and promote immune cell activation. Unlike isoaspartate-modified proteins within cells that can be repaired by the Pcmt1 enzyme, long-lived ECM proteins cannot be repaired by intracellular mechanisms and are thus susceptible to progressive damage over time. Accordingly, age-linked isoDGR modifications have previously been detected in several ECM proteins derived from human carotid plaque tissues, suggesting that these molecules may be capable of enhancing leukocyte binding to the atherosclerotic matrix, thereby accelerating progression of atherosclerosis.

We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1-/- mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-/- and naturally aged wild type (WT) animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR monoclonal antibody was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1-/- mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis. These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders.

Link: https://doi.org/10.15252/emmm.202318526

Researchers here note the existence of what they call "mid-old" cells, cells in tissue stroma that are on the path to becoming senescent, are not yet entered into the senescent state, but nonetheless produce constant inflammatory signaling that is disruptive to tissue structure and function. The researchers find that these cells respond positively to delivery of recombinant SLIT2, diminishing their bad behavior. In very old mice, this treatment resulted in improved muscle mass and function and greater animal activity. This is an interesting finding, and will need further investigation and replication to rule out other mechanisms resulting from SLIT2 delivery. For example, this behavior of mid-old cells could be a bystander effect of senescent cells, and SLIT2 is in some way removing those.

Senescent cell accumulation in tissues is a well-known driver of organ aging and the overall aging process. Multiple studies have consistently revealed the accumulation of senescent cells with the progression of aging. Accumulated senescent cells play a significant role as they cause a halt in the proliferation of functional cells, ultimately resulting in organic dysfunction. Moreover, senescent cells significantly affect the surrounding microenvironment by inducing sterile chronic inflammation through the secretion of senescence-associated secretory phenotypes (SASPs), which are known as "inflammaging" phenomena.

While it has been known that the accumulation of senescent cells in the tissues of the elderly is related to tissue aging, it does not constitute the majority of cells within the tissue. Moreover, it is understood that non-senescent cells within the elderly tissue still proliferate. However, the reason for the decline in organic function in the elderly as they age remains unclear. Therefore, we hypothesized that there might be a subset of cells in an intermediate stage of the cellular senescence process within the tissue, significantly impacting and ultimately leading to organic dysfunction in the elderly. Here, we propose the existence of intermediate stage cells that are neither youthful nor senescent. We termed these cells as "mid-old cells."

Here, we found that the major population of stroma fibroblasts or smooth muscle cells are mid-old status. Moreover, we investigated the cellular characteristics of mid-old fibroblasts and smooth muscle cells in vitro and in vivo, leading us to propose mid-old cells as a new potential target for anti-aging therapy. Upregulation of pro-inflammatory genes (IL1B and SAA1) and downregulation of anti-inflammatory genes (SLIT2 and CXCL12) were detected in mid-old cells. n the stroma, SAA1 promotes development of the inflammatory microenvironment via upregulation of MMP9, which decreases the stability of epithelial cells present on the basement membrane, decreasing epithelial cell function. Remarkably, the microenvironmental change and the functional decline of mid-old cells could be reversed by a young cell-originated protein, SLIT2. Our data identify functional reversion of mid-old cells as a potential method to prevent or ameliorate aspects of aging-related tissue dysfunction.

Link: https://doi.org/10.1038/s41467-023-43491-w