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!