Fight Aging! Newsletter, February 10th 2025
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
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- Request for Startups in the Rejuvenation Biotechnology Space, 2025 Edition
- Mitochondrial Transfer as a Mechanism of Tumor Immunosuppression
- Towards Control of Mitochondrial Dynamics
- Shorter Average Telomere Length in White Blood Cells Correlates with Increased Dementia Risk
- Amphiregulin Secreted by Regulatory T Cells Promotes Thymus Regeneration
- Physical Activity Correlates with Reduced Age-Related Mortality
- Details on Rubedo's Lead Senolytic Program
- Cellular Reprogramming in the Hypothalamus Slows Ovarian Aging in Rats
- Implicating Changes in the Gut Microbiome as a Contributing Factor in Sarcopenia
- Heart Rate Variability as a Proxy Measure for Oxidative Stress
- Targeting NRF2 Regulation of Antioxidant Activities to Treat Aspects of Aging
- Lifestyle Interventions as a Way to Slow the Onset of Immunosenescence
- Distinct Effects of Chronic Inflammation on Different Aspects of Hematopoietic Aging
- Ultrasound as a Basis for Clearing Senescent Cells
- Exosome Therapy Restores Some Lost Ovarian Function in Aged Mice
Request for Startups in the Rejuvenation Biotechnology Space, 2025 Edition
https://www.fightaging.org/archives/2025/02/request-for-startups-in-the-rejuvenation-biotechnology-space-2025-edition/
It is once again time to suggest possible areas of focus for new startups intending to develop means to treat aspects of degenerative aging, or accelerate that development. We live in the formative decades of a barnstorming era of endless possibility when it comes to biotechnology and the manipulation of cellular biochemistry. Sadly, this is joined at the hip to a risk-averse regulatory environment determined to bury every new idea beneath an ever-expanding sea of costs and requirements, most of which are unnecessary. Of the realm of the possible in biotechnology and pharmaceuticals, very little emerges from laboratories and successful animal studies to successfully make the leap into human medicine, and the vast costs force much of that progress to focus on unambitious incremental steps forward, rather than more rapid, radical progress.
Still, even within this dire state of affairs it is possible to build ambitious new medicine. The best approaches can still obtain backing. There are many, many dire unmet needs in the patient population. Aging corrodes the bodies and minds of the entire population, imposing a vast cost on individuals, governments, medical systems. Every potential therapy capable of repairing some of the cell and tissue damage of aging in order to produce rejuvenation has a potentially vast market at the end of the day. That motivates investors even given the daunting hurdle of regulatory costs that lies between a promising preclinical therapy and its adoption in the clinic.
Better Approaches to the Chronic Inflammation of Aging
The present dominant approach to chronic inflammation characteristic of aging and many age-related conditions is a broken record: identify a signal molecule or molecular interaction involved in the inflammatory response, and find a way to suppress it. Small molecules, siRNAs, and monoclonal antibodies are all excellent tools to achieve this sort of result. The identification of targets and attempts to interfere in these targets represents much of modern medical development. The problem here is that the immune system makes use of exactly the same signals and pathways for unwanted chronic inflammation as it does for necessary short-term inflammation. Well established TNF inhibitor therapeutics in use for more than 20 years illustrate the problems facing every future therapy based on this identify-and-interfere approach, in that all such treatments degrade the effectiveness of the immune system as a side-effect of reducing inflammation. There must be a better way forward.
Reversal of Cellular Senescence
Considerable skepticism has attended efforts to reverse cellular senescence, to force such cells back into the cell cycle and change their behavior back to that of an ordinary somatic cell. Senescent cells exhibit a lot of DNA damage as a result of entering the senescent state, and further, many senescent cells are senescent for good reasons - such as potentially cancerous DNA damage. All this said, recent data demonstrates that reversal of senescence throughout the body of an aged mouse is in fact beneficial, producing improved health and extended life. Thus it seems a good time to work towards novel means of allowing cells to escape senescence, expanding on the existing small portfolio of approaches, and better assessing the long term results of doing this in larger mammalian species.
Build a Gut Microbiome in a Capsule
The composition of the gut microbiome changes with age in ways that provoke harm: more inflammation, and the generation of fewer beneficial metabolites. How to address this? Fecal microbiota transplantation enables permanent alteration of the gut microbiome. In animal studies, transplanting a young microbiome into old individuals produces lasting rejuvenation of the gut microbiome, and consequent improvements in health and extension of life span. Unfortunately, there is something like a 1% risk per year in young adults of developing one of the number of chronic pain or autoimmune-like idiopathic conditions, such as fibromyalgia, that may be caused by as yet unmapped microbial activities in the gut microbiomes of patients. If a donor who is otherwise screened as clear of pathogens goes on to develop such a condition, the recipient may do so also. This is a risk that cannot presently be quantified, too little is known.
The solution is to produce artificial gut microbiomes with known constituents, building up to the scores of microbial species known to change in prevalence with age in suitable bioreactors. Delivery could involve, say, use of a handful of enteric-coated capsules to delivery a few ounces of material via oral administration rather than an enema as is presently the case. This goal requires a considerable advance over the present state of the art for culturing commensal microbes at scale. It is, however, the most likely endpoint for this end of the industry. Those developers who are first to market with pseudo-natural youthful mixes of gut microbiota capable of producing lasting change with a single administration will likely do well.
More Initiatives Aimed at Repairing the Aged Extracellular Matrix
The extracellular matrix changes in many ways over the course of aging. Some of this is the result of altered behavior in the cells responsible for maintaining the matrix. Perhaps the most well understood of these situations is the path to osteoporosis, where the activity of cells breaking down bone extracellular matrix progressively outweighs the activity of cells building up bone extracellular matrix. But more generally, all too little is understood of the ways in which maintenance of the extracellular matrix changes with age, how these changes cause further harm, and how best to intervene somewhere close to the causes of these problems.
Further, beyond the question of cell maintenance of the extracellular matrix, matrix molecules become altered and damaged in ways that provoke harm, such as through altered cell behavior in reaction to matrix changes, or altering the physical properties of the tissue, such as elasticity. Cross-linking of molecules is one of the better known issues, but while considerable effort has been devoted towards expanding the size of the research community involved in studying cross-linking, there is a long way to go yet. Few efforts have made the leap to for-profit development. More initiatives here would be welcome, particularly in areas beyond cross-linking where comparatively little work has been carried out on harmful matrix alterations, their characterization, causes, and possible remediation.
An Infrastructure for Cheaper, Faster Clinical Trials
Clinical trials are far too expensive. This dramatically slows the pace of development, and leads to a situation in which a whole range of interventions are never rigorously assessed because it would be impossible for investors to recoup the cost of a clinical trial. Small initiatives have nibbled away at the edges of this problem for years, largely with only small gains to show for it. They range from crowdfunding trials for off-patent drugs such as rapamycin to attempts to establish parallel clinical trial infrastructures outside the US and EU. That latter path has on the one hand given rise to the Australian clinical trial industry which enables early stage trials to run at something like half the cost of the US, by greatly reducing the requirements for GMP manufacturing, and devolving most of the regulation of trials to competing institutional review boards rather than a centralized government agency. At the other end of the spectrum, initiatives such as Próspera attempted to build an even cheaper solution with a far more libertarian regulatory framework. In between these two extremes, one finds countries such as the Bahamas or Eastern European nations trying to attract a clinical trial industry by offering lower regulatory burdens, tax incentives, and cheaper costs.
The existing US and EU pharmaceutical industry, deeply embedded in regulatory capture, is hostile to most of the efforts made to escape the regulatory costs of clinical trials, as it wields those costs as a defense against upstart competitors. The biggest challenge facing any novel effort to reduce costs and streamline trials beyond the line in the sand set by Australia is that companies taking advantage of the lower costs and regulatory burden will suffer attacks on their reputation, informal censure and hindrance by regulators, and other consequences should they try to proceed with clinical development in heavily regulated markets such as the US and EU. Most biotech startup entrepreneurs look at what that would do to their ability to obtain future funding and avoid this path. A solution to this problem is very much needed, one that provides the right incentives to build a sizable parallel clinical trial infrastructure that can operate at a fraction of the present cost.
Fix Medical Tourism, Free the Data
Medical tourism is an extremely messy industry. Discovery of and comparison between the clinics scattered between jurisdictions is extremely difficult, next to no clinic publishes any data beyond a few carefully cherry-picked case studies, and there is little development of an industry of guidance and review to assist with these problems. Nonetheless, enormous amounts of data are being generated for forms of stem cell therapy, to pick one example, and then essentially thrown into the void. There is no incentive for any given clinic to submit to rating and review, or to publish data. There is no incentive for clinics with particularly successful protocols to share those protocols or their data. Too little is known of how to optimize protocols around cell therapy and exosome therapy, a very data-driven endeavor. In principle, there is a vast mine of valuable data out there waiting to be tapped, to accelerate progress and improve widely used therapies. In practice the incentives all line up against that outcome. Somewhere out there is a way to do better than this.
Mitochondrial Transfer as a Mechanism of Tumor Immunosuppression
https://www.fightaging.org/archives/2025/02/mitochondrial-transfer-as-a-mechanism-of-tumor-immunosuppression/
There remains a great deal yet to be learned of the fine details of cellular biochemistry and the interactions between cells and their environments. Even just one cell remains a fantastically complex, incompletely understood collection of mechanisms. As a general rule, given further study, any aspect of cellular biology will turn out to be more complex than the present understanding suggests it to be. This is one of the reasons to advocate for approaches to aging that try to repair known forms of cell and tissue damage rather than adjust cell behavior. To use an analogy, it is a lot easier to periodically remove rust than it is to build and experimentally validate a computational model of how rust progresses to structural failure in a complex arrangement of pipes, and then use the model to test ways to alter the biochemistry of rust or the form of the structure in order to slow the corrosion.
So to today's example of newly understood complexity in cellular biochemistry. It hasn't been all that long since researchers established that cells are capable of using mitochondria as signals, secreting them and taking them up, or exchanging them via short-lived nanotubes established between cells for this purpose. Any mechanism employed by normal cells is on the table for exploitation by cancerous cells, and this is the case for transport of mitochondria. It turns out that tumor cells will feed dysfunctional mitochondria to nearby immune cells, suppressing their normal tendency to attack the cancerous cells. Numerous other immunosuppression techniques are employed by cancer cells; in principle, finding ways to disable any one of them might give some advantage to cancer patients.
Immune evasion through mitochondrial transfer in the tumour microenvironment
Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs.
Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo.
Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.
Towards Control of Mitochondrial Dynamics
https://www.fightaging.org/archives/2025/02/towards-control-of-mitochondrial-dynamics/
Mitochondria are the power plants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP). Every cell contains hundreds of mitochondria, evolved from the symbiotic bacteria that took up residence inside the ancestors of today's eukaryotes. Mitochondria replicate like bacteria, can fuse together or pass around component parts, while damaged mitochondria are culled by mitophagy, a quality control mechanism. Mitochondrial function declines with aging, and this is associated with reduced mitophagy and changes in mitochondrial dynamics. This is an area of active and extensive study, but a complete and concrete understanding of how and why mitochondria become less effective in the cells of old tissues remains to be established.
A number of projects have focused on improving the efficiency of mitophagy in order to slow the age-related decline in mitochondrial function. How exactly the various drugs and supplements used in these programs act to improve mitophagy is largely understood only in outline, if at all. Some drugs are discovered by screening, and their mechanism of action only uncovered later. Others are developed to target a particular mechanism, but a full understanding of why that mechanism is important is only later established. As noted in today's open access paper, another approach is to try to alter mitochondrial dynamics in favorable ways, adjusting the pace of fission or fusion of mitochondria to alter average size or other structural and functional aspects. Mitophagy and mitochondrial dynamics are clearly closely connected, but again, a full understanding of why this is the case remains a work in progress.
Tuning mitochondrial dynamics for aging intervention
The mitochondrion is a double membrane structure within the cytoplasm that contains its own genome and generates the majority of the cell's energy via aerobic respiration. Mitochondria naturally eliminate pathogenic mitochondrial DNA (mtDNA) mutations and repair dynamic architectures by controlling organelle division and fusion via guanosine triphosphatase (GTPase) dependent signaling. In this process, fusion compensates partially damaged mitochondria, whereas fission generates new mitochondria and dilutes the fraction that is dysfunctional. It is known that defects in GTPase-driven biogenesis cause dysfunctional oxidative phosphorylation and this is associated with mammalian aging and organ failure. Therefore, effectively targeting mitochondrial quality has the potential to rejuvenate cellular biology and ameliorate aging-associated disease.
The GTPases Mitofusins 1 and 2 (MFN1 and MFN2) represent important targets in mitochondrial disease as they initiate mitochondrial membrane fusion. Indeed, a hallmark of myocardial aging is the accumulation of dysfunctional mitochondria due to non-redundant functions of MFN1 and 2. To target MFN1 fusion activity, a small molecule agonist was recently developed. Termed S89, it rescued mitochondrial fragmentation and swelling following ischemia/reperfusion injury by interacting with the GTPase domain of MFN1, thus delayed aging-derived senescence resulting from mitochondrial DNA mutations. To modulate MFN2's fusogenic activity, a further peptidomimetic small molecule, MASM7, was recently discovered. MASM7 activates MFN2 pro-tethering conformation and enables mitochondrial fusion resulting in increased membrane potential, mitochondrial respiration, and subsequent ATP production, providing promise to reduce age-related degenerative metabolic disease.
The regulation of mitochondrial fission in human aging has also been studied. The GTPase dynamin-related protein 1 (Drp1) uniquely triggers mitochondrial fission by chemoenzymatically constricting the mitochondrial surface to divide the organelle leading to mitophagy. Uncontrollable Drp1 activation leads to hyper-fragmentation, sustained opening of mitochondrial permeability transition pores and eventually apoptosis, which is commonly detected during aging. The most successful Drp1 inhibitor is Mdivi-1, a derivative of quinazolinone, which has been widely reported to mitigate disease, from myocardial failure to abnormal neurodegeneration. Most recently, a new covalent molecule named MIDI was discovered. MIDI interacts with Drp1 cysteines and effectively blocks Drp1 recruitment instead of directly targeting its tetramerization and GTPase activity. This provides a fresh angle to further establish Drp1 inhibitors that target age-related diseases.
Shorter Average Telomere Length in White Blood Cells Correlates with Increased Dementia Risk
https://www.fightaging.org/archives/2025/02/shorter-average-telomere-length-in-white-blood-cells-correlates-with-increased-dementia-risk/
Telomeres are caps of repeated DNA sequences at the ends of chromosomes. A little telomere length is lost with each cell division, and cells with very short telomeres become senescent or undergo programmed cell death. This is one part of the mechanisms making up the Hayflick limit on the number of times a somatic cell can divide, ensuring turnover of somatic cells making up tissues. New cells with long telomeres are generated by adult stem cell populations. Average telomere length decreases with age, but only when considering large study populations. It is a very blurry measure of declining stem cell function and increased replication stress on cells resulting from the causative mechanisms of aging.
In particular, it is worth noting that telomere length is usually measured in white blood cells from a blood sample, not a tissue sample. Immune cells are subject to a dynamic characteristic of replication and replacement that is quite different from that of cells in tissue. Average telomere length in a sample of immune cells can vary from day to day, by burden of infectious disease, by psychological stress, and everything else that might adjust the behavior of the immune system distinctly from the behavior of tissues. This is one of the reasons why it is a poor biomarker of aging, of little use for planning on the part of any one individual. One does still see correlations in large study populations, however.
Biomarker tied to premature cell aging may signal stroke, dementia, late-life depression
Leukocyte telomere length, which reflects the length of the telomeres within white blood cells (leukocytes), is a known marker of biological aging. Telomeres gradually shorten with age, reducing their ability to protect the chromosomes' genetic material, leading to cellular aging and increased susceptibility to age-related diseases. The length of telomeres is affected by unchangeable factors such as genetics, ancestry, and gender, as well as modifiable factors such as lifestyle choices and environmental stressors, including pollution.
The current study uses data from more than 356,000 participants in the large UK Biobank to address three questions. When participants were recruited for the study between 2006 and 2010, they provided blood samples to analyze leukocyte telomere length. Additionally, they underwent a Brain Care Score assessment, a tool designed to quantify modifiable factors such as physical factors, lifestyle choices, and social interactions. Participants were followed for a median duration of 12 years to monitor the onset of stroke, dementia, or late-life depression.
Compared to participants with longer leukocyte telomeres, people with the shortest leukocyte telomere length had an 8% higher risk of stroke, a 19% higher risk of dementia, and a 14% higher risk of late-life depression. Overall, compared to participants with longer leukocyte telomeres, people with the shortest leukocyte telomere length had an 11% higher risk of developing at least one of the age-related brain diseases studied.
Amphiregulin Secreted by Regulatory T Cells Promotes Thymus Regeneration
https://www.fightaging.org/archives/2025/02/amphiregulin-secreted-by-regulatory-t-cells-promotes-thymus-regeneration/
The thymus is a small but vital internal organ. Thymocytes generated in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. One of the important contributions to the aging of the immune system is that the thymus steadily atrophies with advancing age, losing active tissue that is replaced with fat. This reduces the ongoing supply of replacement T cells to a fraction of the youthful numbers, leading to a adaptive immune system that is ever more populated by malfunctioning, exhausted, and senescent cells that should have been replaced - and ever more dysfunctional as a result. In most individuals, little thymic tissue is left by age 50, starting a slow countdown to the prevalent immunosenescence exhibited by people in their 70s.
A number of research groups and companies are now delving more deeply into the mechanisms governing atrophy of the thymus, tissue maintenance in the thymus, and regeneration of the thymus following injury. The hope is to find a cost-effective way to spur the atrophied, aged thymus into regrowth, and thus rejuvenate some aspects of the aged immune system. Sadly, much of the roadblock remains one of challenges in delivery and side-effects. There are demonstrated means of provoking thymus regeneration, but it is a small organ, and the only ways to bring materials to it efficiently remain direct injection and use of cells that home to the thymus. The former will never be approved for widespread use, because it carries a small but significant risk of severe side-effects in older people, and the latter will be too expensive for widespread use. Thus one needs a therapy that the rest of the body can tolerate or ignore, and so far the only viable means with evidence for modest thymic regrowth are (a) calorie restriction and (b) long-term growth hormone treatment combined with other drugs to blunt the side-effects of growth hormone.
Today's open access research is an interesting example of ongoing work on the mechanisms of thymic regeneration from injury. It remains unclear whether mechanisms identified in this context will also be useful in the context of normal tissue maintenance, however. The way to find out is to try, of course, and this work does at least point to one quite specific mechanism as a target.
Recirculating regulatory T cells mediate thymic regeneration through amphiregulin following damage
Robust thymic function produces a diverse T cell pool and is essential for a competent immune response. Decreased thymic output of T cells, resulting from age-associated thymic involution or thymic injury, increases the risk of malignancies, autoimmunity, mortality, and morbidity. There is an unmet clinical need to identify strategies to boost thymic function, particularly for patients undergoing cancer therapies and for older adults. The regenerative capacity of the thymus involves a complex interplay of stromal cells, innate immune cells, and immigrating bone-marrow-derived progenitor cells. The role of mature recirculating T cells in this process is poorly understood. However, recirculating regulatory T cells (Treg cells) have been identified as drivers of regeneration in specific compartments, such as lung, visceral adipose tissue, muscles, aorta, hair follicle, and skin - in addition to their classically understood roles in regulating adaptive and innate immune responses.
The cytokine amphiregulin (Areg) is specially implicated in the regenerative function of Treg cells at epithelial surfaces. In the thymus, a population of recirculating Treg cells that migrates between the periphery and the thymus coexists with newly generated Treg cells during negative selection. Here, we examined the role of Treg cells in the regeneration of the thymus after injury. We identified a unique population of Rag2GFP-CD4+Foxp3+ Treg cells that accumulate in the thymus after acute injury. Depletion and adoptive transfer of this cell population impaired and promoted, respectively, thymic repair in mice. Single-cell transcriptome analyses of this Treg cell population throughout aging highlighted variation in the expression of Areg, and Treg cell-specific deletion of Areg-impaired thymic regeneration. Analyses of human thymi identified a similar recirculating population of Treg cells. Our findings provide insight into the mechanisms of thymic regeneration and repair, with implications for therapeutic approaches aimed at boosting thymic function in the elderly and in cancer patients.
Physical Activity Correlates with Reduced Age-Related Mortality
https://www.fightaging.org/archives/2025/02/physical-activity-correlates-with-reduced-age-related-mortality/
The concept of "healthy aging" is well-intentioned but pernicious. By definition, aging is a loss of health, the rise of mortality risk due to failure of vital biological systems in the body. Aging less rapidly is better than aging more rapidly, and advocacy for greater physical activity to slow the progression aging is a good thing, but painting any state of aging as "healthy" is the road to acceptance of decline, the road to minimizing the need for rejuvenation therapies, the road to painting a slowing of aging as the only possibility worth talking about. Rejuvenation is clearly possible, as demonstrated by many animal studies of senolytics, reprogramming, fecal microbiota transplantation, and other approaches. Some of the well-established patient advocacy rhetoric relating to later life health needs to change as a result.
Canada's population is aging, with at least 1 in 5 people aged 65 years or older in 2025, and the number of people older than age 85 years is expected to triple in the next 20 years. However, for many people, these added years do not mean healthy years. More than 80% of adults do not meet the recommendations for physical activity. "Physical activity is one of the most important ways to preserve or improve functional independence, including among older adults who are frail or deemed to be at increased risk of falling. Higher levels of physical activity in older age are associated with improvements in cognition, mental health, and quality of life."
A meta-analysis of several large studies found that 150 minutes of moderate physical activity every week reduced risk of death from all causes by 31%. Physical activity is essential for aging well and can help prevent or reduce disease in more than 30 chronic conditions, such as coronary artery disease, heart failure, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, depression, dementia, and cancer. Benefits of activity include the following: protection against risk of death from any cause; falls prevention through increased muscle strength and better balance; bone and joint health, including improved bone density and alleviation of some osteoarthritis symptoms; improved cognitive function, and better mood and mental health; ability to engage in daily activities and improved quality of life.
Details on Rubedo's Lead Senolytic Program
https://www.fightaging.org/archives/2025/02/details-on-rubedos-lead-senolytic-program/
Here find an interview with the founder of Rubedo, a senolytic drug discovery company, also one of the co-founders of Turn Bio, one of the first cellular reprogramming companies. Of note, Rubedo recently released more information on their lead program. The senolytic space is expanding considerably in terms of potential target mechanisms. It begins to resemble the cancer research community, which pioneered development of many of the early senolytic drugs, and indeed one might expect this to continue. The two fields share a similar goal, meaning the selective destruction of specific cells that exhibit complex, incompletely mapped characteristics, where those characteristics likely differ in important ways by tissue type, and will naturally tend to proceed along analogous paths to one another.
We just announced our target: it's GPX4. Our compound RLS1496 is a proprietary GPX4 modulator. We developed a molecule that can modulate GPX4 and target vulnerabilities in senescent cells while sparing healthy cells, and its effects extend beyond skin. GPX4 is central to ferroptosis, a distinct form of cell death different from apoptosis or necroptosis. Though this pathway was only discovered about ten years ago, it's generating a lot of interest.
This target has been studied mostly in the context of oncology so far. Now, people are looking at cardiovascular conditions, inflammation, and fibrosis. Our own next step will be systemic applications targeting inflammation and metabolic disorders. We also have other programs with different targets - for instance, our lung interstitial disease program, supported by the California Institute for Regenerative Medicine (CIRM), targets lung stem cells that become senescent. These cells trigger a cascade leading to fibrosis as in idiopathic pulmonary fibrosis, and tissue degeneration leading to COPD or pulmonary hypertension. We'll start with lung fibrosis before expanding to other indications.
In oncology, ferroptosis has been explored as a therapeutic opportunity studying aggressive cancer cells that resist traditional treatments. Researchers are trying to use synthetic lethality approaches to sensitize treatment-resistant cancer cells to ferroptosis, with GPX4 as a target. This presents challenges because cancer cells proliferate rapidly, develop resistance, and require carefully engineered synthetic lethality. What we discovered is that certain senescent cells are naturally vulnerable to ferroptosis. But senescent cells have an advantage over cancer cells - they don't divide or grow. This means we can use more flexible dosing schedules and don't need to eliminate every single cell immediately. We can gradually reduce their population over time.
We've found that by modulating GPX4 in specific ways, we can trigger ferroptosis in senescent cells while sparing healthy cells, giving us a therapeutic window. Our compound, RLS1496, is a potent GPX4 modulator that can achieve this effect at single-digit nanomolar concentrations. Studies have shown that reducing GPX4 levels throughout life in mice (not completely removing it, which is lethal at birth) increases lifespan by 7-10%, and these mice develop fewer tumors and are generally healthier. While this suggests a broader role in longevity, we're currently focusing on targeting specific pathological senescent cell populations.
Cellular Reprogramming in the Hypothalamus Slows Ovarian Aging in Rats
https://www.fightaging.org/archives/2025/02/cellular-reprogramming-in-the-hypothalamus-slows-ovarian-aging-in-rats/
Researchers here show that long term exposure to reprogramming factors in the hypothalamus of rats slows ovarian aging. It is an interesting result to add to a range of existing studies demonstrating that cell reprogramming can be conducted safely in the central nervous system. Bringing forms of reprogramming to human medicine still looks like a long, slow process, even given the sizable amounts of funding dedicated to this project at Altos Labs and other organizations.
In middle-aged (MA) female rats, we have demonstrated that intrahypothalamic gene therapy for insulin-like growth factor-I (IGF-I) extends the regular cyclicity of the animals beyond 10 months (the age at which MA rats stop ovulating). Here, we implemented long-term Oct4, Sox2, Klf4, c-Myc (OSKM) gene therapy in the hypothalamus of young female rats. The main goal was to extend fertility in the treated animals. We constructed an adenovector that harbors the green fluorescent protein (GFP) gene as well as 4 Yamanaka genes. An adenovector that only carries the gene for GFP or DsRed was used as control. At 4 months of age 12 female rats received an intrahypothalamic injection of our OSKM vector (treated rats); 12 control rats received a vector expressing a marker gene (control rats).
At 9.3 months of age control and treated rats were mated with young males. A group of 12 young intact female rats was also mated. The rate of pregnancy recorded was 83%, 8.3% and 25% for young, MA control, and MA treated animals, respectively. Pup body weight (BW) at weaning was significantly higher in the MA OSKM rats than in MA controls. At the age of estropause (10 months), OSKM treated females still showed regular estrous cycles. The particular significance of the present results is that, for the first time, it is shown that long-term OSKM gene therapy in the hypothalamus is able to extend the functionality of such a complex system as the hypothalamo-pituitary-ovarian axis.
Implicating Changes in the Gut Microbiome as a Contributing Factor in Sarcopenia
https://www.fightaging.org/archives/2025/02/implicating-changes-in-the-gut-microbiome-as-a-contributing-factor-in-sarcopenia/
The relative proportions of various microbial species making up the gut microbiome changes with age, in ways that provoke greater chronic inflammation and reduce the generation of beneficial metabolites such as butyrate. This likely contributes to many different age-related diseases, but producing the data to firmly support that hypothesis remains a work in progress. Papers such as the one noted here are being published at a fair pace these days, building out an understanding of the correlation between specific changes in the gut microbiome and specific age-related conditions. Even as this body of knowledge is established, it already seems clear that interventions capable of restoring a more youthful gut microbiome must be brought to the clinic and widely deployed.
Sarcopenia is an age-related muscle disorder that increases risks of adverse clinical outcomes, but its treatments are still limited. Gut microbiota is potentially associated with sarcopenia, and its role is still unclear. To investigate the role of gut microbiota in sarcopenia, we first compared gut microbiota and metabolites composition in old participants with or without sarcopenia. Fecal microbiota transplantation (FMT) from human donors to antibiotic-treated recipient mice was then performed. Specific probiotics and their mechanisms to treat aged mice were identified.
Old people with sarcopenia had different microbial composition and metabolites, including Paraprevotella, Lachnospira, short-chain fatty acids, and purine. After FMT, mice receiving microbes from people with sarcopenia displayed lower muscle mass and strength compared with those receiving microbes from non-sarcopenic donors. Lacticaseibacillus rhamnosus (LR) and Faecalibacterium prausnitzii (FP) were positively related to muscle health of old people, and enhanced muscle mass and function of aged mice.
Transcriptomics showed that genes related to tricarboxylic acid cycle (TCA) were enriched after treatments. Metabolic analysis showed increased substrates of TCA cycle in both LR and FP supernatants. Muscle mitochondria density, ATP content, NAD+/NADH, mitochondrial dynamics and biogenesis proteins, as well as colon tight junction proteins of aged mice were improved by both probiotics. LR and the combination of two probiotics also benefit intestinal immune health by reducing CD8+ IFNγ+ T cells.
Heart Rate Variability as a Proxy Measure for Oxidative Stress
https://www.fightaging.org/archives/2025/02/heart-rate-variability-as-a-proxy-measure-for-oxidative-stress/
Researchers here review the evidence for age-related changes in heart rate variability to be usefully reflective of age-related disruption to oxidative metabolism, the well-known oxidative stress observed in the tissues of older individuals. The presence of excessive oxidizing molecules in and around cells is harmful to cell function, and thus to tissue function and health. Oxidative stress is also linked to excessive inflammatory signaling, as one can cause the other. Unfortunately the mechanisms are sufficiently complex for suppressing oxidative stress to be a harder problem than simply consuming known antioxidants. Suppression of inflammation or engineering antioxidants to target specific cell structures has been more promising, but none of the existing solutions are all that great in terms of size of effect.
It is increasingly recognized that mild-to-moderate upregulation in the production of free radicals plays an important physiological role in cellular signaling and can trigger the mechanisms of antioxidant defense, supporting an adaptive response to various stressors. This so-called hormetic response results in the improvement of the functional metabolic reserves and is related to healthy aging as well as to the effects of anti-aging interventions. On the other hand, excessive production of free radicals contributes to the development of oxidative stress and leads to aging. Therefore, the search for biomarkers that would allow efficient assessment of redox homeostasis is of great importance in the monitoring of healthy aging.
We hypothesize that heart rate variability (HRV), which measures the changes in the time between successive R waves in an electrocardiogram (ECG), is largely defined by the activity of the redox homeostasis and, therefore, can be used as a biomarker of aging. Such reasoning is based on several lines of experimental evidence suggesting mechanistic links between the autonomic regulation and oxidative load. In this paper, the modulatory effect of well-characterized oxygen sensor H2S on cardiovascular function and pacemaker activity of the sinus node, the studies on the direct effects of free radicals on the functionality of adrenergic and cholinergic receptors, and demonstrated bidirectional interactions between the activity of the autonomic nervous system and immune response were introduced to support the hypothesis about the close interactions between the production of ROS and autonomic regulation and, thus, HRV. At the same time, further studies are needed to improve our understanding of the crosstalk between mitochondrial function and autonomic regulation.
Targeting NRF2 Regulation of Antioxidant Activities to Treat Aspects of Aging
https://www.fightaging.org/archives/2025/02/targeting-nrf2-regulation-of-antioxidant-activities-to-treat-aspects-of-aging/
Oxidative stress and inflammation tend to go hand in hand in aging, one causing the other. Cells naturally produce oxidizing molecules, such as via mitochondrial activities, and have evolved a range of antioxidant mechanisms to defend themselves. Upregulation of some of these mechanisms has been shown to suppress age-related chronic inflammation, improve tissue function, and even modestly extend life span in animal studies using short-lived species. The paper noted here is an example of this sort of work, targeting NRF2 as a regulator of antioxidant activities in the cell.
Hematopoietic stem cells (HSCs) possess the remarkable capability for self-renewal and multilineage differentiation, giving rise to a spectrum of mature blood and immune cells essential for physiological functions. Oxidative stress, a critical cellular stressor, is characterized by an elevation in reactive oxygen species (ROS) levels and the consequent accumulation of oxidative stress byproducts. This surge in ROS and oxidative damage can precipitate a cascade of detrimental cellular responses, including DNA damage, cell cycle dysregulation, premature cell senescence, and, ultimately, the impairment of HSC function.
DDO1002, a potent inhibitor of the NRF2-KEAP1 pathway, modulates the expression of antioxidant genes. Yet, the extent to which it mitigates hematopoietic decline post-total body irradiation (TBI) or in the context of aging remains to be elucidated. Our study has elucidated the role of DDO1002 in modulating NRF2 activity, which, in turn, activates the NRF2-driven antioxidant response element (ARE) signaling cascade. This activation can diminish intracellular levels of ROS, thereby attenuating cellular senescence. In addition, DDO1002 has been demonstrated to ameliorate DNA damage and avert HSC apoptosis, underscoring its potential to mitigate hematopoietic injury precipitated by TBI.
Competitive transplantation assay revealed that the administration of DDO1002 can improve the reconstitution and self-renewal capacity of HSCs in aged mice. Single-cell sequencing analysis elucidated that DDO1002 treatment can attenuate intracellular inflammatory signaling pathways and mitigated ROS pathway in aged HSCs, suggesting its potential to restore the viability of these cells. Consequently, DDO1002 effectively activated the NRF2-ARE pathway, delaying cellular senescence and ameliorating impaired hematopoiesis, thereby demonstrating its potential as a therapeutic agent for age-related hematopoietic disorders.
Lifestyle Interventions as a Way to Slow the Onset of Immunosenescence
https://www.fightaging.org/archives/2025/02/lifestyle-interventions-as-a-way-to-slow-the-onset-of-immunosenescence/
Variation in lifestyle choice clearly affects life expectancy. A sizable body of evidence exists to connect a slower pace of degenerative aging to both forms of calorie restriction and the various means of maintenance of physical fitness into later life. Immune system aging is an important component of aging considered more broadly, and here researchers discuss the relationship between lifestyle choice and immune aging, including a review of what is known of the mechanisms driving this association.
Immunosenescence, the age-related decline in immune function, is a complex biological process with profound implications for health and longevity. This phenomenon, characterized by alterations in both innate and adaptive immunity, increases susceptibility to infections, reduces vaccine efficacy, and contributes to the development of age-related diseases. At the cellular level, immunosenescence manifests as decreased production of naive T cells and naive B cells, accumulation of memory and senescent cells, thymic involution, and dysregulated cytokine production.
Recent advances in molecular biology have shed light on the underlying mechanisms of immunosenescence, including telomere attrition, epigenetic alterations, mitochondrial dysfunction, and changes in key signaling pathways such as NF-κB and mTOR. These molecular changes lead to functional impairments in various immune cell types, altering their proliferative capacity, differentiation, and effector functions. Emerging research suggests that lifestyle factors may modulate the rate and extent of immunosenescence at both cellular and molecular levels. Physical activity, nutrition, stress management, and sleep patterns have been shown to influence immune cell function, inflammatory markers, and oxidative stress in older adults.
This review provides a comprehensive analysis of the molecular and cellular mechanisms underlying immunosenescence and explores how lifestyle interventions may impact these processes. We will examine the current understanding of immunosenescence at the genomic, epigenomic, and proteomic levels, and discuss how various lifestyle factors can potentially mitigate or partially reverse aspects of immune aging. By integrating recent findings from immunology, gerontology, and molecular biology, we aim to elucidate the intricate interplay between lifestyle and immune aging at the molecular level, potentially informing future strategies for maintaining immune competence in aging populations.
Distinct Effects of Chronic Inflammation on Different Aspects of Hematopoietic Aging
https://www.fightaging.org/archives/2025/02/distinct-effects-of-chronic-inflammation-on-different-aspects-of-hematopoietic-aging/
The state of chronic inflammatory signaling in aging is complex, employing many different signaling pathways to regulate the immune system and many different provocations to stimulate those pathways. Hematopoietic stem cells in the bone marrow are responsible for generating immune cells and red blood cells, and their function changes and declines with aging in ways that are similarly complex, driven by many different factors. Here, researchers take a look at one small portion of the intersection between these two complex phenomena, focusing in on the one inflammatory regulator NFκB.
Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, hematopoietic stem cell (HSC) accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes these aging phenotypes. NFκB both responds to and directs inflammation, and we present an experimental model of elevated NFκB activity ("IκB-") to dissect its role in hematopoietic aging phenotypes.
We found that while elevated NFκB activity is not sufficient for HSC accumulation, HSC-autonomous NFκB activity impairs their functionality, leading to reduced bone marrow reconstitution. In contrast, myeloid bias is driven by the IκB- proinflammatory bone marrow milieu as observed functionally, epigenomically, and transcriptomically. A new single cell RNA sequencing framework enabled comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NFκB activity and quiescence, but not myeloid bias.
These findings delineate separate regulatory mechanisms that underlie the three hallmarks of hematopoietic aging, suggesting that they are specifically and independently therapeutically targetable.
Ultrasound as a Basis for Clearing Senescent Cells
https://www.fightaging.org/archives/2025/02/ultrasound-as-a-basis-for-clearing-senescent-cells/
Researchers here show that a form of ultrasound stimulation can be used to provoke lingering senescent cells into behavior that increases the pace of immune clearance of these unwanted cells. The change in markers of the burden of senescence in skin tissue, a reduction of about a third, is similar to the levels of clearance produced in other organs by first generation senolytic drugs. It is worth noting that the researchers used young mice in their study, and a course of irradiation to produce senescent cells. There are differences in the senescent state resulting from irradiation versus other causes of senescence. Further, the immune system becomes less capable of clearing senescent cells in later life. It is unclear whether this approach would work as well on the natural burden of senescence in old mice.
As emerging therapeutic strategies for aging and age-associated diseases, various biochemical approaches have been developed to selectively remove senescent cells, but how physical stimulus influences senescent cells and its possible application in senolytic therapy has not been reported yet. Here we developed a physical method to selectively stimulate senescent cells via low-intensity pulsed ultrasound (LIPUS) treatment. LIPUS stimulation did not affect the cell cycle, but selectively enhanced secretion of specific cytokines in senescent cells, known as the senescence-associated secretory phenotype (SASP), resulting in enhanced migration of monocytes/macrophages and upregulation of phagocytosis of senescent cells by M1 macrophages.
We found that LIPUS stimulation selectively perturbed the cellular membrane structure in senescent cells, which led to activation of the intracellular reactive oxygen species-dependent p38-NF-κB signaling pathway. Using a UV-induced skin aging mouse model, we confirmed enhanced macrophage infiltration followed by reduced senescent cells after LIPUS treatment. Due to the advantages of ultrasound treatment, such as non-invasiveness, deep penetration capability, and easy application in clinical settings, we expect that our method can be applied to treat various senescence-associated diseases or combined with other established biochemical therapies to enhance efficacy.
Exosome Therapy Restores Some Lost Ovarian Function in Aged Mice
https://www.fightaging.org/archives/2025/02/exosome-therapy-restores-some-lost-ovarian-function-in-aged-mice/
Stem cell therapies produce beneficial effects largely via the signaling produced by transplanted cells for the short time that they survive. Much of this signaling is carried between cells by extracellular vesicles, such as exosomes. Exosomes can be harvested from cells in culture, and this is a less costly and logistically easier approach to the production of therapies. Researchers here demonstrate that exosomes from ovarian follicle cells can be used to restore some of the ovarian function lost with aging, at least in mice.
Ovarian aging is mainly characterized by a progressive decline in oocyte quantity and quality, which ultimately leads to female infertility. Various therapies have been established to cope with ovarian aging, among which exosome-based therapy is considered a promising strategy that can benefit ovarian functions via multiple pathways. Here, we isolated and characterized exosomes derived from ovarian follicular fluid and profiled the differential expression patterns of exosomal noncoding RNAs in young and aged women.
Treatment with young mouse-derived exosomes efficiently rescued ovarian function in aged mice. The follicular fluid exosomes from young mice and miR-320-3p can also promote the proliferation of ovarian granulosa cells and improve mitochondrial function from old mice in vitro. The mechanism may be involve that exosomes transfer miR-320-3p to granulosa cells, and inhibit the expression of FOXQ1. Exosomes also can increase the number of primordial and growing follicles, and improve the developmental ability of oocytes in the old mice in vivo. And hnRNPA2B1 controls miR-320-3p entry into exosomes.
This work provides insights into the antiaging potential of follicular fluid-derived exosomes and the underlying molecular mechanisms, which may facilitate prevention of ovarian aging and an improvement in female fertility.