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- A Discussion of What is Need to Speed the Pace at which Drugs to Treat Aging Arrive in the Clinic
- Cellular Senescence in the Aging Brain, a Contributing Cause of Cognitive Decline
- Reviewing What is Known of the Mechanisms of Taurine Supplementation Relevant to Aging and Metabolism
- Blunt Thoughts on Calculating the Revealed Value of Human Life
- A Look Back at 2023: Progress Towards the Treatment of Aging as a Medical Condition
- Towards Adjustment of the Gut Microbiome to Slow Aging
- Gene Therapy Enhances Object Recognition Memory in Young and Old Mice
- Benefits of Semaglutide in Heart Failure are not Just Due to Weight Loss, in Mice at Least
- Can One Develop a Means to Treat Sarcopenia Derived from Present Osteoporosis Medications?
- Toxic Tau Aggregates Alter Cell Nucleus Structure in Harmful Ways
- Fibroblast Senescence in the Aging Dermis
- Angiotensin 1-7 Improves Skeletal Muscle Regeneration
- Amyloid-β Specific Regulatory T Cells to Treat Alzheimer's Disease
- Investigating the Regenerative Prowess of Jellyfish
- CD38 in Ovarian Aging
A Discussion of What is Need to Speed the Pace at which Drugs to Treat Aging Arrive in the Clinic
https://www.fightagi...-in-the-clinic/
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 in funding 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.
Cellular Senescence in the Aging Brain, a Contributing Cause of Cognitive Decline
https://www.fightagi...nitive-decline/
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.
Reviewing What is Known of the Mechanisms of Taurine Supplementation Relevant to Aging and Metabolism
https://www.fightagi...and-metabolism/
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.
Blunt Thoughts on Calculating the Revealed Value of Human Life
https://www.fightagi...-of-human-life/
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.
A Look Back at 2023: Progress Towards the Treatment of Aging as a Medical Condition
https://www.fightagi...ical-condition/
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 plan 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!
Towards Adjustment of the Gut Microbiome to Slow Aging
https://www.fightagi...-to-slow-aging/
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.
Gene Therapy Enhances Object Recognition Memory in Young and Old Mice
https://www.fightagi...g-and-old-mice/
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.
Benefits of Semaglutide in Heart Failure are not Just Due to Weight Loss, in Mice at Least
https://www.fightagi...-mice-at-least/
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.
Can One Develop a Means to Treat Sarcopenia Derived from Present Osteoporosis Medications?
https://www.fightagi...is-medications/
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.
Toxic Tau Aggregates Alter Cell Nucleus Structure in Harmful Ways
https://www.fightagi...n-harmful-ways/
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.
Fibroblast Senescence in the Aging Dermis
https://www.fightagi...e-aging-dermis/
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.
Angiotensin 1-7 Improves Skeletal Muscle Regeneration
https://www.fightagi...e-regeneration/
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.
Amyloid-β Specific Regulatory T Cells to Treat Alzheimer's Disease
https://www.fightagi...eimers-disease/
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.
Investigating the Regenerative Prowess of Jellyfish
https://www.fightagi...s-of-jellyfish/
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.
CD38 in Ovarian Aging
https://www.fightagi...-ovarian-aging/
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.
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