Fight Aging!

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.

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.

Link: https://doi.org/10.1111/acel.14485

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.

Link: https://doi.org/10.18632/aging.206191

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.

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.

Link: https://www.lifespan.io/news/marco-quarta-on-cellular-senescence-in-aging/

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.

Link: https://www.eurekalert.org/news-releases/1071172

Among the many dysfunctions of aging, significant loss of salivary gland activity is one of those that likely never crosses the mind of anyone other than those suffering from or treating its consequences. Nonetheless, the salivary gland is a complex structure, and like all tissues, is negatively impacted by the mechanisms of aging. Inadequate production of saliva and contribute to the difficulties of eating experienced by very old people, as well as alter the oral microbiome in detrimental ways.

As for many aspects of aging, the relative importance of the various mechanisms of aging in salivary gland dysfunction is not known. Today's open access paper focuses on the age-related accumulation of senescent cells, which at this point has been comprehensively demonstrated to contribute to many specific dysfunctions of aging in animal models. Senescent cells secrete inflammatory, disruptive signals. The more senescent cells there are in a tissue, the greater the negative impact on tissue structure and function.

Cellular Senescence Contributes to the Dysfunction of Tight Junctions in Submandibular Glands of Aging Mice

Saliva is essential for maintaining oral health, playing a role in lubrication, taste, chewing, swallowing and initial immune defense. Studies have shown that older people experience decreased salivary secretion, leading to symptoms such as dysphagia, increased risk of dental caries, and dysbiosis of the oral microbiota. Increasing research suggests a strong link between the excessive accumulation of senescent cells and age-related diseases. The accumulation of senescent cells, particularly those positive for p16Ink4a, is associated with inflammatory responses and reduced lifespan. Conversely, the elimination of these cells can attenuate tissue dysfunction and improve health.

Tight junctions, cell-to-cell adhesion complexes located at the apical regions of adjacent epithelial/endothelial cells, dynamically regulate material transport through the paracellular pathway, playing a crucial role in saliva secretion. Recent researches have shown that dysfunction of tight junctions contributes to abnormalities in salivary secretion in diseases such as diabetes mellitus. Numerous studies have demonstrated significant alterations in tight junctions in various tissues and organs during aging, such as the skin, gastrointestinal tract, and blood-brain barrier (BBB).

This study investigates the mechanism of aging-related submandibular dysfunction and evaluates the therapeutic potential of dental pulp stem cell-derived exosomes (DPSC-exos). We found that the stimulated salivary flow rate was significantly reduced in naturally aging and D-galactose-induced aging mice (D-gal mice) compared to control mice. Acinar atrophy and periductal fibrosis in submandibular and parotid glands were observed in naturally aging and D-gal mice, whereas sublingual glands had no notable alterations. We observed the accumulation of senescent cells in the submandibular glands.

Injecting DPSC-exos into the submandibular glands of D-gal mice improved stimulated salivary flow rate, reduced acinar atrophy, and decreased SA-β-gal activity. Our study identified that increased senescence of submandibular glands in aging mice can cause a decrease in salivary secretion by disrupting the expression and distribution of tight junction molecules, and injection of DPSC-exos ameliorates submandibular secretory dysfunction. These findings may provide new clues to novel therapeutic targets for aging-related dysfunction of submandibular glands.

One way to look at the impact of aging versus the impact of an intervention to slow aging is to examine transcriptional changes in cells. Pick a tissue and cell type, assess the whole transcriptome of RNA molecules produced by that cell type, then compare old versus young animals and treated versus untreated old animals. Here, researchers compare the effects of aging in rat muscle versus the effects of calorie restriction, an intervention known to slow aging in mammals. As one might expect, calorie restriction reduces the magnitude of many of the changes in transcription that take place with age.

Age-related muscle wasting, sarcopenia is an extensive loss of muscle mass and strength with age and a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to survey the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a known prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. RNA-seq data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key "hub" proteins involved in their activation.

RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and immune responses; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. This data may provide the initial evidence for several targets for potential future therapeutic interventions against sarcopenia.

Link: https://doi.org/10.1186/s12864-024-11051-1

There is a growing appreciation for the contribution of supporting cells in the brain to the progression of neurodegenerative conditions. Astrocytes perform a diverse range of functions in the brain, but can undergo maladaptive changes in behavior in response to the damage of aging and disease, making things worse. These reactive astrocytes are in some ways analogous to senescent cells, in that they provoke inflammation but are also involved in repair of injury and remodeling of tissue. As is the case for senescent cells, too much of this tips over from being helpful to being harmful to surrounding tissues.

For over a century after their discovery astrocytes were regarded merely as cells located among other brain cells to hold and give support to neurons. Astrocytes activation, "astrocytosis", was considered a detrimental mechanism against neuronal survival. Recently, the scientific view on astrocytes has changed. Accumulating evidence indicate that astrocytes are not homogeneous, but rather encompass heterogeneous subpopulations of cells that differ from each other in terms of transcriptomics, molecular signature, function, and response in physiological and pathological conditions. In this review, we report and discuss the recent literature on the phenomic differences of astrocytes in health and their modifications in disease conditions, focusing mainly on the hippocampus, a region involved in learning and memory encoding, in the age-related memory impairments, and in Alzheimer's disease (AD) dementia.

The morphological and functional heterogeneity of astrocytes in different brain regions may be related to their different housekeeping functions. Astrocytes that express diverse transcriptomics and phenomics are present in strictly correlated brain regions and they are likely responsible for interactions essential for the formation of the specialized neural circuits that drive complex behaviors. In the contiguous and interconnected hippocampal areas CA1 and CA3, astrocytes show different, finely regulated, and region-specific heterogeneity. Heterogeneous astrocytes have specific activities in the healthy brain, and respond differently to physiological or pathological stimuli, such as inflammaging present in normal brain aging or beta-amyloid-dependent neuroinflammation typical of AD.

To become reactive, astrocytes undergo transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. Alterations of astrocytes affect the neurovascular unit, the blood-brain barrier, and reverberate to other brain cell populations, favoring or dysregulating their activities. It will be of great interest to understand whether the differential phenomics of astrocytes in health and disease can explain the diverse vulnerability of the hippocampal areas to aging or to different damaging insults, in order to find new astrocyte-targeted therapies that might prevent or treat neurodegenerative disorders.

Link: https://doi.org/10.3389/fncel.2024.1512985

Autophagy is the name given to a collection of processes for recycling damaged structures in the cell. It is complex, involving means of determining that a structure is in some way damaged or excess to requirements, wrapping that structure in a membrane called an autophagosome, transporting the autophagosome into contact with a lysosome, and then merging autophagosome and lysosome to allow the enzymes of the lysosome to break down and recycle the autophagosome contents. Increased efficiency in autophagy is a feature of many of the interventions demonstrated to slow aging in animal studies, including lifestyle interventions such as exercise and calorie restriction. Evidence suggests that the age-slowing effects of calorie restriction depend upon this upregulation of autophagy, that it is the most important aspect of the changed biochemistry that results from a reduced availability of nutrients.

Given all of this, there is considerable interest in the development of therapies capable of selectively improving the operation of autophagy. Despite a broad range of research and development programs, little beyond the known repurposed calorie restriction mimetic drugs (such as rapamycin) has yet made it as far as the clinic. Still, new programs continually arise in the research community. Today's open access paper offers an example of one such program at an early stage, an attempt to apply upregulation of autophagy to the thorny problem of Alzheimer's disease. The hope is that improved autophagy will reduce amyloid deposition and consequent pathology, perhaps directly by clearing amyloid more rapidly, perhaps indirectly via reduced inflammation or similar mechanisms.

KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly. The imbalance of protein production and degradation processes leads to the accumulation of misfolded and abnormally aggregated amyloid-beta (Aβ) in the extracellular space and forms senile plaques, which constitute one of the most critical pathological hallmarks of AD. KIF9, a member of the kinesin protein superfamily, mediates the anterograde transport of intracellular cargo - such as autophagosomes and lysosomes - along microtubules. However, the exact role of KIF9 in AD pathogenesis remains largely elusive.

In this study, we reported that the expression of KIF9 in the hippocampus of APP23/PS45 double-transgenic AD model mice declined in an age-dependent manner, concurrent with macroautophagy dysfunction. Furthermore, we found that KIF9 mediated the transport of lysosomes through kinesin light chain 1 (KLC1), thereby participating in the degradation of amyloidogenic pathway-related proteins of Aβ precursor protein (APP) in AD model cells through promoting the macroautophagy pathway.

Importantly, genetic upregulation of KIF9 via adeno-associated virus (AAV) diminished Aβ deposition and alleviated cognitive impairments in AD model mice by enhancing macroautophagy function. Collectively, our findings underscore the ability of KIF9 to promote macroautophagy through KLC1-mediated anterograde transport of lysosomes, effectively ameliorating cognitive dysfunction in AD model mice. These discoveries suggest that KIF9 may represent a novel therapeutic target for the treatment of AD.

NF-κB is important in inflammatory signaling, and one of many possible targets for suppression of inflammation. The usual caveats apply, in that unwanted, harmful, chronic inflammation uses the same signaling pathways as normal, necessary, short-term inflammatory responses to pathogens and injury. Researchers have yet to find a suppression approach that only affects chronic inflammation, and does not also suppress beneficial functions of the immune system. In principle the only reliable way to achieve that goal is to remove the damage of aging that causes inflammation, which is not presently the primary focus of researchers concerned with inflammation.

Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells.

In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T cells and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain.

Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation.

Link: https://doi.org/10.1038/s12276-024-01388-8

An exerkine is a signaling molecule secreted in response to exercise. Classifying signaling in this way is a fairly recent development, and so mapping the space of exerkines is an ongoing exercise. Myokines, signal molecules released by muscle, are another recently established category, and there is some overlap between exerkines and myokines. Exerkines are a broader category, and might in principle be produced in any tissue in response to exercise. Evidently regular exercise is beneficial, and the goal of exerkine research is to better understand how those benefits are produced, potentially with the goal of producing exercise mimetic drugs.

Exerkines are bioactive molecules released by various tissues in response to exercise and are essential mediators in the anti-aging effects of physical activity. Initially, it was believed that exerkines were primarily produced by skeletal muscle, but recent studies have shown that multiple organs, including the liver, adipose tissue, bone, and the nervous system, also secrete these molecules. These exerkines not only act locally but also exert systemic effects across the body, regulating metabolic processes, reducing inflammation, supporting tissue repair, and maintaining cognitive function.

The release of exerkines is a highly coordinated process that involves multiple tissues and organs. These exerkines function in a synergistic manner to combat the cellular and molecular changes associated with aging, such as oxidative stress, inflammation, mitochondrial dysfunction, and tissue degeneration. By enhancing the production of these molecules, regular exercise creates an environment that promotes tissue maintenance, metabolic balance, cardiovascular health, and cognitive resilience. This highlights the central role of exerkines in the anti-aging benefits of exercise, as they help to preserve functional capacity and overall health as we age.

Exercise promotes the release of exerkines such as IGF-1, GPLD1, BDNF, clusterin, and PF4, leading to enhanced synaptic plasticity, improved neuroprotection, and reduced neuroinflammation. The upregulation of PGC-1α in response to exercise contributes to cardiomyocyte hypertrophy, increased proliferation, and anti-apoptotic effects, which support overall cardiac health and longevity. Exercise decreases hepatic steatosis and modulates the inflammatory response via the increased secretion of IL-10 and irisin, reducing liver inflammation and improving metabolic homeostasis. Exerkines like FGF-21 and apelin stimulate lipid oxidation, decrease fat mass, and promote the browning of adipose tissue, contributing to improved metabolic function and fat utilization. NOX4 and HSP90 are upregulated during exercise, improving muscular contractility, and enhancing the antioxidant capacity of mitochondria, thereby reducing oxidative stress.

Link: https://doi.org/10.1016/j.exger.2025.112685

Cancer is, evidently, an age-related disease. The immune system becomes less able to prevent precancerous cells from progressing to form a cancer. The burden of mutational damage is higher, increasing the odds of a cancerous combination of mutations arising. Lingering senescent cells pump out pro-growth, pro-inflammatory factors that make tissues more hospitable to growth of cancerous cells. Aging doesn't just affect the odds of cancer, however. The damage and dysfunction of aging induces changes in the behavior of cancer cells and progression of cancer that one might reasonably expect to be just as large and significant as the changes inflicted by aging upon normal cells and tissue function.

In today's open access editorial, researchers consider the intersection between mechanisms of aging and the progression of cancer. Extremely old people differ from younger old cohorts in important ways, including a more advanced decline of immune function, important to the way in which immunotherapies interact with cancerous tissues, and a greater burden of senescent cells, altering the tissue microenvironment with their secretions. Immunotherapies are on their way to eventually becoming the dominant form of cancer therapy, and in their best implementations represent a major advance over chemotherapeutics. As ever more of the standard treatments for forms of cancer become immunotherapies, there will be an ever greater interest in the fine details of interaction between cancer and the aging of the immune system and tissue microenvironment.

Aging and Cancer-Inextricably Linked Across the Lifespan

As patients age, several factors evolve that can profoundly influence cancer progression and responses to therapies. These factors include immune system changes, environmental exposures over a lifetime (exposome), frailty, the cumulative impact of stress (i.e., allostatic burden), comorbidities, and the varying degrees of physical and psychosocial resilience that come with aging and lived experiences. Additionally, a patient's treatment history and the secondary effects of those treatments on organ function play a crucial role in determining the efficacy of future therapies and could be pivotal in tailoring treatment options.

Hematological indications such as leukemias and lymphomas are more readily accessible for such analyses relative to solid tumor indications and represent powerful opportunities to understand the evolutionary process of therapeutic resistance. Notably, the age-dependent expansions of clones (often bearing cancer-associated mutations) in our tissues, which are associated with both malignant and nonmalignant disease risk as shown for the hematopoietic system, still represent a relatively unexplored frontier, particularly regarding the impact of these clonal expansions on patient responses to therapies and overall well-being.

Because the immune system undergoes change throughout the life course (e.g., age-related decline in naïve CD8+ T cells and expansion/exhaustion of memory phenotypes; increasing presence of GMZK+ CD8+ T cells; and biased expansion of myeloid-to-lymphoid cells) the function of immunotherapies such as checkpoint inhibitors and CAR-T cells, as well as immune-related adverse events, may vary accordingly. In infants and children, while CAR T cells have demonstrated success for B-cell acute lymphocytic leukemias, immune checkpoint inhibitor therapies have been less effective, likely due to the low mutation burden of pediatric cancers. Older and geriatric adults who are experiencing immune systemic and cellular senescence changes associated with aging still exhibit responses to checkpoint inhibitors, and CAR-T cell therapy can still be effective against B-cell lymphomas, albeit with reduced responses in those over 75. For older persons, factors such as prior antigen exposure and overall health status should clearly play roles but currently are understudied.

Additional immunotherapeutic opportunities include identifying approaches to limit the accumulation of senescent cells and exhausted cells; limiting genotoxic stress and radiation treatment induced DNA damage and senescence; as mentioned earlier, overcoming tissue contextual changes in the extracellular matrix within the tumor microenvironment that often limit access to tumors; adapting immunotherapies given the age-related increases in PD1 expression on T cells and age-related changes in metabolites (e.g., methylmalonic acid); and anticipating treatment-related complications and comorbidities, such as frailty.

Further to this point, aging is often accompanied by the accumulation of both subclinical and clinical comorbid conditions, which can alter treatment responses and influence disease progression. Different comorbidities (e.g., metabolic disease, cardiovascular disease, inflammatory syndromes) can modulate the pathophysiology of cancer through shared risk factors and biological pathways such as inflammation and immune function. Therefore, acknowledging and addressing these comorbidities is essential in crafting effective, patient-specific treatment plans.

Researchers here demonstrate that the increased level of arginase II observed with advancing age is causing some degree of issues, using mice from a lineage in which arginase II was removed by genetic engineering. Mice lacking arginase II exhibit slowed loss of muscle mass with age, and a lower burden of cellular senescence. Given what is known of arginase II, reduced cellular senescence and inflammatory signaling seem likely to be the important mediating mechanisms, but there are other possibilities to consider. Perhaps the more interesting point is that removing arginase II isn't evidently problematic, only beneficial.

Age-associated sarcopenia decreases mobility and is promoted by cell senescence, inflammation, and fibrosis. The mitochondrial enzyme arginase-II (Arg-II) plays a causal role in aging and age-associated diseases. Therefore, we aim to explore the role of Arg-II in age-associated decline of physical activity and skeletal muscle aging in a mouse model. Young (4-6 months) and old (20-24 months) wild-type (wt) mice and mice deficient in arg-ii (arg-ii-/-) of both sexes are investigated. We demonstrate a decreased physical performance of old wt mice, which is partially prevented in arg-ii-/- animals, particularly in males.

The improved phenotype of arg-ii-/- mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in arg-ii-/- mice. Finally, we demonstrate an increased arg-ii gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells. Our results suggest that increased Arg-II in non-skeletal muscle cells promotes age-associated sarcopenia, particularly in male mice.

Link: https://doi.org/10.18632/aging.206173

The aged intestinal wall exhibits an impaired mucosal barrier, leading to leakage of microbes from the intestines into tissues and circulatory system. This is known to provoke chronic inflammation, which in turn is disruptive to tissue function and contributes to the onset and progression of age-related conditions. Here, researchers identify one specific mechanism by which intestinal microbes can provoke the immune system into a maladaptive inflammatory response. Suppressing that response sounds like a worse option than preventing intestinal barrier dysfunction, as it would likely have negative consequences for immune function considered more broadly. Nonetheless, suppression of specific signaling remains the dominant approach to inflammatory conditions, even given side effects of this nature.

A new study shows how an increase in intestinal permeability allows the natural gut bacteria to cross the intestinal barrier and reach the bone marrow, where they induce epigenetic changes in the stem cells that give rise to immune cells. The epigenetic changes induced by the translocated gut bacteria generate "trained" immune cells primed to respond more efficiently to future infections. However, this same ability to amplify the immune response can also aggravate the inflammatory conditions such as cardiovascular and neurodegenerative diseases.

Until very recently, scientists believed that adaptive immunity was the only type with memory, able to generate cells that 'remember' previous encounters with pathogens and unleash a specific immune response. In contrast, the innate immune response, which is not specific to a particular pathogen, was believed to lack memory. "We now know that innate immunity can be 'trained' to produce a stronger response to later, unrelated infections. What is more, the effects of this training are long-lasting. The main intestinal bacteria we find in the bone marrow is Enterococcus faecalis. These bacteria interact with and activate the pattern recognition receptor Mincle in hematopoietic precursors, inducing epigenetic changes that generate immune cells with an augmented inflammatory capacity."

In animal models, increased intestinal permeability causes colonic inflammation (colitis). This inflammatory reaction does not occur in mice engineered to lack Mincle, suggesting that the detection of translocated bacteria by Mincle plays an important role in the inflammation associated with trained immunity. Strategies aimed at blocking Mincle could thus be protective in the context of these systemic inflammatory diseases.

Link: https://www.cnic.es/en/noticias/immunity-cnic-scientists-discover-how-gut-modulates-development-inflammatory-conditions