Fight Aging!

This post walks through the process of setting up and running a simple self-experiment with taurine supplementation, shown to improve measures of health in old mice and non-human primates. These effects result from enhancing the performance of glutathione, an antioxidant enzyme. You might recall that supplementation with gluthathione precursors to increase gluthatione levels produced suprisingly large effects for a supplement regimen in a small trial in older people.

Taurine levels in blood decline with age, halving from the 20s to 40s-50s in the general population. So while forms of dietary supplementation are usually less compelling than more technological options for improving health in later life, the early decline in taurine, ease of conducting a self-experiment, data in animals, and potential connection to glutathione make it interesting enough to try.

Taurine is a semi-essential amino acid. It is widely used as a supplement, and has undergone rigorous human clinical trials. "Widely used" does not equate to "safe for everyone at any dose", however. Older individuals can and do suffer injury and death from everyday actions, foods, and medications that have no such impact on younger individuals. Regardless of the legions using any particular supplement, it is always wise to gently ease into any personal attempt to join them, rather than leaping in at a full dose on day one.

Contents

• Why Self-Experiment with Taurine?
• Caveats
• Establishing Dosages
• Obtaining Taurine
• Establishing Tests and Measures
• Guesstimated Costs
• Schedule for the Self-Experiment
• Where to Publish?

Why Self-Experiment with Taurine?

A recent study assembled a range of data on taurine levels in blood and taurine supplementation in mice and non-human primates. Taurine levels decline with age and supplementation produces interestingly large benefits to long-term health in these species. Large in the context of what can be achieved by supplements, at least. Further, taurine levels may be connected to the activity of the antioxidant enzyme gluthatione. In a different context, supplementation of glutathione precursor compounds was also shown to produce benefits that are large in the context of supplementation.

It remains unknown as to why taurine levels decline with age, though given that this is an amino acid, we might first think of changes in the gut microbiome and processing of food. There are many, many changes in measurable metabolites in blood that occur with age, but few are demonstrated to produce benefits when reversed, and few are as easily reversed as amino acid levels in the body - just consume more of that amino acid. Amino acid supplementation might be considered a relatively low risk activity, given the large numbers of people who undertake that intervention on a regular basis. A low risk, low cost, modest benefit intervention is unlikely to make you live for a decade longer, but may well be worth the effort for the results obtained.

Caveats

While taurine is widely used as a supplement and accompanied by copious human data on its effects and side-effects (or lack thereof at various doses), one must still think about personal responsibility in any self-experiment. Read the papers reporting on human trials - the effects, side-effects, and dosages - and make an informed personal decision on risk and comfort level based on that information. This is true of any supplement, whether or not approved for use. Do not trust other opinions you might read online: go to the primary sources, the scientific papers, and read those. Understand that where the primary data is sparse, it may well be wrong or incomplete in ways that will prove harmful. Also understand that older bodies can be frail and vulnerable in ways that do not occur in younger people, and that are sometimes not well covered by the studies.

Further, the state of knowledge regarding any particular set of compounds is not static. The science progresses. This post will become outdated in its specifics at some point, as new knowledge and new compounds with similar effects arrive on the scene. Nonetheless, the general outline should still be a useful basis for designing new self-experiments involving later and hopefully better options.

Establishing Dosages

While there is a standard rule of thumb for converting doses in animals to doses in humans, found in the open access paper "A simple practice guide for dose conversion between animals and human", the only definitive way to establish dosing for a supplement or pharmaceutical in order to achieve a given effect is to run a lot of tests in humans.

Fortunately, human trials have been conducted for taurine supplementation. Trial organizers have tended towards 1.5 grams or 3 grams per day for 16+ weeks. Animal studies in mice used 1 g/kg/day, which converts to a 0.08 g/kg/day gram dose in humans, or roughly 5 grams per day for a 60kg human. Animal studies in rhesus monkeys used 0.25 g/kg/day, which also comes to roughly 0.08 g/kg/day for humans, and thus 5 grams per day for a 60kg human.

One can in principle adjust the dose over time to get to a desired level of taurine in the blood, assuming that the desirable level is equivalent to that of a young individual as presented human data from a recent paper. It is relatively cheap to assess blood amino acids, and in many parts of the world one can simply order the tests without involving a physician. Taking 1.5 g/day or 3 g/day for a few weeks and then looking at the outcome before deciding to go to a 5 g/day dose for longer is a reasonable plan.

Obtaining Taurine

Taurine costs little and is readily available from supplement manufacturers in 1 gram pills or powder form. The pill option is more convenient but slightly more expensive. Ordering online is usually a better option than trying to find taurine in specialist supplement stores.

Establishing Tests and Measures

Looking through the literature on taurine supplementation and the various clinical trial designs, measures of inflammation, oxidative stress, and possibly glycation and insulin metabolism in blood samples are the most relevant for this exercise. Many of these tests can be purchased via Quest, Labcorp, or Life Extension Foundation (LEF) without needing a physician in most parts of the US. If cost is less of a concern, services like AgelessRx and Jinfiniti package these and many other assessments into one product. Setting aside considerations of convenience and cost, the following list is a good starting point:

• Taurine: Amino acid level blood test.
• Inflammation: C-reactive protein, TGF-alpha, IL-1, and IL-6, monocyte and granulocyte numbers from a complete blood count.
• Oxidative stress: Oxidized LDL, 8-Oxo-2'-deoxyguanosine for DNA oxidation, glutathione reductase, superoxide dismutase.
• Glycation and insulin metabolism: hemoglobin A1c, fasting glucose, insulin.

It would also be interesting to look at effects on epigenetic age, as no-one appears to have published data on that metric in the context of taurine supplementation. A number of services offer epigenetic age clocks at a variety of price points. One might also consider Phenotypic Age, which can be derived using one of the online calculators from the combination of the following from blood tests: creatine, albumin, fasting glucose, c-reactive protein, alkaline phosphatase (ALP), and the results of a complete blood count.

Guesstimated Costs

The costs given here are rounded up for the sake of convenience, and in some cases are blurred median values standing in for the range of observed prices in the wild.

• Blood tests via Quest / Labcorp / LEF: $500 for each of baseline and final tests
• TruDiagnostic epigenetic age kit: $500 / kit
• Junifinity AgingSOS advanced biomarker panel: $1200 / kit
• 1 kg of taurine powder: $30

Schedule for the Self-Experiment

One might expect the process of discovery, reading around the topic, and ordering materials to take a few weeks. Once all of the decisions are made and the materials are in hand, pick a start date. The schedule for the self-experiment is as follows:

• Week 1: Conduct the baseline bloodwork. Take note of taurine level.
• Weeks 1-4: Daily taurine supplementation at 1.5 g/day or 3 g/day.
• Week 4: Conduct an amino acid test to assess taurine level. Comparing this, the baseline, and published human data, decide on the dose for the remainder of the self-experiment. Either stick with the existing dose, or move to the higher one.
• Weeks 5-20: Daily taurine supplementation.
• Week 20: Conduct the final bloodwork.

Where to Publish?

If you run a self-experiment and keep the results to yourself, then you helped only yourself. The true benefit of rational, considered self-experimentation only begins to emerge when many members of community share their data, to an extent that can help to inform formal trials and direction of research and development. There are communities of people whose members self-experiment with various compounds and interventions, with varying degrees of rigor.

When publishing, include all of the measured data, the compounds and doses taken, duration of treatment, and age, weight, and gender. Fuzzing age to a less distinct five year range (e.g. late 40s, early 50s) is fine. If you wish to publish anonymously, it should be fairly safe to do so, as none of that data can be traced back to you without access to the bloodwork provider. None of the usual suspects will be interested in going that far. Negative results are just as important as positive results. Many interventions will achieve too little to be easily detected for basically fit people younger than 50; the noise in the measures will be larger than the effect size of the intervention.

Why do moles tend to grow hair, even in older people who are well advanced in loss of hair growth elsewhere on the skin? Researchers here provide evidence for this to be due to signals secreted by senescent melanocyte cells. This may provide a path to encourage a reversal of hair loss in all of the various poorly-understood circumstances that lead to balding. Inducing an additional burden of cellular senescence in skin is not desirable, but a better understanding of exactly how the senescence-associated secretory phenotype (SASP) encourages hair growth could provide a more direct way to provide only the necessary signals to the skin.

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration. Altering niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal.

Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles.

Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

Link: https://doi.org/10.1038/s41586-023-06172-8

Another step forward for the magnetic nanoparticle approach to thawing vitrified tissues was recently reported. Vitrification for low-temperature storage is a fairly well established technique, at least for organs. The challenge lies in thawing vitrified organ tissue without causing so much damage that it becomes non-viable for transplantation. Researchers have now managed to make this work for rat kidneys, albeit just barely. The kidneys were damaged, and it remains the case that scaling up to human organs will have its challenges. A greater volume of tissue makes cryopreservation and later thawing much harder, but success will greatly improve the economics and logistics of organ transplantation and tissue engineering, allowing tissues to be stored indefinitely.

For decades bringing organs back from a deep freeze without injury and with full function has remained a frustrating problem for the field. Researchers have already vitrified and revived human, mouse, and pig pancreas islet cells, and vitrified and rewarmed rat hearts and livers. When vitrifying, scientists first infuse the organ or tissue with magnetic nanoparticles and safeguarding chemicals called cryoprotective agents that serve as a kind of antifreeze. Afterward, they cool it quickly - 24 degrees Celsius per minute - to bypass the formation of cell-shredding ice crystals and directly enter a glass-like state.

Researchers have spent years developing technology that can rewarm vitrified materials fast enough to avoid ice-crystal formation in the physical transition back from glass. This rewarming, critically, also must be uniform, to avoid an organ cracking and splitting from its outside surfaces being too different a temperature from its core - like an ice cube in a glass of room-temperature water. Their solution is a technique called nanowarming, which utilizes a radio-frequency copper coil to create a magnetic field that excites iron nanoparticles throughout the organ all at once, similar to a microwave oven, but more uniform.

The experimental thawed rat kidneys produced urine within 45 minutes of transplantation into young rats, compared to a few minutes for their fresh counterparts. And for the first days after surgery, they were slower to clear out creatinine, a chemical waste product that kidneys remove from the body. "The biggest issue is that the kidneys were, in fact, badly damaged. The function of those kidneys was cut in about half. These were kidneys in the peak of life, in perfect health - and they barely made it." On the other hand, the degree to which the kidneys did heal and recover was "remarkable and encouraging." The researchers also noted that because they ended the study 30 days post-transplant, they weren't able to assess longer-term survival.

Researchers said they plan to spend the next six months attempting to scale their cryopreservation method up to pig organs - a size change, kidney-wise, from a large grape (in rats) to about a pear (in pigs). As they go, they will continue to study whether rewarmed animal organs recover their original physiological, chemical, and electrical properties. Down the line, if all goes well, the future might hold living banks where organs, skin, nerves, blood vessels, cartilage, and stem cells are preserved in liquid nitrogen for years until they're matched with the right patients.

Link: https://www.statnews.com/2023/06/21/cryogenic-organ-preservation-transplants/

It is becoming clear that a major factor in the highly variable quality of first generation stem cell therapies has a lot to do with the degree to which cells become senescent when expanded in culture prior to injection. This can vary widely with small differences in culturing technique, even given a similar protocol, or the same team performing the same processes from one batch to the next, absent very rigorous quality control mechanisms of the sort typically not used by clinics in the medical tourism industry. The research community is looking into the use of senolytics to improve outcomes, but it is unclear as to whether this or any of the other possible approaches to minimize cellular senescence in stem cell cultures have yet to be adopted by clinics.

One of the other possible options is the use of photobiomodulation, the use of light to improve mitochondrial function. This may reduce the pace at which cells become senescent meaningfully in cell culture, and perhaps even in tissues, though there is far too little published research on that topic. Even if it isn't that great as a therapy to reduce senescence in people, it may find a use in efforts to ensure that first generation stem cell therapies are less hampered by cellular senescence. Interestingly, the researchers suggest that it may be sufficient to harvest exosomes from stem cells subjected to photobiomodulation and use those to minimize cellular senescence in cultures, though it would seem logistically easier to treat with light.

Photomodulation alleviates cellular senescence of aging adipose-derived stem cells

Mesenchymal stem cells (MSCs) therapies are emerging as a promising approach to therapeutic regeneration. Therapeutic persistence and reduced functional stem cells following cell delivery remain critical hurdles for clinical investigation due to the senescence of freshly isolated cells and extensive in-vitro passage. In this study, cultured adipose-derived stem cells (ASCs) were derived from subcutaneous white adipose tissue isolated from mice fed a normal diet. We performed senescence-associated-β-galactosidase (SA-β-gal) staining, real-time PCR, and Western blot to evaluate the levels related to cellular senescence markers.

The mRNA expression levels of senescence markers were significantly increased in the later passages of ASCs. We show that light activation reduced the expression of senescent genes, and SA-β-Gal in all cells at passages. Moreover, the light-activated ASCs-derived exosomes decrease the expression of senescence, and SA-β-Gal in the later passage cells. We further investigated the photoreceptive effect of Opsin3 (Opn3) in light-activated ASCs. Deletion of Opn3 abolished the differences of light activation in reduced expression of senescent genes, increased Ca2+ influx, and cAMP levels.

We explored the effects of photomodulation on exosome secretion. The concentration of light-treated ASC exosomes represented approximately a fivefold increase compared with non-light-treated ASCs. Light-activated ASC-derived exosomes could represent a new protective paradigm for cellular senescence resulting from in-vitro passaging.

Cellular senescence in the supporting cells of the brain is increasingly implicated in the onset and progression of neurodegenerative conditions. Senescent cells accumulate with age, as the immune system becomes less competent and falters in their timely removal. These errant cells secrete pro-inflammatory factors that are disruptive of tissue structure and function, contributing to the neuroinflammation that is characteristic of age-related cognitive decline and dementia. We can hope that senolytic treatments capable of passing the blood-brain barrier will help to prevent and treat many forms of neurodegenerative disease but reducing the burden of cellular senescence, both in the brain, and elsewhere in the body.

For many decades after their discovery, astrocytes, the abundant glial cells of the brain, were believed to work as a glue, supporting the structure and metabolic functions of neurons. A revolution that started over 30 years ago revealed many additional functions of these cells, including neurogenesis, gliosecretion, glutamate homeostasis, assembly and function of synapses, neuronal metabolism with energy production, and others. These properties have been confirmed, limited however, to proliferating astrocytes.

During their aging or following severe brain stress lesions, proliferating astrocytes are converted into their no-longer-proliferating, senescent forms, similar in their morphology but profoundly modified in their functions. The changed specificity of senescent astrocytes is largely due to their altered gene expression. The ensuing effects include downregulation of many properties typical of proliferating astrocytes, and upregulation of many others, concerned with neuroinflammation, release of pro-inflammatory cytokines, dysfunction of synapses, etc., specific to their senescence program. The ensuing decrease in neuronal support and protection by astrocytes induces the development, in vulnerable brain regions, of neuronal toxicity together with cognitive decline. Similar changes, ultimately reinforced by astrocyte aging, are also induced by traumatic events and molecules involved in dynamic processes.

Senescent astrocytes play critical roles in the development of many severe brain diseases. The first demonstration, obtained for Alzheimer's disease less than 10 years ago, contributed to the elimination of the previously predominant neuro-centric amyloid hypothesis. The initial astrocyte effects, operating a considerable time before the appearance of known Alzheimer's symptoms evolve with the severity of the disease up to their proliferation during the final outcome. Involvement of astrocytes in other neurodegenerative diseases is now intensely investigated.

Link: https://doi.org/10.3390/ijms24108498

Researchers here note that feeding and fasting time appears to meaningfully change the effects of long-term calorie restriction on life span in short-lived mammals. Much of the more recent literature on intermittent fasting, fasting mimicking strategies, and calorie restriction appears, to me at least, to lean towards the conclusion that time spent in a state of hunger is an important factor in the degree to which the intervention slows aging. It is interesting to compare this with protein restriction studies in which hunger and calorie intake is not meaningfully different between restricted animals and the control group. One might think that there are two very different sets of mechanisms at play, (a) those involving cell reactions to a diminished amount of specific proteins versus (b) cellular reactions to the regulatory signaling generated in the state of hunger, such as increased ghrelin secretion.

The modification of diet for longevity has long been of interest, research generally having been conducted in animal experiments. Caloric restriction (CR) is known to contribute to a prolongation of lifespan, even in higher animals. Recently, caloric restriction, fasting, and fasting intervals, and the time of eating with consideration to species-appropriate circadian alignment has been investigated. While caloric restriction itself has been found in numerous species to result in a significant prolongation of lifespan, it has also been shown that fasting regimens can independently promote longevity as well as improve deteriorated metabolic functions.

Researchers have reported that circadian alignment in addition to fasting promotes longevity independently of caloric restriction in male mice. The study compares the contribution of adjusted feeding times in addition to fasting in five caloric restriction groups on behavioral, metabolic, and molecular outcomes using automated feeders. Diet energy was restricted by 30% in all caloric restriction groups of mice fed under five caloric restriction protocols: two of the groups were fed during the active (night) or non-active (day) period for 2 hours; two groups were fed regularly every 90 minutes during half (12 hours) of the active or non-active period; and one group was fed every 160 minutes throughout the 24 hour day.

The results are intriguing. Caloric restriction itself extended the lifespan by 10%; when the fasting time was added, the lifespan was increased to 20%; and when the feeding time was aligned to the active period, the lifespan was further extended to 35%, demonstrating that when food intake is restricted to an appropriate time of the day there is an additional benefit to caloric restriction and fasting on lifespan.

Link: https://doi.org/10.1111/jdi.14033

Most of the varied approaches shown to modestly slow the progression of aging appear to operate through a small number of common mechanisms, largely involving the cellular response to stress. Some of those mechanisms will turn out to be more influential than others, though little progress has been made towards assigning relative importance to the various layers of the exceedingly complex reactions to heat, cold, restriction of nutrients, and other forms of mild stress that can produce beneficial outcomes.

The most compelling evidence to date suggests that improved autophagy is one of the more relevant portions of the cellular response to stress, a greater recycling of worn and damaged cell components leading to improved function over time. Here, researchers discuss TFEB, a regulator of autophagy, in the context of interventions shown to slow aging. In this context, it is worth noting that stress response enhancement of longevity appears to produce much larger effects in short-lived species than in long-lived species. In the two cases where one can compare fairly directly compare humans with mice, the practice of calorie restriction and loss of function mutations in growth hormone signaling, there is no evidence for a sizable increase in life span in our species.

TFEB is a central regulator of the aging process and age-related diseases

Extending lifespan or delaying aging has been shown to protect against degenerative diseases, and interventions that slow down the normal aging process can ameliorate multiple age-related pathologies and increase lifespan. For this reason, age-related diseases may be viewed as organ-specific conditions of accelerated aging. Therefore, slowing down the aging process is vital to prevent age-associated diseases.

Transcription factor EB (TFEB) is a key transcriptional regulator of autophagy and lysosomal biogenesis. Laboratory experiments in model organisms demonstrated that TFEB overexpression promoted longevity and reduced the burden of diseases. In rodents, healthy lifestyle interventions, such as caloric restriction and physical activity, were found to activate TFEB and upregulate autophagy, leading to a lower disease burden and extended lifespan. Pharmacological activators of TFEB, such as metformin and trehalose, also promoted autophagy and therapeutic benefits similar to caloric restriction and physical exercise. In humans, the dysregulation of TFEB is implicated in aging and diseases. Clinical trials are underway to test the safety and efficacy of caloric restriction mimetics known for their potent activation of TFEB and autophagy, such as metformin, trehalose, resveratrol, and spermidine.

Understanding the functional role of TFEB in the aging process and disease could help in the development of new therapeutic interventions for treating age-related diseases, which can extend lifespan. In this review, we provide up-to-date information on the contributions of TFEB activation in the modulation of the various hallmarks of aging and discuss the specific impact these may have on different tissues in the context of aging and age-related diseases. Furthermore, we argue that TFEB activation is a vital effector mechanism by which healthy lifestyle behaviors including caloric restriction, intermittent fasting, and exercise prevent diseases and extend lifespan.

Frailty is known to correlate with risk of dementia, and here researchers observe an inverse correlation with cognitive function in a large study population of older adults. The many manifestations of aging, including age-related conditions, all arise from the underlying burden of molecular damage and disarray. To the degree that an older person is more damaged, one may expect them to exhibit greater tissue dysfunction and a higher risk of suffering many different conditions. Both frailty and neurodegenerative conditions are strongly linked to the chronic inflammation of aging, for example, the state known as inflammaging. This overactivation of the immune system is disruptive to health and tissue function throughout the body.

Frailty has been recognized as a growing issue in older adults, with recent evidence showing that this condition heralds several health-related problems, including cognitive decline. The objective of this work is to determine if frailty is associated with cognitive decline among older adults from different countries. We analyzed the baseline the Study on Global Ageing and Adult Health (SAGE), that includes six countries (Ghana, South Africa, Mexico, China, Russia, and India). A cross-sectional analysis was used to assess how frailty was related with the Clinical Frailty Scale (CFS) decision tree, while cognitive decline was evaluated using standardized scores of tests used in SAGE.

A total of 30,674 participants aged 50 years or older were included. To the best of our knowledge this is the first study to assess the association between cognitive performance tests and frailty measured using the CFS decision tree. Moreover, this adds to the current knowledge on how frailty relates to cognitive status in older adults, the higher the burden of frailty the lower the cognitive test scores.

Previous evidence shows that frailty could precede dementia and other neurocognitive disorders, and even be related to neuropathological findings. On the other hand, there have been some interventions - mainly based in physical activity - that have shown to improve the overall health status of an older adult with frailty, and this has the potential to stop the progression of both cognitive and physical decline. However, this relationship is still not fully understood, and merits further research.

Link: https://doi.org/10.3389/fmed.2023.1166365

Researchers here report on an effort to find small molecule drugs that can favorably adjust cell metabolism in the blood-brain barrier, in order to prevent some fraction of the dysfunction and leakage that occurs with age. The blood-brain barrier is a specialized layer of cells that controls the traffic of molecules between the bloodstream and brain tissue. With advancing age, it becomes less effective, allowing unwanted molecules and cells to leak into the brain to provoke chronic inflammation and other issues. Maintaining effectiveness of the blood-brain barrier could push back the onset of neurodegenerative conditions.

Researchers have evaluated a new therapeutic class of molecules that can be used to treat a leaky blood-brain barrier. The researchers started by looking at WNT signaling, a communication pathway used by cells to promote tissue regeneration and wound healing. WNT signaling helps maintain the blood-brain barrier by promoting cell-to-cell communication that lines brain blood vessels. Scientists have been focusing on frizzled, a protein receptor that initiates the WNT pathway, for blood-brain barrier therapies since mouse mutations in the frizzled gene cause blood-brain barrier abnormalities.

Many different molecules bind to frizzled protein receptors, such as the frizzled receptor FZD4, so to narrow their search for a potential therapeutic molecule, the researchers selected only those that specifically target cells that line the brain's blood vessels. Researchers created L6-F4-2, a FZD4 binding molecule that activates WNT signaling 100 times more efficiently than other FZD4 binders.

Researchers then studied models of ischemic stroke, in which blood vessels and the blood-brain barrier are damaged, and fluid, blood and inflammatory proteins involved in cellular communication can leak into the brain. They found that L6-F4-2 reduced the severity of stroke and improved survival of mice compared with mice that had untreated strokes. Importantly, L6-F4-2 reversed the leakiness of brain blood vessels after stroke. Mice treated with L6-F4-2 had increased stroke survival, compared to those that were not treated. The finding shows that, in mice, the blood-brain barrier could be restored by drugs that activate FZD receptors and the WNT signaling pathway.

Link: https://scopeblog.stanford.edu/2023/06/19/restoring-the-blood-brain-barrier/

Transposable elements in the nuclear genome, also called transposons, are remnant DNA sequences left over from past, often ancient viral infections. A transposon is capable of hijacking the intricate machineries of gene expression to insert further copies of itself into the genome if not suppressed, producing what is effectively DNA damage as these haphazard insertions break existing gene sequences. Further, the transcription of transposon DNA produces viral-like RNA that can provoke an inflammatory innate immune response when present in the cell. Unfortunately, the suppression of transposons weakens with age, allowing these issues to arise and contribute to degenerative aging.

It is entirely unclear as to exactly how much of aging and cancer risk can be attributed to activation of transposons. Absent a means to safely shut down transposon activity near entirely in old animals, efforts to better understand the size of the problem must rely on more indirect approaches. Thus the research community undertakes studies such as the one outlined in today's open access paper. The authors looked over the genomes of selected small mammals with short and long life spans, and compared the differing burden of transposon insertions. It appears that short-lived species at a given body mass tend to have a greater number of potentially active transposons, which might be used to apply some bounds to the degree to which transposon activation constrains life span.

Comparative analysis of bats and rodents' genomes suggests a relation between non-LTR retrotransposons, cancer incidence, and ageing

Transposable element (TE) activity and accumulation can have manifold effects on genomes and biological phenotypes. Multiple studies have linked TEs to ageing and the development of several diseases including cancer. Here, we have studied the relationship between TEs and two different aspects of mammal life: longevity and cancer incidence. In rodents, the short lifespan is associated with the presence of cancer. On the other hand, bats are considered cancer-resistant species. The bats and rodents considered in this study are known to have different lifespans while sharing similar, small, body sizes (under 2 kg). H. glaber is the rodent with the longest lifespan known (31 years) and resistant to cancer while the other rodents show shorter lifespans of 12 (C. porcellus), 4 (M. musculus) and 3.8 (R. norvegicus) years.

By analysing the TE annotations, we found that the main difference between short- and long-lived species of rodents is represented by a drop in non-LTR retrotransposon accumulation at recent times. Similarly, the long-lived species of bats showed a drop in non-LTR retrotransposon accumulation at recent times while presenting an overall accumulation of class II transposons (DNA transposons and Helitrons). Previous studies hypothesised that bats have a higher tolerance for the activity of transposable elements with alternative ways to dampen potential health issues due to this activity. Given our observation on the shared drop of non-LTR retrotransposons accumulation in bats and in H. glaber, we add to the aforementioned hypothesis, that the specific repression of non-LTR retrotransposon activity may enhance cancer resistance. In fact, the non-LTR retrotransposons are the most prevalent types of TEs in rodents and the most extensively investigated by biomedical research given that they are the only active TEs in the human genome.

As expected, cancer-prone species present a higher load of recently inserted non-LTR retroelements than cancer-resistant species. While lifespan of rodents showed a strong relation with the recent activity of non-LTR retrotransposons, the same type of relation for bats is less clear. However, based on a comparison of density of insertion (DI) of retrotransposons, we noticed that the long-lived bats show a DI similar to the sole long-lived cancer-resistant rodent (H. glaber), while the sole short-lived bat (M. molossus) shows a DI value more similar to short-lived rodents. Given the pattern of DI observed in rodents, we speculate that the recent accumulation of non-LTRs may be related to the lifespan of these species.

The increased transcription of non-LTR retrotransposons in humans may contribute to so-called "sterile inflammation", a phenomenon for which a chronic state of inflammation is triggered without the presence of any obvious pathogen and that is exacerbated with age ("inflammaging"). The density of recently inserted non-LTR elements in short-lived bat M. molossus is 8269 per Gb, which is comparable to the value in the short-lived rodent Cavia porcellus (9,163 insertions per Gb). In contrast, the long-lived rodent Heterocephalus glaber has a DI of only 4,550 insertions per Gb, while the long-lived bat Myotis lucifugus has 4,531 insertions per Gb. Therefore, we speculate that the marked accumulation of non-LTR retrotransposons in M. molossus might trigger phenomena similar to the sterile inflammation and inflammaging that can cause a shortening of its lifespan. For these reasons M. molossus, together with the well-known H. glaber, may be an exceptional model for biogerontology.

Killifish exhibit proficient regeneration, but lose regenerative capacity with advancing age. Some of this loss is due to the growing presence of lingering senescent cells, as the balance between the pace of creation of senescent cells and timely immune-mediated clearance of senescent cells is disrupted by the mechanisms of aging. Senolytic drugs that can force senescent cells into apoptosis represent a way to greatly reduce the impact of senescent cells on tissue function in later life. Researchers here show that the production of new neurons is inhibited by senescent cells in aged killifish, and is improved following senolytic treatment, leading to greater regeneration after brain injury.

The young African turquoise killifish has a high regenerative capacity, but loses it with advancing age, adopting several aspects of the limited form of mammalian regeneration. We deployed a proteomic strategy to identify pathways that underpin the loss of regenerative power caused by aging. Cellular senescence stood out as a potential brake on successful neurorepair.

We applied the senolytic cocktail Dasatinib and Quercetin (D + Q) to test clearance of chronic senescent cells from the aged killifish central nervous system (CNS) as well as rebooting the neurogenic output. Our results show that the entire aged killifish telencephalon holds a very high senescent cell burden, including the parenchyma and the neurogenic niches, which could be diminished by a short-term, late-onset D + Q treatment. Reactive proliferation of non-glial progenitors increased substantially and lead to restorative neurogenesis after traumatic brain injury.

Our results provide a cellular mechanism for age-related regeneration resilience and a proof-of-concept of a potential therapy to revive the neurogenic potential in an already aged or diseased CNS.

Link: https://doi.org/10.1038/s41536-023-00304-4

Researchers here show that a gene therapy approach to upregulation of HOXA3 can accelerate wound healing in old mice. HOXA3 regulates a number of different processes related to tissue regeneration, though it is unclear as to which of these is more important in producing the observed outcome. It is worth noting that adjusting macrophage polarization to the M2 state is one of the mechanisms in play. Macrophages can adopt a range of states known as polarizations, where the more inflammatory M1 polarization is more suited to hunting down pathogens than participating in tissue regeneration. The more inflammatory environment of aged tissues may bias macrophages towards M1 and away from the desired M2 state. Methods of adjusting macrophage polarization are under investigation by a broad range of research groups as a potential way to reduce unresolved inflammatory signaling and improve the interaction of these innate immune cells with tissues in disease states and aging.

Chronic wounds are characterized by a persistent, hyper-inflammatory environment that prevents progression to regenerative wound closure. Such chronic wounds are especially common in diabetic patients, often requiring distal limb amputation, but occur in non-diabetic, elderly patients as well. Induced expression of HoxA3, a member of the Homeobox family of body patterning and master regulatory transcription factors, has been shown to accelerate wound closure in diabetic mice when applied topically as a plasmid encased in a hydrogel.

The mechanisms underlying the wound healing ability of HOXA3 has been preliminarily investigated. Macrophages transduced with HOXA3 promoted M2 polarization compared to controls. Furthermore, HOXA3 treatment mobilized and recruited endothelial progenitor cells while attenuating inflammatory pathways when compared to control mice and HOXA3 promotes the differentiation of hematopoietic progenitor cells into proangiogenic myeloid cells that stimulate neovascularization.

We now provide independent replication of those foundational in vivo diabetic wound closure studies, observing 16% faster healing (3.3 mm wounds vs 3.9 mm wounds at Day 9 post original injury of 6 mm diameter) under treatment with observable microscopic benefits. We then expand upon these findings with minimal dose threshold estimation of 1 μg HoxA3 plasmid delivered topically at a weekly interval. Furthermore, we observed similarities in natural wound healing rates between aged non-diabetic mice and young diabetic mice, which provided motivation to test topical HoxA3 plasmid in aged non-diabetic mice. We observed that HoxA3 treatment achieved complete wound closure (0 mm diameter) at 2 weeks whereas untreated wounds were only 50% closed (3 mm wound diameter). We did not observe any gross adverse effects macroscopically or via histology in these short studies. Whether as a plasmid or future alternative modality, topical HoxA3 is an attractive translational candidate for chronic wounds.

Link: https://doi.org/10.1038/s41598-023-36933-4

There is an increasing focus in the research community on the role of the gut microbiome in aging. This is in large part driven by the ability to accurately, cost-effectively measure the composition of the gut microbiome from a stool sample, using 16S rRNA sequencing. The 16S rRNA gene is differs between bacterial species, without being subject to a high rate of mutation and change. Using low-cost modern techniques, researchers can thus read out the relative numbers of different species in the gut microbiome, a service now available to the public at large as well. This allows researchers to see exactly how the balance of populations changes with age and disease states.

The gut microbiome does change with age, and it changes in ways that promote harmful, inflammatory microbial populations at the expense of helpful microbial populations responsible for generating beneficial metabolites such as butyrate. Researchers have shown that transplanting a microbiome derived from stool samples from young animals into old animals can reset the aged microbiome to a more youthful balance of microbial populations. The result is improved health and extended life.

Unfortunately, when it comes to the application of this discovery to human medicine, all too often the focus stops at the application of probiotics to the problem of the aged metabolism. Yes, we know that probiotics are beneficial. Yes, they are cheap and readily available. If present probiotic formulations were a truly effective intervention, capable of restoring a youthful gut microbiome, we would certainly know that by now. Alas, they are not. Given the evidence to date from animal studies, the real focus should be on establishing the infrastructure for widespread us of fecal microbiota transplantation from young donors to old people.

Gut microbiome-mediated mechanisms in aging-related diseases: are probiotics ready for prime time?

Aging is characterized by increased concentrations of many pro-inflammatory factors in the circulation. In addition, chronic low-grade inflammation has been identified as a key process involved in aging. Chronic low-grade inflammation is influenced by changes in different tissues (muscle, adipose tissue), organs (brain, liver), systems (immune system), and ecosystems (gut flora). It can indirectly trigger diseases in other organs (e.g., metabolic diseases, neuroinflammatory diseases, cardiovascular diseases, etc.). Chronic low-grade inflammation is one of the main contributing factors to various age-related diseases in the elderly.

Furthermore, chronic low-grade inflammation is closely related to the dysregulation of gut flora. Many immune cells and microbiota in the digestive tract interact with each other to maintain immune homeostasis. Intestinal microbiota plays a role in maintaining healthy levels of inflammation by integrating gastrointestinal, immune, and neurological information. Data obtained from animal models have demonstrated that age-related microbial ecological disorders can lead to intestinal permeability, systemic inflammation, and premature death. Altering the gut microbiota of older adults with wholesome bacteria exerts positive effects on the maintenance of optimal immune responses, which decline with age. Such effects include delaying the aging of T lymphocytes and increasing the number of immune cells that respond to acute antigen exposure.

Probiotics can effectively assist in maintaining the balance in the composition of gut microbial flora, thereby protecting the gut barrier and regulating gut immunity. Increasing scientific evidence has shown that probiotics exert a positive effect on chronic low-grade inflammation and play a key role in healthy aging and improving age-related diseases. Probiotics might be an important therapeutic strategy for the prevention, delay, or even reversal of low-grade inflammation in old age. However, robust controlled clinical trials are warranted to further validate this hypothesis.

Why do patients with metabolic disorders such as obesity and type 2 diabetes exhibit what appears to be an accelerated progression of aging, such as increased risk of disease, shorter life expectancy, and so forth? One increasingly well established candidate mechanism is the presence of a greater burden of senescent cells, these cells generating chronic inflammation and harmful alterations to the behavior of other cells via their secretions. Senolytic therapies to clear these senescent cells may prove to be a first step towards decoupling obesity from the consequences of obesity, but there are numerous other ways in which excess fat tissue or a dysfunctional, diabetic metabolism can provoke chronic inflammation and dysfunction of organs and bodily systems.

Cellular senescence is generally driven by aging and is strongly associated with age-related disorders. It promotes the common age-associated phenotypes of reduced number of functional cells and size of tissues/organs, increased fibrosis, inflammation, and accumulation of cells with genetic defects. However, other disorders such as type 2 diabetes (T2D), obesity, and NAFLD/NASH are also characterized by increased cellular senescence in metabolic cells.

Aged tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance promote cellular senescence in both human adipose and liver cells. Similarly, increased cellular senescence promotes cellular insulin resistance, showing their interdependence. Furthermore, the increased adipose cellular senescence in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic or senolytic therapy may become important for treating these common metabolic disorders.

Link: https://doi.org/10.1172/JCI169922

If a heart attack is survived, it leads to long-term damage to heart tissue. Scarring, detrimental remodeling of heart muscle, and other dysfunctions result. Researchers here show that a raised burden of cellular senescence in cardiomyocytes specifically predisposes the aged heart to greater harm following a heart attack. This well illustrates that periodic senolytic treatments or related strategies that can minimize the presence of senescent cells in aged tissues are highly desirable. The presence of lingering senescent cells is harmful in many ways, directly causing organs to become less functional and more vulnerable.

Myocardial infarction is a leading cause of morbidity and mortality. While reperfusion is now standard therapy, pathological remodelling leading to heart failure remains a clinical problem. Cellular senescence has been shown to contribute to disease pathophysiology and treatment with the senolytic navitoclax attenuates inflammation, reduces adverse myocardial remodelling and results in improved functional recovery. However, it remains unclear which senescent cell populations contribute to these processes.

To identify whether senescent cardiomyocytes contribute to disease pathophysiology post-myocardial infarction, we established a transgenic mouse model in which p16 (CDKN2A) expression was specifically knocked-out in the cardiomyocyte population. Following myocardial infarction, mice lacking cardiomyocyte p16 expression demonstrated no difference in cardiomyocyte hypertrophy but exhibited improved cardiac function and significantly reduced scar size in comparison to control animals. This data demonstrates that senescent cardiomyocytes participate in pathological myocardial remodelling.

Importantly, inhibition of cardiomyocyte senescence led to reduced senescence-associated inflammation and decreased senescence-associated markers within other myocardial lineages, consistent with the hypothesis that cardiomyocytes promote pathological remodelling by spreading senescence to other cell-types. Collectively this study presents the demonstration that senescent cardiomyocytes are major contributors to myocardial remodelling and dysfunction following a myocardial infarction. Therefore, to maximise the potential for clinical translation, it is important to further understand the mechanisms underlying cardiomyocyte senescence and how to optimise senolytic strategies to target this cell lineage.

Link: https://doi.org/10.1038/s41514-023-00113-5

The aging of the immune system is widely considered a progressive loss of functional capacity, such as the ability to effectively destroy pathogens and errant cells (known as immunosenescence), coupled to rising levels of unresolved, chronic inflammation (known as inflammaging). In today's open access paper, the authors are more interested in how well the immune system brings itself back to an equilibrium state following the disruptions of an inflammatory response. They call this capacity for restoration "immune resilience". In this framework, aging brings a loss of the ability to restore normality to the immune system following a period of stress, such as that resulting from infection, and it is this loss of resilience to stress that leads to morbidity and mortality.

Is this a useful way to look at immune aging? It is similar to the view of aging as a whole, a loss of the ability to restore homeostasis in the face of disruptive perturbation, that has been presented by Gero in recent years. At some point, the disruption pushes the body beyond its capacity for restoration, and into terminal decline. Does this building of frameworks lead to any usefully different approach to therapy than the present concept of progressively greater immunosenescence and inflammaging, however? At some point one has to match frameworks to the underlying biology, the mechanisms, the targets for therapy.

Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection

Why do individuals manifest such wide differences in lifespan, health status across age, and susceptibility to infectious diseases? One possibility is that variations in an immune trait contribute to these differences. Given that infections are among the most impactful environmental factors that shape the human genome, optimal host responses to these microbial drivers of natural selection may have played a role in increasing longevity. Hence, immune mechanisms may have evolved based on conferred resistance to the ancestral burden of inflammatory stress associated with infectious diseases. Resistance mechanisms could include higher immunocompetence and prevention of uncontrolled inflammation. In contemporary times, these infection-resistance mechanisms may confer advantages for a lower comorbidity burden and longevity.

Our hypothesis regarding the identity of this advantageous trait is immunologic resilience (IR). We define optimal IR as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance and longevity (immunocompetence), as well as control inflammation during acute, repeated, or chronic immune (antigenic) stimulation associated with inflammatory stressors (e.g., infections or autoantigens). IR is rooted in the principle that repeated inflammatory (antigenic) exposures are inevitable throughout life, necessitating allostatic processes that mediate adaptation, ideally returning immunocompetence and inflammation to optimal or pre-exposure levels. With this definition, optimal IR is linked to a conjoined high immunocompetence (IC)-low inflammation (IF) state.

Individuals preserving optimal IR metrics manifested advantages for longevity and survival as well as resistance to severe COVID-19, HIV-AIDS, common acute respiratory viral infections, recurrent skin cancer, and sepsis-associated mortality. These advantages were observed after controlling for age, sex, and/or level of antigenic stimulation. Collectively, our findings suggest that the lower immune status observed with age may be driven by two distinct mechanisms, one being dependent on age and the other attributable to IR erosion/degradation, which occurs concurrently with age but is not dependent on age per se. Thus, among persons of similar age, an individual's susceptibility to disease risks/severity and mortality may relate to their antecedent and current capacity for preservation and/or restoration of optimal IR when experiencing inflammatory stress.

The endothelium lines the interior of blood vessels, and endothelial dysfunction is a feature of aging. Inflammation and changed cell behavior in the endothelium contributions to the formation of atherosclerotic lesions, as well being disruptive of normal management of blood flow by constriction and dilation. A rising burden of cellular senescence in the endothelium is thought to contribute to this age-related dysfunction of the tissue, and thus senolytic treatments to selectively destroy these errant cells are under consideration as a means of treatment. Given the sizable funding devoted to this part of the field in recent years, it isn't surprising to see scientists in search of novel senolytic approaches, ones that may be more tissue-specific and or more effective in specific tissues than the first generation small molecule treatments like the combination of dasatinib and quercetin.

Aging is the major risk factor for chronic disease development. Cellular senescence is a key mechanism that triggers or contributes to age-related phenotypes and pathologies. The endothelium, a single layer of cells lining the inner surface of a blood vessel, is a critical interface between blood and all tissues. Many studies report a link between endothelial cell senescence, inflammation, and diabetic vascular diseases.

Here we identify, using combined advanced AI and machine learning, the Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B (DYRK1B) protein as a possible senolytic target for senescent endothelial cells. We demonstrate that upon induction of senescence in vitro DYRK1B expression is increased in endothelial cells and localized at adherens junctions where it impairs their proper organization and functions. DYRK1B knock-down or inhibition restores endothelial barrier properties and collective behavior. DYRK1B is therefore a possible target to counteract diabetes-associated vascular diseases linked to endothelial cell senescence.

Link: https://doi.org/10.1016/j.mad.2023.111836

Gathering data on the fine details of aging proceeds a good deal more rapidly than making use of that data. The new Aging Fly Cell Atlas is a representative example of the many large databases being generated using modern omics techniques. It provides details of gene expression changes over the course of aging for different cell types in the fly body. Taking this data and tying it to specific causes and consequences of aging remains a sizable undertaking, a work in progress in its earliest stages. Progress towards therapies to treat aging cannot wait for the greater understanding of the fine details of aging that lies decades ahead at this point; it is important that we forge ahead now, building on what is known of the causes of aging. If one can in fact address a cause of aging, then the best way to learn how that cause affects gene expression profiles is to treat it.

Researchers have published the first Aging Fly Cell Atlas (AFCA), a detailed characterization of the aging process in 163 distinct cell types in the laboratory fruit fly. Their in-depth analysis revealed that different cell types in the body age differently, each cell type following a process involving cell type-specific patterns. As the flies aged, the researchers took samples when the animals were 30, 50 and 70 days old (the latter is equivalent to an 80-year-old person). At each time point, the team conducted single-nucleus RNA sequencing to analyze gene expression changes in individual cells in different organs and compared the results to those of young flies (5 days old).

The team examined four different aging features: cell composition changes, number of differentially expressed genes, change in the number of expressed genes and decline of cell identity. They found that as flies age, these features change as a group according to cell type-specific patterns. Aging impacts cellular composition across the whole fly. Fat body cells were among the cell types that increased in number the most, while muscle cells decreased the most. Neurons, however, did not show major changes in the number of cells during the fruit fly's life. In addition, the analysis of the genes expressed by different cell types in time revealed that fat cells show the largest difference between the number of genes expressed in young versus old fruit flies. The researchers also found that about 80% of all the cell types analyzed decreased the number of genes expressed, and 20% increased this number.

"A critical observation of this study is that cell type-specific aging patterns in cells can be used to gauge biological age, that is the relative aging status of an organism, independent of its chronological age. This will provide further insight into factors, such as diets, drugs and diseases, that may change the aging trajectory and hence make an organism 'younger' or 'older' than its chronological age."

Link: https://www.bcm.edu/news/close-up-on-aging-reveals-different-cells-age-at-different-pace

Many diseases of aging are strongly associated with chronic inflammation, and inflammatory signaling is involved in disease pathology. Unresolved low-grade inflammatory signaling and excessive immune system activation increases with advancing age, producing the state of immune dysfunction known as inflammaging. Many different factors contribute to this chronic inflammation of aging. They include the presence of lingering senescent cells that actively produce inflammatory secretions, as well as mitochondrial dysfunction resulting in mislocated mitochondrial DNA fragments that can cause an innate inflammatory response. It is also the case that one-time or persistent infections can spur greater lasting inflammation.

Inflammatory signaling is essential to health in the short term, a necessary part of the immune response to infection and injury, but when sustained over the long term it changes cell behavior for the worse and degrades tissue function.

Is Alzheimer's disease a condition primarily driven by infection and consequent inflammation, particularly chronic inflammation? Or is inflammation only one of a number of factors, and possibly a consequence of other disease pathology? These and related questions are much debated these days, given the failure to achieve significant patient benefits by clearing amyloid-β from the brain. Alzheimer's disease has long been known to have a strong inflammatory component, but could it be near all a matter of chronic inflammation, with pathologies such as protein aggregation trailing along as consequences?

The role of peripheral inflammatory insults in Alzheimer's disease: a review and research roadmap

Alzheimer's disease (AD), a neurodegenerative condition that affects approximately 24 million people worldwide, accounts for 60 to 70% of all dementia cases. Despite tremendous recent advancements in neurodegenerative disease research, the understanding of AD biology remains incomplete. Although amyloid-beta (Aβ) plaques and tau neurofibrillary tangles are considered hallmark features of AD, the past two decades have seen a surge in genomic studies that consistently point to the central role of microglia and neuro-immune dysfunction in the pathogenesis of AD. Concurrently, a large body of work has highlighted the potential relevance of peripheral immune changes, particularly pro-inflammatory signaling, in AD pathogenesis.

Evidence for a relationship between peripheral immune factors and AD has come primarily from epidemiological and observational research studies which demonstrate associations between circulating inflammatory markers and neurocognitive features. However, there is a growing body of literature supporting the role of acute inflammatory insults as potential catalysts for cognitive decline and AD. Here, we define acute inflammatory insult as an immune challenge - typically tissue injury or exposure to a pathogen - that produces, in most cases, a time-limited inflammatory response.

This review focuses on the evidence from clinical and translational research linking acute inflammatory insults to cognitive decline and AD. We review evidence for the role of both pathogen- and damage-mediated inflammatory insults in AD and provide current conceptualizations of mechanisms for and treatment of immune-mediated cognitive decline. Importantly, we outline critical next steps for understanding how acute inflammatory insults might impact AD pathological processes and influence clinical presentation. We provide guidelines to address gaps in the literature, outline methods for appraisal of infection-mediated outcomes, and highlight future studies that may accelerate therapeutic interventions.

Senescent cells accumulate in tissues with age, a circumstance that appears largely the result of the progressive failure of the immune system to destroy these errant cells in a timely fashion. Senescent cells provoke chronic inflammation and altered cell behavior via the senescence-associated secretory phenotype (SASP), their pro-inflammatory signaling actively maintaining a degraded state of tissue structure and function. Removing senescent cells has been shown to produce rapid, sizable rejuvenation in mice, reversal of many age-related conditions. Separately, researchers have linked the accumulation of senescent cells in aged tissues to scores of age-related diseases and forms of dysfunction. The example here, showing the negative effects of senescent cells on fat tissue, is but one of many.

Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8+ immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks.

Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function.

Xenotransplantation experiments show that human S100A8+ immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.

Link: https://doi.org/10.1038/s41467-023-38842-6

A growing body of evidence points to an altered gut microbiome in Alzheimer's patients. If only a specific subset of the varied age-related changes observed to take place in the gut microbiome across the broader population provide a significant contribution to the early pathology of the condition, this may help to explain why many older people fail to develop Alzheimer's disease despite exhibiting all of the other known risk factors. Are gut microbiome characteristics that appear in Alzheimer's patients a contributing cause of the condition, or do they stem from, perhaps, greater immune dysfunction with age, and that immune dysfunction is the important factor? That has yet to be determined, but since the aging gut microbiome can be rejuvenated by fecal microbiota transplant from young individuals, it seems that whether or not the gut microbiome contributes to Alzheimer's disease could be determined given the will and funding to run a clinical trial.

Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited.

In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process.

We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.

Link: https://doi.org/10.1126/scitranslmed.abo2984

In today's popular science article, the SENS Research Foundation offers a more rosy picture of the near future of amyloid-β clearance than is the usual fare these days. Amyloids are misfolded or otherwise altered proteins that can aggregate to form solid deposits that disrupt cellular biochemistry. In principle they should all be removed. Their existence is a form of harmful change that takes place with age, and the connections to cell dysfunction are quite clear. The failure of amyloid-β clearance to produce meaningful benefits in Alzheimer's patients has led to some disillusionment, however.

Alzheimer's may be a condition in which amyloid-β aggregation is not the major pathological mechanism. I still agree with much of what is said here, that amyloids should be cleared regardless of whether Alzheimer's transitions to a later stage in which amyloid-β is irrelevant to pathology, regardless of whether amyloid-β is the primary agent in the onset stage of Alzheimer's. There is enough evidence for harms to result from amyloid-β that it should be removed. My primary concern regarding that point is that the present technologies capable of effective amyloid-β clearance in the brain, forms of immunotherapy, are just not safe enough to be deployed across the entire population, even setting aside the question of whether costs could be sufficiently reduced at that scale. Better approaches are needed.

From Parachutes to Jetpacks: Clearing Brain Beta-Amyloid with Donanemab or Lecanemab Works, Though More Must be Done

In its Phase III clinical trial, lecanemab became the first therapy to unambiguously put the brakes on the trainwreck of neurodegenerative aging. The monoclonal antibody cleared beta-amyloid protofibrils from patients' brains and slowed the downward plunge of Alzheimer's disease by some 27%, leading to FDA approval. And now comes donanemab, a monoclonal antibody that for the first time specifically targets beta-amyloid that has been cut down to and modified into pyroglutamate at position 3 (pE3-Abeta). While we are still awaiting publication in a peer-reviewed journal, the press release from Eli Lilly tells us that over the course of a relatively short trial, donanemab passed the goalpost of slowing the progression of Alzheimer's-type neurodegenerative aging (AD).

The people expressing disappointment with the donanemab trial results are absolutely right to insist that the ultimate goal should be to prevent AD from emerging - and to reverse it in its early stages if it does. As we've been highlighting for years, achieving this triumph will require the application of one of two "damage-repair" strategies. One approach is to begin removing beta-amyloid as soon as it starts to accumulate in the brain - meaning, in a person's forties or fifties. This would prevent beta-amyloid from driving tau aggregates widely across the brain, and thus prevent the destruction of neurons downstream. It would also likely prevent some of the excess senescent cell burden in the AD brain and better-preserve brain mitochondrial function.

Of course, that is not how these medicines are being used today. But while the clinical trials for these amyloid-clearing therapies didn't start that early in the disease process, part of the reason they succeeded was exactly that they began treating patients earlier in the disease process than had been done in previous trials. Starting to clear the brain of beta-amyloid alone in people experiencing "mild" cognitive impairment or early-stage AD was still not an early enough start to head off the cascade of horrors in the AD brain entirely - but it was early enough that doing so could still have a substantial effect.

To realize the full potential of removing beta-amyloid alone, you would want to begin treatment before the cascading destruction downstream of beta-amyloid had set in earnest - before people even began questioning whether they might be starting to slip. Happily, after the success of lecanemab in Phase III, the National Institutes of Health joined forces with Esai and decided to take this next logical step. Together, they have launched the AHEAD Study. This clinical trial will test lecanemab in volunteers with no evidence of cognitive impairment, but who have either intermediate (in one trial) or higher (in another) levels of beta-amyloid in their brains. The goal will be to see if starting at this early stage can keep people free from ever developing MCI and dementia in the first place.

Beta-amyloid clearance can potentially be made safer and more effective by replacing the current generation of binding antibodies with catabodies. Catabodies are catalytic antibodies that cleave their targets directly where they encounter them instead of having to bind to them and drag them to the circulation for eventual disposal via the liver or passive degradation. Catabodies offer the potential of greater safety since they break up their target on site, instead of having to drag it out through the brain's vasculature, where it may cause damage and inflammation. Indeed, the damage inflicted by wrenching beta-amyloid out of the brain is the most worrisome risk associated with the current beta-amyloid targeting antibodies, taking the form of vascular swelling and microbleeds.

The balance of microbial populations making up the gut microbiome shifts with age, favoring potentially harmful, inflammatory microbes over those that produce beneficial metabolites. This is increasingly associated with the development of disease, and particularly with neurodegenerative conditions, though every age-related condition with a strong inflammatory component to its pathology is likely accelerated by the aging of the gut microbiome. There are ways to adjust the balance of populations to restore a more youthful configuration, such as fecal microbiota transplantation from a young donor, but the research community has yet to earnestly assess this type of approach as a potential treatment or mode of prevention for age-related neurodegeneration.

The human gut microbiome contains the largest number of bacteria in the body and has the potential to greatly influence metabolism, not only locally but also systemically. There is an established link between a healthy, balanced, and diverse microbiome and overall health. When the gut microbiome becomes unbalanced (dysbiosis) through dietary changes, medication use, lifestyle choices, environmental factors, and ageing, this has a profound effect on our health and is linked to many diseases, including lifestyle diseases, metabolic diseases, inflammatory diseases, and neurological diseases. While this link in humans is largely an association of dysbiosis with disease, in animal models, a causative link can be demonstrated. The link between the gut and the brain is particularly important in maintaining brain health, with a strong association between dysbiosis in the gut and neurodegenerative and neurodevelopmental diseases.

This link suggests not only that the gut microbiota composition can be used to make an early diagnosis of neurodegenerative and neurodevelopmental diseases but also that modifying the gut microbiome to influence the microbiome-gut-brain axis might present a therapeutic target for diseases that have proved intractable, with the aim of altering the trajectory of neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, and attention-deficit hyperactivity disorder, among others. There is also a microbiome-gut-brain link to other potentially reversible neurological diseases, such as migraine, post-operative cognitive dysfunction, and long COVID, which might be considered models of therapy for neurodegenerative disease. The role of traditional methods in altering the microbiome, as well as newer, more novel treatments such as faecal microbiome transplants and photobiomodulation, are discussed.

Link: https://doi.org/10.3390/ijms24119577

Transthyretin can produce amyloid, a harmful misfolded form of the protein that aggregates in the cardiovascular system and contributes to forms of heart disease. Clearing the build up of these aggregates is a work in progress. A variety of therapies entered the market in recent years, but have yet to make the leap to widespread preventative use in the broader population of older individuals. Cost is one factor. In this context, it is interesting to note a report of spontaneous reversal of transthyretin amyloidosis in a small number of individuals, likely mediated by immune clearance of amyloid, as the condition is not viewed as one in which this sort of recovery is possible.

Transthyretin amyloidosis (ATTR) is caused by amyloid deposits composed of a blood protein called transthyretin (TTR). It can be hereditary or non-hereditary ("wild-type"). The build-up of these protein deposits in the heart is called ATTR amyloid cardiomyopathy (ATTR-CM). Current treatments aim to relieve the symptoms of heart failure, but do not tackle the amyloid, although a number of "gene-silencing" therapies are currently being trialed which reduce TTR protein concentration in the blood and thereby slow ongoing amyloid formation.

Advances in imaging techniques has meant substantially more people being diagnosed with the disease than was the case 20 years ago. Previously, diagnosis needed a biopsy (involving tissue taken from the heart). The imaging techniques also mean the burden of amyloid on the heart, and consequently the progression of the disease, can be more precisely monitored, making it easier to detect cases where the condition has reversed, rather than merely remaining stable. The latest study began when one man aged 68 reported his symptoms improving. This prompted the research team to look through records of 1,663 patients diagnosed with ATTR-CM. Out of these patients, two more cases were identified.

The three men's recoveries were confirmed via blood tests, several imaging techniques, and, for one patient, an assessment of exercise capacity. Scans showed heart structure and function had returned to a near-normal state and amyloid had almost completely cleared. An in-depth look at the records and assessments for the rest of the 1,663 patient cohort indicated that these three patients were the only ones whose condition had reversed.

One of the three men underwent a heart muscle biopsy that revealed an atypical inflammatory response surrounding the amyloid deposits (including white blood cells known as macrophages), suggesting an immune reaction. No such inflammatory response was detected in 286 biopsies from patients whose disease had followed a normal progression. Investigating this further, the researchers found antibodies in the three patients that bound specifically to ATTR amyloid deposits in mouse and human tissue and to synthetic ATTR amyloid. No such antibodies were present in 350 other patients in the cohort with a typical clinical course. If these antibodies could be harnessed, they could be combined with new therapies being trialed that suppress TTR protein production, enabling clinicians to clear away amyloid as well as preventing further amyloid deposition.

Link: https://www.ucl.ac.uk/news/2023/jun/devastating-heart-condition-can-be-reversed-study-shows-first-time

The history of transcranial electromagnetic treatments suggests that there is something interesting there to be found, but also that it is challenging to discover the right parameters of treatment that can produce meaningful benefits in at least some patients. There is a very large space of possibilities to explore in terms of amplitude, frequency, length and timing of treatment, and so on, in an environment in which the interactions between electromagnetic fields and cell behavior are poorly understood at best.

In today's open access paper, a few sizable claims are made on the basis of small long-term trials in humans, but it is worth balancing that against the history of this field and the point that small trial success quite often fails to translate to large trial success. Skepticism and a wait and see attitude are probably justified. Still, might it be possible to reliably dial down the chronic inflammation of aging given the right approach to electromagnetic treatments? That would be a valuable achievement if so.

More generally, the use of electromagnetism as an approach to induce cells to change their behavior for the better is greatly understudied and underdeveloped in comparison to the small molecule approach. That doesn't mean that it won't work given far greater investment and the time taken to develop a far greater understanding of mechanisms and interactions. Interesting results are published in the literature for wound healing, neurodegeneration, and so forth, enough to show potential. This is nonetheless a part of the medical research and development communities still in search of mainstream legitimacy and the first widely accepted applications.

Transcranial Electromagnetic Wave Treatment: A Fountain of Healthy Longevity?

There is substantial evidence that most diseases in older age involve inflammation in the brain and/or body due to a chronic over-activation of pro-inflammatory cytokines over anti-inflammatory cytokines ("inflammaging"). By contrast, individuals in young adulthood and middle age have an immune system balanced in these two components, as do many centenarians (100+ years), effectively providing immune protection from environmental and body insults. We have therefore proposed that a gerotherapeutic that can "rebalance" pro- and anti-inflammatory cytokines in aged individuals will reduce the risk or severity of age-related diseases and increase healthy longevity. This perspectives paper provides clinical evidence that such a "rejuvenating" gerotherapeutic is not a drug, but rather a bioengineered medical device that provides Transcranial Electromagnetic Wave Treatment (TEMT), the MemorEM. In that regard, TEMT administration to aged/diseased individuals could be comparable to them receiving continual blood infusions from young adult or middle-aged individuals who have a balanced (youthful) immune system in their blood-the result being much reduced systemic inflammation and increased longevity through TEMT.

The results presented, and conclusions reached in this paper are based on our three published clinical papers involving the same mild/moderate Alzheimer's disease subjects given TEMT for a period of 30 months and evaluated at 2 months, and 14-31 months into that period. At 2 months into treatment, analysis of 11 cytokines in blood and 7 cytokines in brain/CSF revealed an extraordinarily consistent ability of TEMT to "rebalance" the largely pro-inflammatory status of the immune system in these subjects. Specifically, if a given cytokine's level was high in blood plasma or cerebrospinal fluid, TEMT reduced its levels to normal aged individuals, and vice versa if they were low. The mechanism for blood rebalancing of cytokines by TEMT appears to involve the unique ability of red blood cells to concentrate cytokines and to respond to electromagnetic waves by increasing their membrane fluidity to rebalance plasma cytokines with an appropriate flux of cytokines in or out across their membranes. We believe that the same rebalancing of blood/plasma cytokines by TEMT will occur in both normal aged and age-diseased individuals. This is because those cytokine levels in individual subjects that were near normal levels at baseline did not show a TEMT-induced change in their levels thereafter.

In principle, machine learning can be used to make small molecule drug discovery run more rapidly, more cost-effectively, and with a greater chance of success. The development of senolytic drugs to clear senescent cells is a good proving ground for this type of approach, and will likely accelerate investment into machine learning driven drug discovery platforms with broad application. Firstly, the state of the science shows that senescent cells are vulnerable to mechanisms that can be targeted effectively by small molecules. Secondly, it is also clear that far from all of these mechanisms are known and much remains to be discovered, as new approaches are emerging on a regular basis. Thirdly, the field is not well developed, yet potentially very large, with everyone much over the age of 50 as an intermittent patient. There is plenty of room to run a drug development program and achieve economic success, even given many other groups doing the same, and there will be many customers in the future for a marketplace of machine learning services. These incentives and predictions matter; they are necessary for a field to attract interest and grow.

Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis, and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin, and oleandrin in human cell lines under various modalities of senescence.

The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives. Our approach led to several hundred-fold reduction in drug screening costs and demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data, paving the way for new open science approaches to early-stage drug discovery.

Link: https://doi.org/10.1038/s41467-023-39120-1

CD47 is a "don't eat me" decoration found on the surface of cells. This is a necessary mechanism for the prevention of autoimmunity, but it is also subverted by cancer in order to prevent the innate immune system from attacking tumor cells. The cancer research community has investigated a range of approaches to prevent CD47 from holding back the immune response to cancerous cells. One possibility, demonstrated here, is to engineer the innate immune cells known as macrophages in order to block the CD47 interaction and thus ensure an aggressive response to cancerous cells.

Cancer remains one of the leading causes of death in the U.S. at over 600,000 deaths per year. Cancers that form solid tumors such as in the breast, brain, or skin are particularly hard to treat. Surgery is typically the first line of defense for patients fighting solid tumors. But surgery may not remove all cancerous cells, and leftover cells can mutate and spread throughout the body. "Due to a solid tumor's physical properties, it is challenging to design molecules that can enter these masses. Instead of creating a new molecule to do the job, we propose using cells that 'eat' invaders - macrophages."

Macrophages, a type of white blood cell, immediately engulf and destroy - phagocytize - invaders such as bacteria, viruses, and even implants to remove them from the body. A macrophage's innate immune response teaches our bodies to remember and attack invading cells in the future. This learned immunity is essential to creating a kind of cancer vaccine. "Macrophages recognize cancer cells as part of the body, not invaders. To allow these white blood cells to see and attack cancer cells, we had to investigate the molecular pathway that controls cell-to-cell communication. Turning off this pathway - a checkpoint interaction between a protein called SIRPa on the macrophage and the CD47 protein found on all 'self' cells - was the key to creating this therapy."

The engineered macrophages were put to the test on "tumoroids," conglomerates of mouse melanoma cells in culture plates. The macrophages cooperatively clustered around the cancer cells, picked them apart and progressively destroyed the tumor. When tested in vivo, the engineered cells were able to eliminate tumors in 80% of mice. Importantly, tumor elimination triggered an adaptive immune response. Weeks later, the anti-cancer immunoglobulin G antibody increased. This engineered macrophage therapy works best in combination with existing antibody therapy. One day, patients may be able to rely on these engineered cells to eliminate solid tumors as well as the need for future treatments.

Link: https://blog.seas.upenn.edu/engineered-white-blood-cells-eliminate-cancer/

A sizable fraction of the therapies produced by the medical industry are, not to put too fine a point on it, garbage. The benefit is not worth the cost of diverting the resources into the full scale production of the drug, versus those resources going towards some better form of medical research and development. Giving a cancer patient an extra month or two of life, reducing fibrosis in the liver by 10% over a year of treatment, incrementally improving mitophagy to half the degree that exercise achieves, and so forth. Small molecule development in particular excels at producing this sort out outcome, as the effects on gene expression and protein interactions produced by small molecules tend to be much smaller than the effects produced by genetic interventions carried out during proof of concept studies in the lab.

The overbearing, overburdened regulatory system for medical development has become optimized towards determining the difference between a garbage therapy that produces a small positive effect and a garbage therapy that has no positive effect. That goal is an expensive proposition in principle, even setting aside all of the unnecessary costs imposed by regulators. When that regulatory system starts from the position of "first, do no harm," one can see how it may evolve to use the lever of imposed cost to discourage an influx of treatments that are not really expected to meet a sane cost-benefit threshold. Many of us feel that it isn't the role of government employees to be making that decision for everyone, but that is the situation, alas.

Given evident, clear success in medical development, however, the system becomes far less of a roadblock. When a new therapy definitively cures a rare disease, as happens ever more often in this era of progress in biotechnology, the sponsoring team might find regulators moving directly from a phase II trial in 20 or so patients right into clinical approval. The usual obstacles and further costs put in place for marginal therapies melt away in this situation. Severe diseases tend to be accompanied by clear success criteria in the form of disease symptoms and patient mortality. It is obvious that a therapy has produced a cure, or managed the condition down to negligible pathology.

Will this also be the case for the first therapies to produce meaningful rejuvenation? The immediate issue here is that there is no practical, consensus measure of rejuvenation. Yes, epigenetic clocks exist alongside clocks derived from other omics data, but we are nowhere near the point at which the world, or regulators, would accept a reliable ten year reversal of epigenetic age in patients at face value, as representing actual rejuvenation. But the real question is whether a proven rejuvenation therapy would in fact produce a melting away of regulatory obstacles, given that yet to be established consensus measure of age-related decline.

People will think very differently about a cure for multiple sclerosis versus a rejuvenation therapy that grants ten additional healthy years, on balance. Multiple sclerosis exhibits what regulators call "high unmet need," a condition that disables and kills, and for which current treatments do too little. A robust cure for multiple sclerosis would rapidly reverse disabling symptoms in an obvious way. In comparison, a therapy that gives people ten additional years, and turns back the clock in terms of measures of aging, has (a) less evident immediate benefit, and (b) will be used by far more people if approved by regulators. That changes the calculus in the minds of regulators.

It is interesting to contemplate future obstacles, or lack of same, but the first step remains the production of working rejuvenation therapies. The most important of those presently heading towards significant, widespread clinical use in the 2030s are senolytics and perhaps the first uses of partial reprogramming. It will remain to be seen as to how great an improvement they produce in late life human health, and how much of a roadblock is put in their way by regulatory bodies.

Mutations in stem cell populations can spread throughout a tissue, and the occurrence of mutations over time leads to a pattern of mutations known as somatic mosiacism. Most mutations cause little to no functional change in the cells in which they occur, as most of the genome is dormant. Does somatic mosaicism provide a significant contribution to degenerative aging due to the few mutations that do cause functional change and spread throughout tissues? There are only a few definitive correlations to date, but we might expect more to emerge as researchers continue to investigate. The brain is an interesting case, as neurons do suffer random mutations, but they are long-lived and rarely replaced. It is the supporting cells of the brain in which we might expect to see age-related somatic mosaicism similar to that occurring elsewhere in the body.

Every cell in the human brain possesses a unique genome that is the product of the accumulation of somatic mutations starting from the first postzygotic cell division and continuing throughout life. Somatic mosaicism in the human brain has been the focus of several recent efforts that took advantage of key technological innovations to start elucidating brain development, aging, and disease directly in human tissue. On one side, somatic mutation occurring in progenitor cells has been used as a natural barcoding system to address cell phylogenies of clone formation and cell segregation in the brain lineage. On the other side, analyses of mutation rates and patterns in the genome of brain cells have revealed mechanisms of brain aging and disorder predisposition.

Accumulation of somatic mutations in aging brain cells informs on cell-type-specific disease predisposition. Somatic mutation in neurons is linked to neurodegeneration. In glial cells, however, somatic mutation may play a role in predisposing to tumor insurgence as we become older. Since there is very little neuronal turnover in the postnatal brain, clonal expansions are either congenital or the product of postnatal expansions within the glia lineage. Indeed, an increase in clonal oncogenic somatic mutations was observed in the white matter of the normal human cerebral cortex compared to the adjacent grey matter.

Recent studies have shown how certain pathological states are associated to increased somatic mutation rates in the human brain and to disease-specific mechanisms. Although current knowledge seems to suggest that increased somatic mutation in Alzheimer's disease is due to oxidative damage due to the disorder, the exact role of increased rates of somatic mutation in neurodegeneration remains unclear, as well as the limit beyond which somatic mutations are not tolerated, thus leading to cell death.

Link: https://doi.org/10.3389/fnins.2023.1172469

There is plenty of evidence for particulate air pollution to raise mortality. A range of interesting natural experiments in which similar populations are exposed to greater or lesser particulate air pollution demonstrate that the groups with greater particulate exposure have increased risk of mortality and age-related disease. The mechanism likely involves an increase in chronic inflammation produced by particulates in lung tissue. All of the common age-related conditions are accelerated by sustained inflammatory signaling.

When cooking with biomass and fossil fuels, their incomplete burning can lead to air pollution, which can trigger pernicious effects on people's health, especially among the elderly, who are more vulnerable to toxic and harmful environmental damage. This study explored the association between different cooking fuel types and the risk of cancer and all-cause mortality among seniors constructing Cox regression models. Data were obtained by linking waves of 6, 7, and 8 of the Chinese Longitudinal Healthy Longevity Survey, which included a total of 7,269 participants who were 65 years old and over. Cooking fuels were categorized as either biomass, fossil, or clean fuels. And the effects of switching cooking fuels on death risk were also investigated using Cox regression models.

The results indicate that, compared with the users of clean fuels, individuals using biomass or fossil fuels were at a greater death risk for cancer [hazard ratios: biomass, 1.13; fossil, 1.16] and all causes [hazard ratios: biomass, 1.29; fossil, 1.32]. Furthermore, compared with sustained users of biomass fuels, individuals converting from biomass to clean fuels significantly reduced death risk for cancer [hazard ratio: 0.81] and all causes [hazard ratio: 0.76]. Similarly, all-cause death risk [hazard ratios: 0.77] was noticeably reduced among these participants converting from fossil to clean fuels than persistent users of fossil fuels.

Link: https://doi.org/10.1007/s11356-023-27873-7

The former Longevity Therapeutics conference series was renamed to the Age-Related Disease Therapeutics Summit and held its fifth event recently in San Francisco. It was a smaller meeting than in past years, perhaps a result of the recent downturn in the global financial and investment environment. Few investors were present. Nonetheless, one can usually learn something interesting from the presenting biotech founders and executives. I took a few notes while I was there to present on progress at Repair Biotechnologies, and they follow in the order of the conference program.

Birget Schilling from the Buck Institute for Research on Aging discussed the role of cellular senescence in bone aging. She focused on techniques for discovering signatures of aging in human bone tissue, looking at protein expression and composition of the bone extracellular matrix. This included the use of bone organoid models derived from patient cells and patient tissue samples. This was a snapshot of early-stage investigative research, some distance from any preclinical development and application to medicine.

Abdlkadar Rahmo from SMSbiotech, a cell therapy company, presented on the merits of in vitro human cell and tissue models of aging. Using such models can be cost-effective, but there are of course meaningful differences between an in vitro model and tissue in a living organism, and a great deal of work remains to be accomplished in standardization and reliability. The primary focus was on organoids derived from patient tissue samples, and a number of different models were described, including skin, brain, and intestinal structures. The company works on a specific type of adult stem cell found in human tissus that they call small mobile stem (SMS) cells. The company uses these cells in the manufacture of cell models, as SMS cells readily produce extracellular matrix that encourages blood vessel formation.

A panel discussed how to better improve translation from animal models to humans, always a challenge in every field. The general sentiment was that greater use of human organoids enables a more rapid process of fundamental discovery, skipping over animal studies until later in the process. It remains challenging to match animal models to diseases sufficiently well to avoid issues, and the field is littered with models that may be too artificial to be useful, but finding out that this is the case is a lengthy, expensive process. Making animal models better is a tough problem, and it was suggested that use of human organoids will at some point take over from that project. It was also suggested that gene therapies make animal models more useful, as there is a greater known consistency in the way the therapy interacts with animal versus human biochemistry.

Adam Kaplin of MyMD Pharmaceuticals presented on their inhibitory molecule that targets TNF-alpha and other important cytokines in inflammation and oxidative stress. Treatment dials down chronic inflammation in age-related disease and autoimmune disease. It is presently in clinical trials for sarcopenia and rheumatoid arthritis. Some of the fine details of the cytokine profiles following dosing were outlined. They believe their molecule is somewhat more selective for excessive inflammatory signaling versus needed inflammatory signaling than is the case for earlier inhibitors, which is an important issue in this part of the field. They demonstrate in mice that this inhibition of excessive inflammation can slow aging meaningfully, improving function and reducing mortality to a greater degree than rapamycin.

I presented on recent progress at Repair Biotechnologies. We develop a gene therapy, lipid nanoparticle delivery of mRNA, that can selectively clear excess intracellular free cholesterol. Our latest data shows sizable, rapid, safe reversal of the pathology of NASH in mouse models of the condition. We can also reverse atherosclerosis, removing plaque lipids in the same rapid, safe manner in animal models. We aim to conduct our first pre-IND meeting with the FDA later this year, and thereafter work towards an initial clinical trial in humans.

Peter Fedichev of Gero presented on their analysis of aging and disease. They make extensive use of machine learning to produce insights from large longitudinal data sets, both animal and human. Their view is one of regulatory systems and disturbance of homeostasis, a growing instability in regulation of complex processes in the body. Mice are less stable than humans, less resilient to disturbance of homeostasis, and a longer species life span might be considered a matter of better maintained stability. Gero tests a variety of approaches known to slow aging in mice in the context of their computational models for regulation of aging, seeking a better understanding of how exactly these treatments act on the body. From analysis of human data they identify a point of regulation and potential therapeutic, then confirm in mice, and thereafter hope to bring their best candidates into human trials.

Robin Mansukhani of Deciduous Therapeutics presented on their approach to clearing senescent cells via adjusting behavior of the immune system. They are advocates of the view that the growing burden of senescent cells with age is primarily an issue of immune dysfunction, though this is a multifaceted failure in many different immune cell types and recognition processes. The company is focused on natural killer T cells, and use small molecules to provoke these immune cells into more actively recognizing and destroying senescent cells. A single dose produces lasting improvement in senescent cell clearance, retraining aged immune cells into greater activity. Deciduous uses this approach to therapy to treat pulmonary fibrosis and type 2 diabetes, both conditions associated with cellular senescence, and are working towards clinical trials.

Doug Ethell of Leucadia Therapeutics discussed progress towards a small implantable device, essentially just a sensor-controlled valve, that restores cerebrospinal fluid drainage through the cribriform plate behind the nose. The company's preclinical evidence, including imaging of a large human study population and studies in ferrets, support a role for impaired drainage through the cribriform plate in the early development of Alzheimer's disease. The channels of the cribriform plate ossify and close with age. Without efficient drainage, metabolic waste of all sorts, including extracellular amyloid aggregates, accumulates in the brain, and this leads to neurodegeneration. At this point, the company is a year or so away from initial human trials of their device.

Michael Fossel of Telocyte started by outlining a view of aging as a growing imbalance between dynamic, constantly active processes of (a) damage and dysfunction versus (b) repair and restoration. This led to a discussion of changes in average telomere length as an important feature in tissues in aging, while noting that measuring telomere length in leukocytes from a blood sample is uninformative as to the state of the body. In this view, extending telomeres with telomerase expression is not targeting a cause of aging, but it is intervening at a convenient point in the processes of aging to adjust cell behavior for the better, restore more youthful epigenetic patterns to some degree, and improve tissue function. The company currently has unnamed sources of sufficient funding to conduct clinical trials of telomerase gene therapy as a treatment for various diseases of aging including Alzheimer's disease, but the timeline is unclear.

Jerry McLaughlin of Life Biosciences focused on their efforts in the hot field of partial reprogramming. They use an OSK cocktail, leaving out MYC from the original Yamanaka factors in order to prevent dedifferentiation and tumor formation. This approach, as with other reprogramming approaches, can reverse the characteristic epigenetic changes associated with aging, producing rejuvenation. They deliver an AAV carrier with a payload of conditionally activated OSK, only expressed in the presence of doxycycline. Their target indications for the clinic involve retinal damage and aging, as the eye is an isolated site and a good target for AAV gene therapies. They presented recent positive data on treatment of optic neuropathy in a non-human primate, resulting from ischemic damage in the retina. The treated primates showed a lesser loss of a measure of visual function, and exhibited improved survival of axons in the retina. The company is aiming for an initial clinical trial to start in late 2024.

Louis Hawthorne of NaNotics outlined the basis for their technology, a silica nanoparticle decorated with binding agents and covered by a shield layer that can efficiently remove specific molecules from the bloodstream without interacting with cell surfaces. Essentially a programmable sponge, and much more effective than antibodies. Mounting evidence points to various signal molecules in the bloodstream that increase in amount with age as contributing to various age-related diseases. One might consider pro-inflammatory cytokines, for example. Some groups have used expensive plasmapheresis to remove specific inflammatory molecules with good results, such as soluble tumor necrosis factor receptors (sTNFR) removal in the treatment of cancer, and NaNotics aims to do much the same thing more effectively. PD-L1 is another oncology target, and the company are moving to human trials in 2024 on the strength of a Mayo Clinic collaboration.

James Peyer of Cambrian Bio painted an interesting picture: that the challenge for our field is not that we cannot run trials for aging, nor designating aging as a disease, but that geroprotective drugs as a class of therapy require preventative trials for multiple comorbidities that are too lengthy to be economically viable in the current regulatory framework, given the venture capital mindset on duration of funds and need for return in a given timeframe. Thus we need to build new types of long-term research and development organizations, ones with sufficient funding to run multi-disease prevention trials over a longer timeframe than is presently possible. This way of thinking about the market is how Cambrian Bio came about, a well-capitalized entity intended to take programs all the way from academia through to these long clinical trials. Cambrian Bio has a sizable number of subsidiary biotechs, mostly stealth mode. Peyer talked about one of them, Telos Biotechnology. The company is focused on the ability of telomere lengthening to improve the performance of CAR-T cells in cancer therapy. The hypothesis is that current challenges in producing sufficient numbers of CAR-T cells for older patients has a lot to do with shorter telomeres and thus more replicative senescence during expansion in culture. The resulting cells are also less effective. The company develops an approach to increase telomere length in these CAR-T cells during expansion in cell culture, making a big difference in the cost-effectiveness and efficacy of CAR-T therapy.

Lorna Harries of SENISCA discussed progress on a platform for adjusting age-related dysregulations in RNA processing, such as altered RNA splicing resulting from changing expression of splicing factors, in order to suppress the burden of cellular senescence. Restoration of lost splicing factor expression can prevent and even reverse cellular senescence. Interestingly it also repairs some of the DNA damage characteristic of senescent cells. (This doesn't work in oncogene-induced senescence, where there is catastrophic DNA damage). To achieve this goal, the company uses a portfolio of oligonucleotides that can alter expression of various splicing factors and their regulators. The company is initially targeting idiopathic pulmonary fibrosis, as are many groups that work on clearance of senescent cells, and showed in vitro data in cells taken from pulmonary fibrosis patients, demonstrating restored markers of cell function. They have similar data for other cell models of age-related diseases connected to cellular senescence, such as cartilage degeneration.

Marco Quarta of Rubedo Life Sciences presented on the poorly catalogued differences that exist between senescent cell types, by origin and tissue type. It seems unlikely that any one small molecule senolytic would be able to effectively target all senescent cells. Chemotherapy and checkpoint inhibitor survivors exhibit increased senescent cells and reduced quality of life, but different chemotherapies apparently produce different states of cellular senescence, with varying vulnerability to specific senolytic drugs. So it may not be as straightforward as hoped to use senolytics to prevent lasting side-effects of cancer treatment. This example extends into other conditions and origin of senescence. Thus the company works on a big data, machine learning platform to identify senescent states associated with specific tissues and conditions, and then screen new senolytic small molecules tailored to these senescent cell states. They are aiming for an initial clinical trial in 2024.

Viktoria Kheifets of Alkahest discussed the current state of the art in altering levels of specific blood factors in order to suppress detrimental metabolic changes characteristic of aging. Alkahest is owned by a large medical-industrial blood plasma organization, acting as a research arm that can develop new commerical uses for its products. They see blood plasma as a master communication highway, transferring information between cells throughout the body. The company presently undertakes a great deal of data collection and analysis of the contents of blood samples in various ages and conditions, identifying clusters of various molecules and matching them to phenotypes. They then conduct studies in mice to see if plasma fraction transfusion can produce meaningful therapeutic benefits by altering specific plasma molecule levels. It is unclear as to which of the current preclinical programs will in fact be taken forward to the clinic, as this depends on the slow economic calculations of the large owning company. One interesting item is that the company has tried delivery of only albumin into old animals, and have seen no meaningful benefit. You might recall that there is some question over whether dilution of plasma works to improve health because albumin is delivered with the saline, and the result depends on replacement of existing, perhaps age-damaged, albumin. This may not be the case, and it is really the dilution of other harmful factors that causes improved health.

Szilard Voros of G3 Therapeutics talked about efforts to use big data analysis, of omics and epidemiological databases of thousands of individuals assessed over time, to rationally design entire clinical programs targeting age-related diseases, from the mechanistic target through to predicted odds of success of a clinical trial of a small molecule targeting that mechanism. The company has built a vast set of data, down to the level of expression patterns in specific tissues, and uses that data to move therapeutics towards the clinic.

Andrei Gudkov of Roswell Park Cancer Center presented a contrarian position on senescent cell biochemistry. Researchers used a mouse model which they lethally irradiated and then rescued by replacement of bone marrow, expecting greater cellular senescence and accelerated aging, but while the mice had a 20% shorter life span, their late life frailty was actually reduced in comparison to controls. Oddly, these mice also exhibited no sign of increased cellular senescence using traditional biomarkers such as P16 and inflammatory signaling. Their conclusion was that most P16 and SA-beta-gal expressing cells in old tissues that are pumping out inflammatory cytokines are actually macrophages, not what are presently thought of as senescent cells. Strangely, mesenchymal cells of these irradiated mice immediately become senescent when put into culture and forced to divide, while remaining non-senescent and non-dividing in vivo. Also the mice have impaired wound healing and excessive appearance of senescent cells in injuries. Further, if they are given a high fat diet grow fat, then they exhibit raised mortality. This is all connected to cell proliferation. The implication is that the mice have genotoxic stress due to radiation-induced DNA damage, but this dormant harm is only realized when cells are forced to proliferate. This all says something interesting about how senescence and DNA damage interact, that damage can remain dormant, a potential for senescence to be realized later.

A panel discussion focused on choice of biomarkers as important in achieving success in clinical trials. When setting up a clinical trial, one has to convince the regulators that the proposed biomarkers are appropriate. A poor choice, whether it originates with the company or the FDA, can doom a trial even if the therapy actually works. Biomarkers might be (a) predictive, in the pre-disease state, though few clinical trials are conducted for prevention, or (b) diagnostic to establish the state and progression of established disease. One also needs easily measured biomarkers that determine the degree to which the therapy is active in a patient. In the best of worlds, these choices are obvious and straightforward. But it is rarely that simple, particularly in the matter of aging or new mechanisms of action.

Joshua McClure of Maxwell Biosciences presented on the company's broad anti-inflammatory platform derived from innate immune system antimicrobial peptides, which is progressing towards clinical trials. These factors were discovered using big data analysis of heterochronic parabiosis studies, looking at old and young blood and comparative omics profiles. The company has taken the non-dilutive funding approach to fundraising, and has been largely funded by government research grants rather than venture capital. Their primary candidate molecules are derived from LL37, a ubiquitous antimicrobial peptide that appears to have a range of other helpful, protective functions both connected and unconnected to immune function. The preclinical data is quite impressive, and this therapy may go on to improve outcomes in many infections, cancers, and other conditions.

Hans Keirstead of Immunis presented on their approach to culturing stem cells in order to produce a secretome as a drug that can improve immune function, reducing immunosenescence and inflammaging. This manufacture isn't as easy as it might sound. Standardization of any sort of product that involves cell populations is a challenge. That it is hard and expensive and failure-prone to manufacture cell therapies is a large part of why there is strong interest in moving to cell secretions as a basis for therapies derived from what we know about how cell therapies influence tissues. It is easier to control cells in a dish to produce a secretome that can be assessed on ~10 marker proteins than it is to produce cells for transplant. Delivering a secretome to improve immune function to mice produces a wide range of benefits, and the hope is that enough of this will translate to humans to succeed in clinical trials for indications that have traditionally been targeted for the development of stem cell therapies.

Hanadie Yousef of Juvena Therapeutics discussed their approach to therapy. The company has used proteomic analysis of secretomes from various cell types known to promote regeneration in order to identify regulatory molecules that are enriched in scenarios of regeneration. They use machine learning based on the library of proteins they created in order to predict which secreted molecules are likely to be useful for given indications. They then engineer improved versions of these proteins. Their lead protein is at the pre-IND stage, initially to treat a form of muscular dystrophy, and they hope to start clinical trials by the end of 2024.

David Furman of the Buck Institute for Research on Aging talked initially about a project to build a large omics database of human imune aging. This data led to an unbiased search for makers of inflammaging, which lead to the inflammatory age (iAge) clock. This clock correlates with health outcomes and mortality, as one might expect given what is known of the role of inflammation in aging. A company and drug discovery program resulted, and various candidate drugs that reduce iAge have been tested in human trials. The presentation moved on to the use of accelerated aging models to make studies run more rapidly. This specific effort involves the apparent acceleration of aging that occurs as a result of time spent in microgravity. A company, Cosmica, to run drug discovery programs targeting mechanisms of aging more rapidly than is usually possible based on this class of accelerated aging, using organoids in a microgravity environment, with human astronaut data for validation. Perhaps the most interesting point here is that measures of accelerated aging in astronauts reverse once back on the ground again, and one might ask: what are the driving biological mechanisms of that restoration? The company believes that the primary mechanisms they are observing are related to cell mechanosensing of the extracellular matrix, and microgravity disrupts this in ways that somewhat mimic some of the biochemistry-driven issues with cell/extracellular matrix interaction that occur in aging.

Noah Davidson of Rejuvenate Bio discussed progress towards the clinic for their leading gene therapies. They use AAV as a vector platform, and intend to take its use beyond the present correction of rare genetic disorders into a broader set of age-related conditions. They are primarily focused on cardiac disease, picking genes and mutations that have been shown to extend life in mice and that will address specific issues that occur in cardiac diseases, such as fibrosis and mitochondrial dysfunction. They screened combinations of upregulation and downregulation of various genes, and settled on the current favored combination of FGF1 and anti-TGF-beta-1 - increasing FGF1 expression and decreasing circulating TGF-beta-1 using a binding receptor fragment. They have been using the therapy in companion dogs for a few years, with a good safety profile. A single treatment is expected to last for a decade or longer, but the expression is inducible; it requires taking a pill daily to activate expression of the therapeutic genes, for an additional layer of control of the therapy. The company aims to expand out into a broad veterinary market for dogs, and thus will provide supportive data for clinical development of the same class of therapy for human use.

A panel discussed how aging-focused biotech companies might better build bridges to large pharma entities, which are typically slow to engage meaningfully with any change in the state of the science and the industry. This quite quickly turned into an exchange about the various groups that are trying to circumvent the established regulatory environment, and build alternative paths to clinical application and revenue. It seems clear that many people in the longevity industry as it stands put pharma entities in the same category as regulators: a mountain that lies ahead, an unpleasant but necessary task of engagement if one is to play the game as the rules are written. The conversation then moved on to the power of data. A truly curative, impressive therapy will shape the system around it, and will find a way, the obstacles will melt away. In the matter of aging, the biggest challenge is how to measure such an impressive therapy in order to prove that it is in fact impressive in something less than a decade-long study.

Alexander Picket of Juvenescence talked about a drug development program leading on from the discovery of a small population of humans with a loss of function mutation in PAI-1 and who appear to exhibit a longer life expectancy as a result, an additional seven years. This gene lives at the border of immune function and fibrinolytic system responsible for clotting, and has a lot of activities beyond that. It touches on cellular senescence, for example. There was some discussion of how, even given this very obviously interesting mechanism, and a drug that replicates the effect to some degree, it is still complicated and hard to find a way through the regulatory system as it exists today. A lot of this involves downstream effects of government regulation of medicine, insurers, and medical pricing, as at the end of the day the large funding sources will only invest in clinical trials for drugs wherein a profit can be made, and regulation ensures that many types of treatment simply cannot be profitable in any of the ways they are permitted to be deployed.

Pankaj Kapahi of the Buck Institue for Research on Aging discussed glycation in aging. Advanced glycation endproducts (AGEs) produce a number of issues, such as inflammation due to interaction with receptors and the reaction of the immune system to glycated proteins, and also cross-linking in the extracellular matrix. This is most evident in the sugar-heavy dysfunctional metabolism of diabetics, but in aging it seems likely that persistent AGEs also generate meaningful pathology. The research here focused on methylglyoxal, a precursor of AGEs. Scientists found a way to reduce methylglyoxal levels in the body using a cocktail of supplements. This led to a spinout company Juvify Health and a supplement product. In mice this improves insulin metabolism and reduces body weight in addition to achieving the expected biochemical measures such as degree of glycation of proteins. The body weight change appears to be because targeting AGEs in this way suppresses hunger mechanisms, and the mice eat less, which is an interesting finding.

The theme for the industry at this time appears to be that many clinical trials of novel therapeutics targeting mechanisms of aging will start up in the next few years, assuming funding can be found. Impressive data tends to attract that funding. Market downturns don't last, and the next boom period will be characterized by the advent of a range of methods to greatly enhance immunity, slow aging, and turn back specific age-related conditions presently resistant to treatment. Interesting times!

Researchers here report that a few cell types in aged skin begin to generate large amounts of IL-17, an inflammatory signal molecule. While the obvious suspect here is cellular senescence, as we know that senescent cells accumulate with age and energetically secrete pro-inflammatory signal molecules, this data suggests that this may not be the case, at least for this particular signal molecule in this particular tissue. The researchers show that blocking IL-17 slows the manifestations of skin aging. The challenge in this sort of approach is that inflammatory signal molecules are needed for the normal immune response to function correctly. The treatment of autoimmune conditions via blockade of various inflammatory signals has meaningful side-effects that include suppression of necessary immune responses. This is less of a concern if treatments target only the skin, but we should hope that researchers can identify more targeted, subtle ways to eliminate only excess inflammatory signaling in the rest of the aging body.

During aging, tissue-specific alterations in the stem cell niche synergize with stem cell-intrinsic changes to contribute to the development of age-associated traits. Aging has been proposed to drive a tissue-dependent proinflammatory microenvironment that perturbs adult stem cell behavior. Infiltration of immune cells into the stem cell niche, or a transcriptional switch of stem cells, contributes to this proinflammatory environment that negatively feeds back to their own fitness. Here we have characterized the effects of the proinflammatory cytokine IL-17 on skin aging.

Our results show that elevated IL-17 signaling, secreted by aged dermal CD4+ T-helper cells, γδ T cells, and innate lymphoid cells, orchestrated many of the age-associated tissue dysfunctions by exertion of pleiotropic effects. IL-17-mediated signaling is heavily linked to the development of chronic inflammatory and autoimmune diseases. In the skin, these diseases include psoriasis, pemphigus, and alopecia areata. Even if none of the clinical signs of these diseases are common with physiological aging, they share an increased aberrant IL-17-based signaling that impedes correct skin function.

Our results strongly suggest that, intriguingly, the local environment of the aged skin resembles a low-level but persistent state of chronic inflammation, with deficient permeability and impaired wound healing that is reminiscent of what occurs in serious skin diseases such as psoriasis. Consequently, anti-IL-17 therapies, already approved for treatment of psoriasis, might be repositioned to other age-associated ailments such as excessive skin dryness or difficulty in repairing damaged skin in the elderly.

Link: https://doi.org/10.1038/s43587-023-00431-z

Taurine levels drop with age, and correlate with health in aged humans. Researchers here show evidence for taurine supplementation to improve health and extend life span in mice. While it isn't mentioned in this paper, if one takes a look around the literature on this topic, taurine may act on the pace of aging by increasing levels of the antioxidant enzyme glutathione, and has been shown to diminish oxidative stress. You may recall that supplementation with glutathione precursors has been shown to improve health in both old mice and old humans. Glutathione itself is harder to deliver directly, hence the more indirect strategies. The observed effects on health and life span may be due to improved mitochondrial function, reducing the dual impact of mitochondrial dysfunction: loss of ATP production needed to power cell processes on the one hand, and and excessive production of oxidative molecules that can damage molecular machinery elsewhere in the cell on the other.

Aging is associated with systemic changes in the concentrations of molecules such as metabolites. However, whether such changes are merely the consequence of aging or whether these molecules are drivers of aging remains largely unexplored. If these were blood-based drivers of aging, then restoring their concentration or functions to "youthful" levels could serve as an antiaging intervention. Taurine, a semiessential micronutrient, is one of the most abundant amino acids in humans and other eukaryotes. Earlier studies have shown that the concentration of taurine in blood correlates with health, but it is unknown whether blood taurine concentrations affect aging. To address this gap in knowledge, we measured the blood concentration of taurine during aging and investigated the effect of taurine supplementation on health span and life span in several species.

Blood concentration of taurine declines with age in mice, monkeys, and humans. To investigate whether this decline contributes to aging, we orally fed taurine or a control solution once daily to middle-aged wild-type female and male C57Bl/6J mice until the end of life. Taurine-fed mice of both sexes survived longer than the control mice. The median life span of taurine-treated mice increased by 10 to 12%, and life expectancy at 28 months increased by about 18 to 25%. A meaningful antiaging therapy should not only improve life span but also health span, the period of healthy living. We, therefore, investigated the health of taurine-fed middle-aged mice and found an improved functioning of bone, muscle, pancreas, brain, fat, gut, and immune system, indicating an overall increase in health span.

Investigations into the mechanism or mechanisms through which taurine supplementation improved the health span and life span revealed that taurine positively affected several hallmarks of aging. Taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammation. An association analysis of metabolite clinical risk factors in humans showed that lower taurine, hypotaurine, and N-acetyltaurine concentrations were associated with adverse health, such as increased abdominal obesity, hypertension, inflammation, and prevalence of type 2 diabetes. Moreover, we found that a bout of exercise increased the concentrations of taurine metabolites in blood, which might partially underlie the antiaging effects of exercise.

Link: https://doi.org/10.1126/science.abn9257

Mitochondrial transplantation is potentially a way to restore more youthful mitochondrial function without the need for a far greater understanding of exactly how exactly mitochondria become dysfunctional with age. Cells will readily ingest mitochondria from the surrounding intercellular space and make use of them. If those mitochondria work well in comparison to the state of the cell's native mitochondria, then cell function will be improved for some time. Animal studies suggest that the effect is lasting. In that context, it is always interesting to see studies in which outcomes are assessed for mitochondrial transplantation from young animals into old animals, as in today's open access paper.

Other approaches to reducing the age-related decline in mitochondrial function have been implemented based on a combination of advances in scientific understanding and fortunate discoveries in small molecule screens. These largely appear to work at least in part via improved mitophagy, the quality control process responsible for recycling worn and broken mitochondria. Unfortunately, these treatments fail to improve on exercise when it comes to enhancing measures of health. This category of interventions in includes increasing NAD levels via delivery of precursors, urolithin A and its effects on mitochondrial dynamics, mitochondrially targeted antioxidants such as mitoQ, and so forth.

While potentially more interesting approaches are under development, such as copying mitochondrial DNA into the cell nucleus to provide a backup source of proteins when mitochondrial DNA becomes damaged, these are still very much works in the progress. Even given that a company has held clinical trials for a gene therapy to introduce a backup copy of one mitochondrial gene, there are still a range of other mitochondrial genes to deal with in this way. Mitochondrial transplantation is somewhat closer to the clinic, however. The only significant roadblock is the efficient manufacture of large numbers of mitochondria, and several venture funded companies are working on solutions.

Chronic stress-induced apoptosis is mitigated by young mitochondria transplantation in the prefrontal cortex of aged rats

Apoptosis is common and often comorbid with aging and stress-related mood disorders. Evidence suggests that fresh mitochondria could reverse age-related dysfunctions in organs, especially in the brain. Therefore, this study investigated the effect of young mitochondria administration on the apoptosis process in the prefrontal cortex (PFC) of aged rats exposed to chronic stress.

Aged (22 months old) male rats were randomly assigned into four groups: aged control (AC), aged rats treated with young mitochondria (A+M), aged rats subjected to chronic stress for four weeks (A+St), and aged rats subjected to chronic stress and treated with young mitochondria (A+St+M). A+M and A+St+M groups received a single intracerebroventricular injection (10 μl) of fresh mitochondria isolated from the brain of young rats. Finally, the levels of malondialdehyde (MDA), cytochrome c (Cyt c), Bax, Bcl-2, and Caspase-3 expression were investigated in the PFC.

The results of the present study demonstrated that the transplantation of young mitochondria ameliorated oxidative stress in the PFC of aged and chronic stress-exposed aged rats, as indicated by diminished MDA levels and reduced Cyt c release. Young mitochondria also markedly attenuated apoptosis markers in the PFC of aged and chronic stress-exposed aged groups, which was characterized by down-regulated expression levels of pro-apoptotic proteins, Bax and caspase-3, and up-regulated expression levels of anti-apoptotic protein Bcl-2. These results suggest mitochondrial transplant therapy could reverse cell viability and mitochondrial dysfunction-induced apoptosis in the PFC tissue of aged rats subjected to stressful stimuli.

Excess visceral fat tissue produces a greater burden of senescent cells, so in that sense one might argue that it is literally causing accelerated aging. Generally researchers content themselves with pointing to the epidemiological data, in which being overweight correlates with greater incidence of age-related disease, greater lifetime medical costs, and a shorter life expectancy. Here, however, an effort is made to prove causation in human data: that the excess weight does in fact cause all of these problems.

Limited by the quality of evidence, possible potential reverse causality and residual confounding, observational studies have been almost unable to identify a causal association between being overweight and aging. In this regard, randomized controlled trials (RCTs) can be used to reveal cause and effect. However, RCTs are costly in terms of money, time and manpower. Instead, Mendelian randomization (MR) is a popular and effective method for causal inference in recent years. It takes genetic variation (single nucleotide polymorphism, SNP) as the instrumental variable to deduce the causal association between outcome and exposure, which can effectively avoid the confounding bias of traditional epidemiological studies.

We collected genetic variants associated with overweight, age proxy indicators (telomere length, frailty index, and facial aging, etc.), from genome-wide association studies datasets. Then we performed MR analyses to explore associations between overweight and age proxy indicators. MR analyses were primarily conducted using the inverse variance weighted method, followed by various sensitivity and validation analyses.

MR analyses indicated that there were significant associations of being overweight on telomere length, frailty index, and facial aging. Overweight status also had a significant negative causality with life expectancy. Moreover, the findings tend to favor causal links between body fat mass or body fat percentage on aging proxy indicators, but not body fat-free mass. In conclusion, this study provides evidence of the causality between overweight and accelerated aging (telomere length decreased, frailty index increased, facial aging increased) and lower life expectancy. Accordingly, the potential significance of weight control and treatment of overweight status in combating accelerated aging need to be emphasized.

Link: https://doi.org/10.1111/acel.13899

Researchers here show that great fat infiltration of skeletal muscle tissue correlates well with the progressive loss of cognitive function that occurs with advancing age. It is well demonstrated that greater visceral fat mass accelerates the declines of aging, but researchers here suggest that fat deposition in skeletal muscle correlated with cognitive decline independently of the degree to which study participants were overweight. The underlying reasons as to why two people of the same overall adiposity may have different degrees of intramuscular fat deposition are not well understood, but this manifestation of aging correlates well with many aspects of age-related dysfunction, including chronic inflammation, metabolic syndrome, and other usual suspects. In a web of correlations, it can be challenging to identify cause and effect.

Obesity and loss of muscle mass are emerging as risk factors for dementia, but the role of adiposity infiltrating skeletal muscles is less clear. Skeletal muscle adiposity increases with older age. In 1,634 adults (69-79 years), we obtained thigh intermuscular adipose tissue (IMAT) via computerized tomography at Years 1 and 6, and mini-mental state exam (3MS) at Years 1, 3, 5, 8 and 10.

A linear mixed effects models tested the hypothesis that increased IMAT (Year 1-6) would be associated with 3MS decline (Year 5-10). Models were adjusted for traditional dementia risk factors at Year 1 (3MS, education, APOe4 allele, diabetes, hypertension, and physical activity), with interactions between IMAT change by race or sex. To assess the influence of other muscle and adiposity characteristics, models accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass (all measured in Years 1 and 6). Models were also adjusted for cytokines related to adiposity: leptin, adiponectin, and interleukin-6.

Thigh IMAT increased by 4.85 cm^2 (Year 1-6) and 3MS declined by 3.20 points (Year 6-10). The association of IMAT increase with 3MS decline was statistically significant: an IMAT increase of 4.85 cm^2 corresponded to a 3MS decline of an additional 3.60 points, indicating a clinically important change. Interactions by race and sex were not significant. Clinicians should be aware that regional adiposity accumulating in the skeletal muscle may be an important, novel risk factor for cognitive decline independent of changes to muscle strength, body composition, and traditional dementia risk factors.

Link: https://doi.org/10.1111/jgs.18419

Senescent cells accumulate in tissues throughout the body with age. Cells become senescent constantly throughout life, largely by reaching the Hayflick limit on replication, but a small number due to potentially cancerous mutations, or other forms of damage and stress. Senescent cells are rapidly removed by the immune system in youth, keeping their numbers low, but the balance between creation and destruction is disrupted with aging. There is greater stress, but perhaps more importantly the immune system becomes less efficient, less able to clear senescent cells in a timely fashion. Since senescent cells actively secrete pro-inflammatory, pro-growth signals, they are a disruptive, harmful influence on tissue structure and function with present for the long term in even comparatively small numbers.

It is fair to say that near every tissue and system in the body examined to date suffers from the late life presence of lingering senescent cells and their inflammatory secretions. These cells contribute meaningful to the onset and progression near every age-related condition. This includes the decline of the immune system into immunosenescence and inflammaging. It would be surprising indeed to find that removal of senescent cells failed to improve late life immune function in humans, considering what we know of the mechanisms involved, and the impressive array of evidence from animal studies. Even only considering the point that senescent cells encourage constant, unresolved inflammation, their removal should be beneficial to immune function.

The ageing immune system as a potential target of senolytics

The immune system is essential in protecting the body from various pathogenic mechanisms and infection, in particular, there are significant changes to immune function as we age. Recent studies have suggested that the cellular senescence of immune cells impairs clearance of pathogenic material, increasing the risk of severe infections and mortality. These processes lead to the build-up of inflammatory mediators, causing inflammageing - a state of chronic immune activation that is associated with blunted innate and adaptive immune responses. The cumulative effect of these processes triggers downregulation of immune responses, via mechanisms such as defective lymphocyte responses and a reduction in regulatory immune cells. Thus leading to deterioration of the immune system with age, termed immunosenescence. Thus, clearance of senescent immune cells could be beneficial to the immune system, as has been witnessed in other tissues. This has driven research into modalities which can delay, or reverse, these age-related immune changes.

Current senolytics aim to clear all senescent cells, regardless of their cell type, however, refining this to target specific senescent cell populations may be of benefit, by increasing the efficacy of drugs whilst reducing potential side effects, as seen in other fields such as cancer therapies. One of the major concerns of an ageing immune system is its diminished immune response, which in part is driven by senescent immune cells. This effect of an ageing immune system can be seen clinically, as older populations are at greater risk of succumbing to serious infections and have poorer efficacies with regards to vaccines. Senolytics targeting senescent immune cells may provide a solution to help improve immunity within elderly populations.

Targeting senescent immune cells has further drawn interest in the treatment of age-related diseases. Recent studies have implicated senescent immune cells in driving senescence and ageing in tissues including the liver in mouse and rat models, although the precise mechanism behind this is yet to be determined. Given these findings, it is tempting to speculate that senescent immune cells are driving similar age-related changes in other tissues and organs. Targeting senescent immune cells therapeutically could therefore provide benefits beyond that of targeting individual tissue-based senescent cell populations.

Although current senolytics may have some degree of senescent immune cell clearance, a senolytic specifically targeting senescent immune cells has not yet been developed. Given the impact of senescent immune cells on the pathophysiology of age-related disease and the diminution of the immune response, senolytics targeting these cells may have multi-faceted benefits. Additionally, whilst research is still in early stages, pre-clinical models show that senolytics could modulate a more favourable immune response to infection in older mice and humans.

Advanced glycation end-products (AGEs) are a threefold problem. Firstly, a few species of persistent AGEs can form lasting cross-links between structural molecules of the extracellular matrix that alter its tensile properties, such as a loss of elasticity. Human biochemistry is ill-suited to the task of removing these cross-links, particularly those based on glucosepane. Secondly, AGEs can bind to proteins and modify their function, acting as a form of damage that cells must clear. Thirdly, transient AGEs interact with the receptor for AGEs, RAGE, to produce chronic inflammation and cellular dysfunction. This is characteristic of the abnormal, high-sugar environment of type 2 diabetes, but also an issue to a lesser degree in the broader aged population.

Advanced glycation end-products (AGEs; e.g., glyoxal, methylglyoxal, or carboxymethyl-lysine) are heterogenous group of toxic compounds synthesized in the body through both exogenous and endogenous pathways. AGEs are known to covalently modify proteins bringing about loss of functional alteration in the proteins. AGEs also interact with their receptor, receptor for AGE (RAGE) and such interactions influence different biological processes including oxidative stress and apoptosis.

Previously, AGE-RAGE axis has long been considered to be the maligning factor for various human diseases including, diabetes, obesity, cardiovascular, aging, etc. Recent developments have revealed the involvement of AGE-RAGE axis in different pathological consequences associated with the onset of neurodegeneration including, disruption of blood brain barrier, neuroinflammation, remodeling of extracellular matrix, dysregulation of polyol pathway and antioxidant enzymes, etc.

In the present article, we attempted to describe a new avenue that AGE-RAGE axis culminates to different pathological consequences in brain and therefore, is a central instigating component to several neurodegenerative diseases (NGDs). We also invoke that specific inhibitors of TIR domains of TLR or RAGE receptors are crucial molecules for the therapeutic intervention of NGDs. Clinical perspectives have also been appropriately discussed.

Link: https://doi.org/10.3389/fnmol.2023.1155175

The research and development community continues to focus on amyloid-β as a primary target in Alzheimer's disease, despite the failure to produce meaningful benefits in patients in human clinical trials of immunotherapies targeting amyloid-β. It may yet prove to be the case that safer approaches than immunotherapies, used widely to reduce amyloid-β prior to the development of symptoms, could lower incidence of Alzheimer's disease. It seems evident that extracellular amyloid-β is not the right target in later stages of the condition, however.

Accumulation of amyloid β in the brain is regarded as a key initiator of Alzheimer's disease pathology. Processing of the amyloid precursor protein (APP) in the amyloidogenic pathway yields neurotoxic amyloid β species. In the non-amyloidogenic pathway, APP is processed by membrane-bound ADAM10, the main α-secretase in the nervous system. Here we present a new enzymatic approach for the potential treatment of Alzheimer's disease using a soluble form of ADAM10.

The ability of the soluble ADAM10 to shed overexpressed and endogenous APP was determined with an ADAM10 knockout cell line and a human neuroblastoma cell line, respectively. Using proteomic approaches, we identified soluble ADAM10 substrates. Finally, a truncated soluble ADAM10, based on the catalytic domain, was expressed in Escherichia coli for the first time, and its activity was evaluated.

The soluble enzyme hydrolyzes APP and releases the neuroprotective soluble APPα when exogenously added to cell cultures. The soluble ADAM10 inhibits the formation and aggregation of characteristic amyloid β extracellular neuronal aggregates. Our in vitro study demonstrates that exogenous treatment with a soluble variant of ADAM10 would shift the balance toward the non-amyloidogenic pathway, thus utilizing its natural neuroprotective effect and inhibiting the main neurotoxic amyloid β species. The potential of such a treatment for Alzheimer's disease needs to be further evaluated in vivo.

Link: https://doi.org/10.3389/fnagi.2023.1171123

Nerves require myelin sheathing in order to function correctly. With age, some degree of dysfunction in myelin maintenance takes place, with consequent cognitive and other nervous system degeneration as a consequence. This loss of myelin integrity takes place to a lesser degree than is the case in severe demyelinating conditions such as multiple sclerosis. Nonetheless, that lesser degree may be contributing to the early stages of Alzheimer's disease by reducing immune clearance of amyloid-β aggregates.

At present a question hovers over the role of amyloid-β in Alzheimer's disease due to the failure of amyloid-clearing immunotherapies to improve patient outcomes in the clinic. The research and development communities remain largely wedded to the idea that amyloid-β aggregation will turn out to be relevant to the early onset of the condition, but it remains to be seen as to whether even that is correct, accepting that the later stages have moved on to other primary mechanisms of harm associated with neuroinflammation and tau aggregation.

Poorly insulated nerve cells promote Alzheimer's disease in old age

Intact myelin is critical for normal brain function. Researchers have shown that age-related changes in myelin promote pathological changes in Alzheimer's disease. Their work focused on a typical feature of the disease; Alzheimer's is characterized by the deposition of certain proteins in the brain, the so-called amyloid beta peptides (Aβ). The Aβ peptides clump together to form amyloid plaques. In Alzheimer's patients, these plaques form many years and even decades before the first symptoms appear. In the course of the disease, nerve cells finally die irreversibly and the transmission of information in the brain is disturbed.

Using imaging and biochemical methods, the scientists examined and compared different mouse models of Alzheimer's in which amyloid plaques occur in a similar way to those in Alzheimer's patients. For the first time, however, they studied Alzheimer's mice that additionally had myelin defects, which also occur in the human brain at an advanced age. Researchers saw that myelin degradation accelerates the deposition of amyloid plaques in the mice' brains. The defective myelin stresses the nerve fibers, causing them to swell and produce more Aβ.

At the same time, the myelin defects attract the attention of the brain's immune cells called microglia. Normally, microglia detect and eliminate amyloid plaques, keeping the buildup at bay. However, when microglia are confronted with both defective myelin and amyloid plaques, they primarily remove the myelin remnants while the plaques continue to accumulate. The researchers suspect that the microglia are 'distracted' or overwhelmed by the myelin damage, and thus cannot respond properly to plaques.

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease

The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter of which is associated with secondary neuroinflammation. As oligodendrocytes support axonal energy metabolism and neuronal health, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD.

Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage.

In recent years, researchers have implicated the activation of transposable elements such as retrovirus sequences in degenerative aging. Transposable elements are largely the remnants of ancient viral infections, and have the ability to copy themselves in the genome. In youth, transposable elements are effectively suppressed, but with advancing age this suppression falters. Transposable elements can then act as a form of DNA damage, as well as provoking cell dysfunction via other means, such as inflammatory signaling resulting from innate immune sensing of viral signatures, which may meaningfully contribute to harmful outcomes in aging.

The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Efforts have been made to reveal molecular events that trigger aging-related dysfunctions in FL, however intrinsic alterations in neurons in response to aging are not completely understood.

Using the neuronal aging-in-a-dish model derived from human embryonic stem cells, we genetically perturbed the expression of Lamin B1 and Lamin B2 in human neurons and pinpointed that decreased B-type lamins drive the activation of endogenous retrovirus (ERV) retrotransposons during neuronal aging, which leads to elevated senescence and inflammation. Our study demonstrated that this in vitro human neuronal model could mimic the aging-related phenotypes of neurons from primate brains and study cell-autonomous mechanisms underlying primate neuronal aging.

ERV element activation has been reported to be associated with cellular senescence. In addition, increased expression of ERV elements was found to contribute to neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the links between ERV derepression and physiological brain aging have not been established. For the first time, our study revealed that ERV retrotransposable elements are derepressed in aged human neurons, which activate cGAS signaling, exacerbating neuroinflammation, thus providing a vivid paradigm of how this cascade functions in a highly physiologically and pathologically relevant context, the aging brain.

We previously found that the inhibition of reverse transcription of the endogenous retrovirus can alleviate cartilage degeneration and aging-related inflammation. In this study, we further found that treatment with abacavir can attenuate the augmented inflammation and protein aggregates in human neurons during prolonged culture and in the neurons of FL from aged mice, indicating ERV targeting as a promising strategy to delay brain aging and extend healthspan.

Link: https://doi.org/10.1016/j.celrep.2023.112593

All large mammals must evolve ways to suppress cancer risk more effectively than their smaller relatives. More mass means more cells, and thus more chances for a cell to suffer the mutations that will lead to cancer. Elephants evolved additional copies of P53 and other tumor suppression genes, for example. Bowhead whales, on the other hand, appear to manage with more efficient DNA repair mechanisms. We can hope that some of these explorations may lead to ways to improve human resistance to cancer. Improved DNA repair in particular is an attractive goal, given that DNA damage is linked to aging in a number of ways, such as via somatic mosaicism and the possibility of causing detrimental epigenetic change.

At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg. In spite of its very large number of cells, the bowhead is not highly cancer-prone, an incongruity termed Peto's Paradox. This has been explained by the evolution of additional tumor suppressor genes in larger animals, which is supported by research on elephants demonstrating expansion of the p53 gene.

However, we show here that bowhead whale fibroblasts undergo oncogenic transformation after disruption of fewer tumor suppressors than required for human fibroblasts. Instead, analysis of DNA repair revealed that bowhead cells repair double-strand breaks with uniquely high efficiency and accuracy compared to other mammals. Further, we identified two proteins, CIRBP and RPA2, that are present at high levels in bowhead fibroblasts and increase the efficiency and fidelity of DNA repair in human cells.

These results suggest that rather than possessing additional tumor suppressor genes as barriers to oncogenesis, the bowhead whale relies on more accurate and efficient DNA repair to preserve genome integrity. This strategy, one that does not eliminate cells but repairs them, may be critical for the long and cancer-free lifespan of the bowhead whale. Our work demonstrates the value of studying long-lived organisms in identifying novel longevity mechanisms and their potential for translation to humans.

Link: https://doi.org/10.1101/2023.05.07.539748

It is fair to say that the mainstream of environmentalism prioritizes conservation of the environment over human comfort and health. Environmental concerns are high on the list of objections raised against treating aging as a medical condition, because most people believe that this will lead to a larger population, and also believe that population increases cannot occur without degrading the environment. Both of those beliefs are false, the latter evidently so given the improvements in the environment created since the 1950s, over a period of considerable population growth. Models strongly suggest that the future is one in which population growth diminishes with increasing wealth, as is already happening in countries like Japan, and we certainly live in a world in which the wealth of individuals and populations is increasing, quite rapidly in the poorest regions.

In this context, it is interesting to see commentary from someone who values both (a) the high profile goals of environmentalism, and (b) the high profile goals of efforts to treat aging and thereby extend the healthy human life span. There is no reason as to why we can't have the cake and eat it in this case. Given the will, we can have both great longevity and the world recreated as an unspoiled garden. The conflicts between these goals are illusionary, an outcome of mistaken ideas as to what greater longevity will mean, and how technological progress and economic incentives work to create new resources and greater abundance, not simply exhaust the resources we have.

Geroscience and climate science: Oppositional or complementary?

Two of this century's most significant public health challenges are climate change and healthy aging. The future of humanity will be both warmer and older than it is today. Taken in isolation from each other, tackling either one of the novel public health challenges of climate change or healthy aging requires foresight, scientific innovation, and collaborative governmental action. However, the public health challenges of the 21st century are even more Herculean because climate change and population aging are occurring simultaneously. And this means that science communication concerning what constitutes empirically valid and morally defensible ways of navigating these dual public health challenges must be sensitive to both the interdependence of the environment and the mechanisms of aging, as well as the common (mis)perceptions about the potential conflict between the goals of climate science and geroscience.

It is a common and accepted role for scientists to get involved in public policy debates, especially if their research pertains to public health. "Responsible biology" entails that scientists conceive of themselves as artisans working for the public good, and thus, they have a moral obligation to reflect on the ends (and not just the means) of scientific research. Is it socially responsible, in a warming planet of a population exceeding 8 billion people, for science to aspire to develop gerotherapeutic drugs? That is, drugs that target pathways involved in aging with the aim of reducing the burden of aging-related diseases and increasing lifespan and healthspan. This question is, for the field of geroscience, the "elephant in the room." It is a question the field must tackle head on vs avoid, lest it risk marginalizing the science of healthy aging.

Unlike scientific innovation for pharmaceuticals treating specific diseases, like cancer, heart disease, or Alzheimer's, biomedical gerontology often faces concerns that arise from what has been called "gerontologiphobia" - "the irrational fear that aging research is a public menace bound to produce a world filled with non-productive, chronically disabled, unhappy senior citizens consuming more resources than they produce." Climate anxiety among younger persons, coupled with "egalitarian advocacy" (a motivation to take action and enact equality-based change), may lead to "succession"-based ageism - the belief that older adults should step aside to free up coveted opportunities. The case for shifting public health priorities from the goal of making further increases in lifespan for older populations via disease control toward the goal of increasing the human healthspan via rate (of aging) control can help abate the assumptions of intergenerational conflict underpinning such problematic sentiments.

Rather than conceptualizing the distributional effects of an applied gerontological intervention as something that would only benefit persons in late life (e.g., increasing lifespan), and climate change as something that only imposes health and economic risks primarily on younger generations, attention must be given to the reality that aging and climate change are intricately connected. Not only are older persons at higher risk for climate change mortality, but the health of the environments we inhabit (including planetary health) influence aging and the healthspan. Rate (of aging) control would improve the quality of life of adults at all ages and for future generations versus simply increasing the number of years of survival for the older persons of today. In addition, the economic benefits of slowing aging will better enable populations (especially those in lower income countries) to invest in the adaptations (e.g., changing land and cropping practices; installing better-draining pavements to deal with floods; improving water storage and use) necessary to minimize some of the harms of climate change.

Dehydration can be an issue in older people. As in every complex system in the body, the mechanisms by which hydration is regulated become dysfunctional with advancing age. Researchers here look at the brain region responsible for regulating some of the response to dehydration, cataloging altered gene expression in search of the more important mechanisms involved in the vulnerability of old people to harmful levels of dehydration.

Ageing is accompanied by an increased prevalence of disorders of body salt and water composition. As revealed by the UK Dehydration Recognition In Our Elders (DRIE), 20% of residents in care are dehydrated. Many elderly patients admitted to the hospital present osmotic balance disorders, and dehydration (DH) is often a cause of morbidity and mortality in senior citizens. Thus, to improve healthy living among the elderly, we need to understand why salt and water imbalances occur in this age group. Both peripheral and central mechanisms controlling salt and water homoeostasis change with age. Ageing is accompanied by a gradual decline in renal function, with urine-concentrating capacities reduced in the elderly compared to younger subjects. This diminished ability to conserve bodily water, accompanied by reduced thirst and insufficient water intake after fluid deprivation, makes the elderly more prone to DH.

Ageing is associated with altered neuroendocrine function. In the context of the hypothalamic supraoptic nucleus (SON), which makes the antidiuretic hormone arginine vasopressin, ageing alters acute responses to hyperosmotic cues, rendering the elderly more susceptible to dehydration. Chronically, vasopressin has been associated with numerous diseases of old age, including type 2 diabetes and metabolic syndrome.

We compared the transcriptomes of the SON in adult and aged euhydrated rats and found massive changes in gene expression associated with ageing, including genes involved in extracellular matrix (ECM) organisation and cell adhesion. It is known that the SON has a complex and dynamic ECM that has been implicated in its physiological functioning. The transcriptomic response to dehydration is overall blunted in aged animals compared to adults, and there is a specific enrichment of differentially expressed genes related to neurodegenerative processes in the aged cohort, suggesting that dehydration itself may provoke degenerative consequences in aged rats.

Dysfunctional water homoeostasis in ageing is associated with the inappropriate release of the antidiuretic hormone arginine vasopressin (AVP). The capabilities of the AVP system to respond to osmotic stress decrease with age. In the aged animal, the capacity of the AVP system to respond to dehydration is attenuated. These deficits may be associated with dysfunction in mechanisms controlling transcription, mRNA stability, or translation. Indeed, we have previously shown that the steady-state response to dehydration of a number of selected gene transcripts is attenuated in aged animals. This appears to be a transcriptome level effect, with many of the common genes regulated by dehydration showing a blunted response in aged animals compared to adults. This generalised attenuation of the transcriptomic response to dehydration is likely to greatly affect SON function and overall osmoregulatory effectiveness.

Link: https://doi.org/10.1038/s41514-023-00108-2

Researchers here present data for excess weight to accelerate the involution of the thymus, a process that is no doubt sensitive to mechanisms such as the increased inflammation that accompanies obesity. The thymus is an organ in the chest, the destination for thymocytes created in the bone marrow. Thymocytes mature into T cells of the adaptive immune system over a period of weeks in the thymus. Unfortunately, active thymus tissue is progressively replaced by fat over the course of adult life. A good fraction of middle-aged people have negligible tissue remaining, and thus a negligible supply of new T cells. Without reinforcements, the adaptive immune system steadily collapses into a collection of senescent, malfunctioning, exhausted cells, incapable of fending off pathogens or clearing harmful senescent or potentially cancerous cells.

Fatty degeneration of thymus (or thymus involution) has long been considered a normal ageing process and the role of thymus in adults has drawn little attention. However, there is emerging evidence that thymic involution is linked to T cell aging, chronic inflammation, and increased morbidity. Other factors than chronological age have been proposed to affect the involution rate. However, thymus involution and its determinants have been little studied at a general population level.

In the present study, we investigated the imaging characteristics of thymus on computed tomography (CT) in a Swedish middle-aged population. In total, 1,048 randomly invited individuals (aged 50-64 years, 49% female) were included and thoroughly characterized. CT evaluation of thymus included measurements of attenuation, size, and a 4-point scoring system. A majority, 615 (59%) showed complete fatty degeneration, 259 (25%) predominantly fatty attenuation, 105 (10%) half fatty and half soft-tissue attenuation, while 69 (6.6%) presented with a solid thymic gland with predominantly soft-tissue attenuation.

Age, male sex, high BMI, abdominal obesity, and low dietary intake of fiber were independently associated with complete fatty degeneration of thymus. Also, fatty degeneration of thymus as well as low CT attenuation values were independently related to lower proportion of naïve CD8+ T cells, which in turn was related to lower thymic output, assessed by T-cell receptor excision circle (TREC) levels. In conclusion, among Swedish middle-aged subjects, nearly two-thirds showed complete fatty degeneration of thymus on CT.

Link: https://doi.org/10.21203/rs.3.rs-2499784/v1

A great deal has changed in these last few decades in the field of aging research. From the 60s onward to the 90s, aging research was increasingly characterized by a philosophy of "look but don't touch", an effort to distance academia from the growing anti-aging industry and its hype. It made itself a backwater science in which talk of intervention was aggressively discouraged by leaders in the field. Starting in the 90s, with studies showing significant life extension in lower animals following single gene mutations, it became impossible to ignore the potential to treat aging as a medical condition in humans.

Nonetheless, change comes only slowly in the scientific community. It was still a battle following the turn of the century to dismantle the old scientific culture and replace it with one in which researchers and funding institutions were enthusiastic about intervention in aging. That required a great deal of advocacy and philanthropic funding, accompanied by incremental advances in the science, a matter of bootstrapping progress. Ultimately it worked, of course, and now the research community is openly focused on producing therapies to slow and reverse aging, targeting the underlying mechanisms of aging. An industry has arisen, applying a great deal more funding to the challenge than is available to academia, and a wave of clinical trials will take place over the next five years.

Aging research: A field grows up

When I joined the longevity field, there had already been a shift from simply observing animals as they age to instead identifying regulators that could greatly alter lifespan, thanks to pioneering invertebrate genetic studies in the 1990s and early 2000s that discovered most well-conserved longevity pathways, particularly caloric restriction and the insulin/IGF-1 and TOR signaling pathways. What has changed in the past two decades? There have been at least three major shifts the aging/longevity research that will shape the field in the years to come.

The first shift is in the perspective of regulation: the concept that aging is indeed regulated, and not simply the result of accumulated damage. Once the regulators of longevity were found, there was still a general notion that these pathways primarily determine levels of cell autonomous damage repair. As molecular regulators of longevity and their networks have been identified, it has become clear that non-cell autonomous signaling coordinates rates of aging and response to damage across cells and tissues. In the future, the acknowledgment that these signals are integrated and can affect the body systemically will shape the types of therapeutics we develop, focusing on whole-body versus tissue-specific approaches, depending on the problem being solved.

A second large shift is in the aims of the field, from lifespan to healthspan. While maximum lifespan is still often the focus of the popular press, there is growing recognition that treating aging and age-related diseases are not mutually exclusive goals. Therefore, better understanding of how metabolic disorders, frailty, cardiovascular diseases, cognitive decline, reproductive aging, and other age-related changes are regulated might not only yield treatments for those disorders, but might ultimately increase lifespan as well. Maintaining functions with age may not only have a great impact on quality of life, but also may help us find treatments that generally slow aging.

A third shift is the translational focus of the longevity field, from an almost entirely academic endeavor to one that is being taken up by industry and clinics - that is, the findings we have made in academic labs are on the verge of becoming actual aging treatments. In the most immediate future, large-scale clinical trials of some of the best-studied longevity drugs (e.g., rapamycin and metformin) and testing of dietary interventions and mimetics may lead to aging treatments. New biotech companies have sprung up with a wide range of goals, from repurposing already-approved drugs for new aging treatments and exploring how the pathways we have discovered over the past 20 years might be harnessed to treat aging, to high-throughput and AI-driven approaches to search for new candidate aging drugs. Circulating blood factors first identified in parabiosis experiments, drugs that target senescent cells, and cell reprogramming and regeneration approaches have moved from concepts to testing, while molecular clocks are beginning to be used as diagnostics.

Luckily, we have finally matured beyond asking whether it is right to study aging, as it is being increasingly recognized that efforts to slow aging will be broadly beneficial; in fact, some of those approaches will help those with other disorders (e.g., muscle diseases, menopause and mid-life issues, and neurodegenerative diseases). Instead, we can ask, which of the multiple approaches being tested now will have the greatest impacts on our lives in the foreseeable future, and how can we all benefit?

Researchers here report on the outcome of six months of monthly senolytic therapy in cynomolgus macaques. The results are broadly positive, as one might expect from the established human data. Dasatinib is a chemotherapeutic drug, but senolytic dosing is not sustained as is the case in the treatment of cancer, and side-effects are much reduced as a result. It remains to be seen as to what the optimal dose and dose schedule for this treatment will be. Researchers are trying a range of options, and arguably the human trials conducted by the Mayo Clinic are using too low a dose. Time will tell, but there is a need for more clinical trials, and an opportunity for philanthropists to step in and run few-hundred individual, affordable, safe clinical trials of this cheap senolytic treatment to provide support for physicians to use the therapy off-label for many age-related conditions.

Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow estimation of the main translatable effects of the senolytic combination dasatinib (D) and quercetin (Q), with and without caloric restriction (CR). A multi-systemic survey of age-related changes, including those on immune cells, adipose tissue, the microbiome, and biomarkers of systemic organ and metabolic health are reported.

Age-, weight-, sex-, and glycemic control-matched NHPs (D + Q, n = 9; vehicle [VEH] n = 7) received two consecutive days of D + Q (5 mg/kg + 50 mg/kg) monthly for 6 months, where in month six, a 10% CR was implemented in both D + Q and VEH NHPs to induce equal weight reductions. D + Q reduced senescence marker gene expressions in adipose tissue and circulating PAI-1 and MMP-9. Improvements were observed in immune cell types with significant anti-inflammatory shifts and reductions in microbial translocation biomarkers, despite stable microbiomes. Blood urea nitrogen showed robust improvements with D + Q. CR resulted in significant positive body composition changes in both groups with further improvement in immune cell profiles and decreased GDF15, and the interaction of D + Q and CR dramatically reduced glycosylated hemoglobin A1c.

This work indicates that 6 months of intermittent D + Q exposure is safe and may combat inflammaging via immune benefits and improved intestinal barrier function. We also saw renal benefits, and with CR, improved metabolic health. These data are intended to provide direction for the design of larger controlled intervention trials in older patients.

Link: https://doi.org/10.1007/s11357-023-00830-5

Now that increasing attention is given to senescent cells in the biology of aging, their involvement in a wide range of conditions has been uncovered. The transient creation of senescent cells is a part of wound healing, a process that is harmed by the growing burden of lingering senescent cells that occurs with advancing age, and the inability of the aged immune system to remove these cells in a timely fashion. Given the role in wound healing, is perhaps not surprising to find senescent cells involved in graft-versus-host disease following surgical transplantation of tissue. Senolytic therapies may prove to be useful here, as they have in animal studies of many other conditions.

Graft-versus-host disease (GVHD) is a life-threatening systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by dysregulation of T cell and B cell activation and function, scleroderma-like features, and multi-organ pathology. The treatment of cGVHD is limited to the management of symptoms and long-term use of immunosuppressive therapy, which underscores the need for developing novel treatment approaches.

Notably, there is a striking similarity between cytokines/chemokines responsible for multi-organ damage in cGVHD and pro-inflammatory factors, immune modulators, and growth factors secreted by senescent cells upon the acquisition of senescence-associated secretory phenotype (SASP). In this pilot study, we questioned the involvement of senescent cell-derived factors in the pathogenesis of cGVHD triggered upon allogeneic transplantation in an irradiated host. Using a murine model that recapitulates sclerodermatous cGVHD, we investigated the therapeutic efficacy of a senolytic combination of dasatinib and quercetin (DQ) administered after 10 days of allogeneic transplantation and given every 7 days for 35 days.

Treatment with DQ resulted in a significant improvement in several physical and tissue-specific features, such as alopecia and earlobe thickness, associated with cGVHD pathogenesis in allograft recipients. DQ also mitigated cGVHD-associated changes in the peripheral T cell pool and serum levels of SASP-like cytokines, such as IL-4, IL-6, and IL-8Rα. Our results support the involvement of senescent cells in the pathogenesis of cGVHD and provide a rationale for the use of DQ, a clinically approved senolytic approach, as a potential therapeutic strategy.

Link: https://doi.org/10.3390/biology12050647

Is is now going on three decades since the first flush of excitement for regenerative medicine in the form of stem cell therapies. Unfortunately, producing meaningful, reliable regeneration with cell therapies turned out to be a great deal harder then hoped. It is still not a solved problem, outside a few narrow applications. In the intervening time, the field of regenerative medicine has expanded considerably beyond cell therapies, now of many varieties, to encompass approaches such as immune modulation and reprogramming native cell behavior. As today's commentary notes, there is still no magic button to turn on regeneration, but progress continues on what turned out to be a far harder challenge than first thought.

Emerging frontiers in regenerative medicine

Nearly every human malady, be it injury, infection, chronic disease, or degenerative disease, damages tissues. Moreover, 45% of all deaths can be traced to inflammation- and fibrosis-related regenerative failures. Restoring health after damage requires the answer to a key question: How can human tissues be coaxed to regenerate? Identifying instructive cues that direct refractory tissues down a regenerative path remains a critical yet elusive goal. Nonetheless, approaches to target roadblocks that impede regeneration, including insufficient and/or functionally inadequate progenitor cells, fibrosis, and chronic inflammation, are continuing to progress from bench to bedside. Pivotal advances have been made to overcome these hurdles using cell therapy, in vivo reprogramming, synthetic biology, and antifibrotic and anti-inflammatory therapies, but many challenges remain and knowledge gaps must be addressed to make regeneration a mainstay of modern medicine

The most conspicuous requirement for regenerative therapies is to replace the components of tissues that were lost or compromised by disease. Invigorating endogenous stem cells is an appealing strategy, but, to date, the greatest benefits have emerged from cell therapies. Adult stem cell-based regenerative therapies have shown clinical benefit to treat hematological malignancies, burn wounds, and ocular degeneration. Human pluripotent stem cell (hPSC)-based therapies have also shown promise and have entered clinical trials in the United States for type 1 diabetes, Parkinson's disease, and age-related macular degeneration. These three diseases are particularly amenable to stem cell-based therapies because they are associated with deficiency of a defined cell type.

Despite these early glimpses of success, cell therapies are hampered by many biological and technical hurdles. Autologous hPSC-based therapies derived from induced pluripotent stem cells (iPSCs) avoid immune aggravation, but this cost- and labor-intensive strategy requires safety testing for each use. A major concern with nonautologous cell therapy is immune rejection of the graft. Thus, "off-the-shelf" allogeneic therapies must be coupled to strategies that allow them to avoid rejection. Producing sufficient numbers of cells for engraftment has been successful in the skin but poses a major challenge for regenerating tissue in other organs, particularly if only a small proportion of cells survive after transplant.

An alternative approach to overcome the challenge of directing and integrating grafts in hard-to-reach internal organs is to repurpose cells that are present at the damage site by reprogramming them in situ with specific transcription factors. Reprogramming has been a particularly attractive strategy for the adult heart, which, unlike the embryonic heart, lacks bona fide progenitors. A subset of in vivo cellular reprogramming efforts are aimed at converting fibroblasts into cardiomyocytes to maintain cardiac function. Alternatively, transient expression of pluripotent transcription factors in adult cardiomyocytes induced proliferation, resulting in improved outcomes in adult mice after myocardial infarction.

In addition to replacing lost tissue with cell therapies and in vivo reprogramming, many injurious and complex disease states evoke inflammatory responses that must also be suppressed (see the figure). The state of the recipient tissue, often diseased, remains a challenging facet of applying cell therapies. New approaches to modulate inflammation include engineering stem cells with bioresponsive gene circuits that can sense inflammatory factors such as cytokines or reactive oxygen species and, in turn, induce the production of anti-inflammatory factors, allowing endogenous progenitors or transplanted cells to repair damage.

What was once considered the future of medicine is now becoming reality. But there is no magic pill for regeneration (yet). In addition to scientific and technological innovation, there are also practical considerations of cost and production. Achieving regeneration in humans will require a rapid transition from rodent models to clinically relevant large animal and human studies. Ascending the summit of human regeneration demands an interdisciplinary effort that brings together biologists, biomedical engineers, and clinicians. The view from the top will reveal a transformed medical landscape that is able to seamlessly rejuvenate organs, ultimately extending human life span and health span.

Chronic inflammation is a feature of aging, driven by mechanisms such as an increased burden of senescent cells and overactivation of the innate immune system in response to cellular stress. Researchers here present data to suggest that chronic inflammation contributes to age-related anemia, a reduced production of red blood cells that perhaps occurs via an indirect disruption of iron metabolism by inflammatory signaling, and that in turn lowers the available levels of iron needed for the creation of red blood cells.

Anemia is a common hematological disorder that affects 17% of persons older than 65 years. The World Health Organization (WHO) defines anemia as a decreased number of erythrocytes and/or decreased hemoglobin (Hb) levels of less than 12.0 g/dL in women and 13.0 g/dL in men. In older adults, anemia can be divided into nutritional deficiency anemia, bleeding anemia, and unexplained anemia that might be caused by the reduced erythropoietin (EPO) activity, the progressive erythropoietin resistance of bone marrow erythroid progenitors and the chronic subclinical pro-inflammatory state. Overall, one-third of older patients with anemia have a nutritional deficiency which mainly includes iron, folate or vitamin B12 deficiency, one-third have a chronic subclinical pro-inflammatory state and a chronic kidney disease, and one-third suffer from anemia of an unknown cause.

Understanding the pathophysiology of anemia in this population is crucial because it contributes to frailty syndrome and falls, cognitive decline, depression, functional ability deterioration, and early mortality. A prospective cohort analysis of 3758 patients aged 65 years and older showed that a new-onset anemia was associated with an increased mortality risk with a drop in Hb of 1 g/dL.

The pro-inflammatory state in older age, called inflammaging, is manifested by the release of a large number of inflammatory mediators that are produced to repair damage at the tissue level. Inflammaging is a result of changes in the immune system also known as immunosenescence. The inflammatory molecules produce adverse effects on the cells of the hematological system, and these include iron deficiency, reduced EPO production and elevated phagocytosis of erythrocytes by hepatic and splenic macrophages, and also enhanced eryptosis by oxidative stress in the circulation.

In this study, low Hb concentration was observed to be associated with subclinical, chronic inflammation, exhibited by high levels of IL-1β and TNFα. In the large InCHIANTI study, the unexplained anemia cohort (36% of all the anemic population) was found to have higher levels of pro-inflammatory markers and higher resistance of bone marrow erythroid progenitors to erythropoietin compared to non-anemic controls. The mechanisms underlying low Hb levels in older adults are multifactorial and complex. Our study suggested that the underlying mechanisms involve subclinical chronic low-grade inflammation, bone marrow resistance to EPO, and changes in hepcidin levels, ultimately affecting iron metabolism and resulting in lower serum iron levels.

Link: https://doi.org/10.3390/ijms24108944

Continued efforts to clear amyloid-β in the brain have failed produce significant benefits in Alzheimer's disease patients. This has led to a great deal of theorizing, researchers proposing other disease mechanisms, or different interpretations of the relevance of amyloid-β to the development of neurodegeneration. Most of these hypotheses will be wrong, but that doesn't prevent them from being interesting reading. One class of alternative views of Alzheimer's disease involves placing an increased emphasis on vascular dysfunction in the development of the condition, and the paper here is an example of the type.

Alzheimer's disease (AD) is the most common cause of dementia, accounting for over 70% of dementia cases in individuals above the age of 65 years. The two main pathological hallmarks of AD are extracellular deposits of the amyloid-β (Aβ) protein in the form of amyloid plaques and intracellular aggregates of hyperphosphorylated tau protein in the form of neurofibrillary tangles. Current disease models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and ultimately leads to synaptic injury and neurodegeneration.

Vascular disease, including arteriolosclerosis, atherosclerosis, microinfarcts, and cerebral amyloid angiopathy (CAA), is a common co-pathology which is observed in 20-80% of AD brains at autopsy. Furthermore, almost all AD brains display evidence of endothelial and capillary degeneration even in the absence of other forms of macrovascular pathology. Significant and bidirectional interactions between AD and various forms of vascular pathology have been well documented; amyloid and tau toxicity disrupts the blood-brain barrier (BBB) and alters vascular permeability, and structural or functional damage to cerebral vasculature impairs amyloid clearance and promotes tau aggregation.

Previous neuropathological studies examining vascular pathology in AD have focused primarily on pathology within the small- and medium-sized arteries and arterioles; however, there is growing evidence to suggest that "micro"-vascular disease (i.e., at the capillary level) and alterations to specific vascular constituents, such as endothelium and pericytes, play an important role in AD pathogenesis. Impaired cerebral blood flow (CBF) is a common and early predictor of AD pathology, which possibly precedes abnormal protein aggregation and directly contributes to neuronal and synaptic loss in even the earliest pre-symptomatic stages of the disease. These observations support the notion that the onset of AD may be primarily influenced by vascular, rather than neurodegenerative, mechanisms and emphasize the importance of further investigations into the vascular hypothesis of AD.

Link: https://doi.org/10.3390/biom13050830

Reprogramming involves inducing expression of reprogramming factors, canonically OSKM (OCT4, SOX2, KLF4, and MYC), the Yamanaka factors. When expressed for a sufficiently long time, a period of days to weeks, some fraction of OSKM-expressing cells dedifferentiate into induced pluripotent stem cells (iPSCs). Before that happens, however, beneficial epigenetic changes occur, resetting a cell to a more youthful pattern of gene expression, resulting in improvements such as restored mitophagy and mitochondrial function. The present focus of the industry is to find a way to safely apply transient exposure to reprogramming factors as a therapy, producing epigenetic rejuvenation without dedifferentiation. Initial results in animal models are promising, but a great deal of work yet lies ahead.

Because the bulk of medical research and development is focused on small molecule development rather than gene therapy, the excitement surrounding therapeutic reprogramming as a whole translates to a strong interest in finding ways to use small molecules to induce reprogramming factor expression. This idea that reprogramming can be applied directly as a therapy, rather than being a way to produce iPSCs for regenerative medicine, is still in the comparatively early stages, however. There is a great deal of funding, and new information is arriving at a fast pace, but it still takes time to make meaningful progress.

Development of a next-generation endogenous OCT4 inducer and its anti-aging effect in vivo

Octamer-binding transcription factor 4 (OCT4) is a member of the POU transcription factor family and functions as one of the master regulators in initiating reprogramming and maintaining pluripotency. Independent groups have observed rejuvenation in partially reprogrammed mice, characterized by the reversal of aging marks and improved tissue regeneration. Consequently, chemicals capable of (partially) activating endogenous reprogramming-associated transcription factors hold promise as potential candidates in anti-aging therapy.

Several studies have reported small molecule inducers of endogenous OCT4, including forskolin (a cAMP agonist), and pyrrolo[2,3-b]pyridine based OCT-activating compound 1 (OAC1). However, to date, a small molecule capable of completely replacing or reactivating OCT4 or its analogues in the reprogramming of somatic cells, has not yet been reported.

Recently, we conducted high-throughput screening and identified a series of compounds called OCT4-inducing compounds (O4Is). These compounds have the ability to sustain the maintenance of human iPSCs by promoting the expression of endogenous OCT4, including 4-(benzyloxy)phenyl derivatives (O4I1s), 2-aminothiazoles (O4I2s) and imidazopyrimidines (O4I3s).

In this work, analysis of cellular metabolic products revealed that hydrolysis, especially in pluripotent cells, ablated the activity of O4I2-ester derivatives, which led us to design a second generation of O4I2 derivatives with improved metabolic stability, including a compound called O4I4. By combining O4I4 with the ectopic expression of SOX2, KLF4, L-MYC and LIN28 (collectively designated as "CSKML"), we successfully reprogrammed human fibroblasts into iPSCs. In C. elegans and Drosophila O4I4 extended their lifespans, suggesting the potential application of O4I4 and other reprogramming-associated chemicals in regenerative medicine and anti-aging therapy.

The extensive, well-funded search for genetic differences in long-lived individuals has found little: small effect sizes, and only a few genetic variants that replicate in multiple studies. Will the search for gut microbiome differences characteristic of long-lived individuals do any better? This remains to be seen, as the research community is only a few studies into this exercise, and it takes more than a few studies to build a consensus. The evidence to date suggests cautiously optimism, as researchers do see differences in microbial species abundance in exceptionally old individuals versus merely old individuals. As noted here, viral diversity may also be important.

Studying 176 healthy Japanese centenarians, the researchers learned that the combination of intestinal bacteria and bacterial viruses of these people is quite unique. Among other things, the new study shows that specific viruses in the intestines can have a beneficial effect on the intestinal flora and thus on our health. "We found great biological diversity in both bacteria and bacterial viruses in the centenarians. High microbial diversity is usually associated with a healthy gut microbiome. And we expect people with a healthy gut microbiome to be better protected against aging related diseases."

Once we know what the intestinal flora of centenarians looks like, we can get closer to understanding how we can increase the life expectancy of other people. Using an algorithm designed by the researchers, they managed to map the intestinal bacteria and bacterial viruses of the centenarians.

"We have learned that if a virus pays a bacterium a visit, it may actually strengthen the bacterium. The viruses we found in the healthy Japanese centenarians contained extra genes that could boost the bacteria. We learned that they were able to boost the transformation of specific molecules in the intestines, which might serve to stabilise the intestinal flora and counteract inflammation. If you discover bacteria and viruses that have a positive effect on the human intestinal flora, the obvious next step is to find out whether only some or all of us have them. If we are able to get these bacteria and their viruses to move in with the people who do not have them, more people could benefit from them."

Link: https://healthsciences.ku.dk/newsfaculty-news/2023/05/why-do-some-people-live-to-be-a-100/

The gut microbiome changes with age, the relative abundance of microbial populations shifting in ways that appear connected to chronic inflammation and dysfunction of the intestinal epithelium and intestinal barrier function. Cancer of the colon is an important cause of human mortality, and there is some hope that finding ways to prevent or reverse gut microbiome aging, such as via fecal microbiota transplant from young individuals, will go some way to minimizing colon cancer incidence.

Colorectal cancer is the second leading cause of cancer-related death in the U.S., and rates of colorectal cancer are rising among young adults. Nearly all colorectal cancers arise from a precancerous polyp. One of the best ways to reduce the incidence of colorectal cancer is to stop the growth at the polyp stage. There's more than one way for a polyp to develop. The two main types of polyps are tubular adenomas and sessile serrated polyps. Risk factors for colorectal cancer and polyps include lifestyle factors like being overweight or obese, low physical activity levels, a diet high in red and processed meats, smoking, and alcohol use. These factors also influence the bacteria that live in our intestines, collectively known as the gut microbiome.

Researchers took data from 1,200 people getting routine screening colonoscopies. They gathered information on their health, diet, medications, and lifestyle, as well as analyzed stool samples to determine the bacterial makeup of their gut microbiome. he new research is the biggest study from an extensive collaborative research program, the GI Disease and Endoscopy Registry (GIDER). This registry remains active and ongoing data collection will enable longitudinal follow-up.

The new study is the largest of its kind and analyzed the differences in the gut microbial signature of people without colon polyps, with tubular adenomas, or with sessile serrated adenomas. They also correlated this data with the patient's health and family histories. Bacterial signatures clustered into three groups based on the type and presence of polyps in the colon. Nineteen bacterial species were significantly different in patients with tubular adenomas than in other populations. In patients with sessile serrated adenomas, eight species were significantly different. "The hope is that by changing specific aspects of the diet or the microbiome, we can alter the natural history of these polyps. Interventions to prevent polyp formation or alter their growth patterns may ultimately prevent colorectal cancer."

Link: https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/gut-microbiome-changes-linked-to-precancerous-colon-polyps

A number of lines of evidence implicate senescent microglia in the development of neurodegenerative conditions. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Microglia appear to become more inflammatory with age, but this isn't just an amplification of inflammatory signaling that arises due to age-related dysfunctions such as mislocalization of mitochondrial DNA. Some microglia become senescent, and like other types of senescent cell, they energetically produce inflammatory signaling. Clearing such cells from the brain has produced benefits in animal models of neurodegeneration, but it remains to be seen as to whether that works well in humans.

The materials here summarize the work of researchers who suggest that failing autophagy is an important cause of microglial senescence in the aging brain. Autophagy is a collection of cell maintenance processes responsible for recycling damaged and worn proteins and cell components, sending them to a lysosome for disassembly by enzymes. It is well known that autophagy falters with advancing age, though a full accounting of why this is the case remains to be established. Inefficient autophagy leads to a greater burden of dysfunction in a cell, and, in principle, more cells tipped over the edge into a state of senescence.

The one caution here is that researchers essentially disabled autophagy rather than dialing it back to a lesser degree of efficiency. This produces a more obvious result, more easily measured, but the outright breakage of major mechanisms in a cell can lead to outcomes that are not reflective of what takes place inside the body as a result of a mere decline in efficiency. Still, one can look at this work in the context of other avenues of research that also implicate microglia and autophagy in the onset of neurodegeneration.

When Autophagy Stops, Microglia Sour into Senescence

When deprived of their ability to dispose of detritus via autophagy, microglia become annoyed, transitioning into a senescent, dysfunctional state. That was the upshot of a recent study in which researchers used conditional knockout mice to disable the "self-eating" pathway in microglia. Some of the cells shut down their cell cycle and revved up secretion of cytokines - behavior typical of senescent cells. In amyloid-laden mice, these autophagy-deficient microglia refused to transition into a bona fide disease-associated microglia (DAM) state, failing to properly contain plaques or to protect nearby synapses from shriveling. The findings further raise the profile of microglial autophagy as an essential part of the brain's response to proteopathic insults.

Neurons suffer dramatic impairments in autophagy both in the Alzheimer's disease (AD) brain and in mouse models of amyloidosis. While neurons need autophagy to clean up their own waste, microglia need this pathway for an additional purpose, that is, to help them mop up protein aggregates and detritus spewed by sickly neurons. Recent studies have cast microglial autophagy - a bioenergetically demanding process - as quelling amyloid-β (Aβ) plaques, tau pathology, and neuroinflammation.

Researchers conditionally deleted, from wild-type mice, the Atg7 gene, which encodes a protein critical for autophagosome biogenesis, only from microglia. They knocked out Atg7 in 2-month-old mice, then examined their brains six months later. Using single-cell transcriptomics, the scientists detected eight gene-expression clusters of microglia in wild-type and Atg7-cKO mice. Zeroing in on one that was far more abundant in the conditional knockouts, they found a cadre of microglia that appeared to have transitioned into a senescent state.

In 5xFAD AD model mice given these conditional Atg7 knockouts, microglia also did not assume a DAM state, opting instead for a senescence-associated profile. "SAMs" expressing S100a4, a marker of this senescent profile, appeared disinterested in amyloid. As a result, Aβ sprawled into diffuse plaques, which were surrounded by hyperphosphorylated tau and dystrophic neurites. This suggests that, without autophagy available to them, microglia became recalcitrant and no longer contained Aβ plaque formation, allowing the aggregates to become more of a hazard to nearby neurons.

Finally, the researchers treated the double-transgenic mice with dasatinib and quercetin, a combination therapy with proposed senolytic effects. The treatment reduced the number of microglia that were clogged with a backlog of autophagy substrates and expressed senescence markers. The findings place autophagy upstream of the microglial transition to a beneficial, disease-associated state, the authors proposed. Considering reports that autophagy declines with age while senescent cells become more numerous, the authors blame this combination for the dearth of DAM-like cells detected in human AD brains.

Evidence suggests a multidirectional relationship between cellular senescence, chronic inflammation, and toxic tau aggregation in the aging brain. Inflammation is well known to be associated with the onset and progression of neurodegenerative conditions, and lingering senescent cells present throughout the aging body provide a significant contribution to chronic, unresolved inflammatory signaling. Clearing senescent cells in animal models of neurogeneration has been shown to reduce both inflammation and tau aggregation. Here, researchers show that the presence of pathogenic forms of tau protein can provoke cellular senescence and forms of vascular dysfunction in the brain. It is rarely the case that a damaging mechanism of aging stands on its own; it usually makes other damaging mechanisms worse in addition to causing its own direct consequences.

Vascular mechanisms of Alzheimer's disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits.

Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from the brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice.

Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.

Link: https://doi.org/10.1038/s41467-023-37840-y

There is a growing interest in the manipulation of the gut microbiome. Changes in the balance of microbial populations occur with age, leading to an increase in harmful, inflammatory species at the expense of species that produce beneficial metabolites. Animal studies have demonstrated that even radical changes in the microbiome from a one-time procedure, such as that produced by fecal microbiota transplant from a young individual, can be sustained over time, rejuvenating the balance of microbial populations and improving health as a result. As yet there seems to be little enthusiasm or funding to run clinical trials in older people, however, despite the sizable benefits produced in animal models.

Far from being a static entity, the gut microbiome (GM) suffers various modifications during different life stages of the individual. The transformation of these biocommunities in older adults is particularly evident after considering that when a person reaches an advanced age, they have been exposed to different environmental factors over an extended period. Multiple studies that analysed GM compositions from people of advanced age concluded that there is a general decrease in microorganism diversity and probiotics, together with an increase in opportunistic agents that could be related to age-related chronic diseases. Although the modifications vary according to the specific age group, numerous studies that found differences in the GM composition of elderly groups (ages 99-80 and 79-60) agree on the predominance of the phyla Bacteriodetes and Firmicutes, the first one being more prevalent in the elderly than in younger adults where the phylum Firmicutes is more abundant.

Similarly, studies have also found decreases in several bacterial groups, including Actinobacteria, certain Ruminococcaceae and Bacteroidaceae members, and Bifidobacterium, Faecalibacterium, Eubacterium, Bacteroides, Clostridium, and Oscillospiraceae genera. In addition, numerous microorganisms, mainly opportunistic pathogens and those related to chronic inflammation, increase during ageing.

In recent years, scientific evidence has shown the possibility of delaying ageing by manipulating the regulatory pathways involved in its bidirectional relationship with the GM. It is known that there is a relationship between intestinal dysbiosis and multiple age-related diseases, such as inflammatory bowel disease and musculoskeletal diseases and neurological conditions. Nevertheless, there are beneficial bacteria that, rather than deleterious consequences of ageing, may contribute to homeostasis maintenance and healthy ageing. In this respect, prebiotics, probiotics, a healthy diet, regular physical activity, and drugs have gained scientific interest in microbial activity regulation.

Link: https://doi.org/10.3390/ijerph20105845

The average small molecule drug development program starts with a mechanism, an intended outcome such as inhibition, and then screening of as many molecules as possible from the libraries. Sometimes it is possible to make educated guesses as to what types of molecule are more likely to be useful, but often screening must be very broad and with little direction. In principle, low cost computation makes it possible to dramatically reduce the cost of discovery of useful molecules given a specific target mechanism. This shift from physical to in silico screening has been underway for a while, for example at Insilico Medicine, but is still a work in progress.

Small molecule medicine has its limitations, and in the future it seems likely that much of its present portfolio will be overtaken by gene therapies that can act precisely on target mechanisms: greater efficacy, far fewer side-effects, no expensive initial screening needed. Extending the life span of small molecule development into that era will require a dramatic reduction in its costs. At the end of the day the whole industry revolves around how much time and effort is needed to produce the prospect of a given benefit to patients.

The materials here are an example of the present state of the art when it comes to the use of in silico initial screening of small molecules. It needs something like the senolytics field to spur the development of better infrastructure for small molecule development. Small molecules can work well here, as demonstrated by animal data for dasatinib and quercetin, among others; there are many clear mechanistic targets for the clearance of senescent cells; there is a very large market, meaning the entire elderly population impacted by the burden of senescent cells in aged tissues; and the field is still young enough for an end to end development program to run for years and nonetheless find sizable profit at the end of it, if successful.

Artificial intelligence identifies anti-aging drug candidates targeting 'zombie' cells

Senolytics are compounds that selectively induce apoptosis, or programmed cell death, in senescent cells that are no longer dividing. A hallmark of aging, senescent cells have been implicated in a broad spectrum of age-related diseases and conditions including cancer, diabetes, cardiovascular disease, and Alzheimer's disease. In their new study, researchers trained deep neural networks on experimentally generated data to predict the senolytic activity of any molecule. Using this model, they discovered three highly selective and potent senolytic compounds from a chemical space of over 800,000 molecules.

All three displayed chemical properties suggestive of high oral bioavailability and were found to have favorable toxicity profiles in hemolysis and genotoxicity tests. Structural and biochemical analyses indicate that all three compounds bind Bcl-2, a protein that regulates apoptosis and is also a chemotherapy target. Experiments testing one of the compounds in 80-week-old mice, roughly corresponding to 80-year-old humans, found that it cleared senescent cells and reduced expression of senescence-associated genes in the kidneys.

Discovering small-molecule senolytics with deep neural networks

The accumulation of senescent cells is associated with aging, inflammation, and cellular dysfunction. Senolytic drugs can alleviate age-related comorbidities by selectively killing senescent cells. Here we screened 2,352 compounds for senolytic activity in a model of etoposide-induced senescence and trained graph neural networks to predict the senolytic activities of more than 800,000 molecules.

Our approach enriched for structurally diverse compounds with senolytic activity; of these, three drug-like compounds selectively target senescent cells across different senescence models, with more favorable medicinal chemistry properties than, and selectivity comparable to, those of a known senolytic, ABT-737. Molecular docking simulations of compound binding to several senolytic protein targets, combined with time-resolved fluorescence energy transfer experiments, indicate that these compounds act in part by inhibiting Bcl-2, a regulator of cellular apoptosis. We tested one compound, BRD-K56819078, in aged mice and found that it significantly decreased senescent cell burden and mRNA expression of senescence-associated genes in the kidneys. Our findings underscore the promise of leveraging deep learning to discover senotherapeutics.

Experiment is a crowdfunding platform for small scientific projects. It has been running for quite a few years now, one of the few survivors from the first wave of attempts to make crowdfunding platforms to fund scientific research. It is a challenging goal, the motivations and incentives are completely different from those operating in commercial product crowdfunding. SENS Research Foundation is now using Experiment to raise a modest amount of funds for a senotherapeutic screening program. The Foundation does good work, and I donated.

That part of the industry presently seeking approaches to clear senescent cells, or prevent their formation in order to let the immune system catch up on clearance, is still in the comparatively early stages at this point. It is becoming clear that senescent cells have many different states and origins, and react quite differently to given small molecule drugs. There will be many different senotherapeutics at the end of the day, and more targets and options are needed.

As we become old, the number of senescent cells in our body increases, as well as their harmful effects. Approaches aimed at eliminating senescent cells as they accumulate may not be enough since these cells are continuously produced in our body. We reasoned that preventing healthy cells from becoming senescent in the first place may represent a viable option for treating aging. We have developed a cell model that will allow us to identify candidate therapeutics that prevent cells from becoming senescent. Candidate therapies will then be used either alone or in combination with senolytics for comprehensive targeting of senescence, a strategy that is expected to have superior effects at improving health at older age.

As a model to study senescence in a dish, we will use mouse embryonic fibroblasts that we have isolated from the p16 3MR mouse model. These cells express luciferase driven by the promoter of the senescence related gene p16. Therefore, they become luminescent when they are induced into senescence. This assay will allow us to assess relatively quickly the efficacy of therapeutic candidates that inhibit senescence. Using this cellular model, we will screen a large library of FDA approved drugs for their ability to delay senescence. The cells will be forced into senescence, and drugs applied appropriately. We will be able to measure the efficacy of each drug by measuring luminescence.

Link: https://experiment.com/projects/discovery-of-potential-anti-senescence-therapeutics

Oxidative stress increases with age, the result of a number of age-related dysfunctions that give rise to excessive levels of oxidative molecules. Increasing levels of commonly available antioxidants does not do any good, however, as illustrated by the failure of supplements such as the antioxidant vitamin C to improve health in anything other than cases of vitamin C deficiency. In the case of vitamin C some of this failure may be due to the fact that vitamin C becomes oxidized and loses its function. Here researchers employ an aptamer that binds to vitamin C to provent oxidation, and show that it improves some measures of function in aged mice by allowing vitamin C to become a much more potent antioxidant.

We have developed Aptamin C320, a DNA aptamer that specifically binds to vitamin C and inhibits its oxidation. Aptamers are single-stranded DNA-based oligonucleotides, and Aptamin C320 inhibits the oxidation of vitamin C and preserves its antioxidant activity in the body. NXP032, a complex of vitamin C and Aptamin C320, effectively removes reactive oxygen species (ROS) and increases antioxidant enzyme activity. It maintains a stable antioxidant effect by inhibiting oxidative stress induced by the activation of the antioxidant response element (ARE) pathway in aged mice.

In this study, we investigated the effect of NXP032 on neurovascular stabilization through the changes of PECAM-1, PDGFR-β, ZO-1, laminin, and glial cells involved in maintaining the integrity of the blood-brain barrier (BBB) in aged mice. NXP032 was orally administered daily for 8 weeks. Compared to young mice and NXP032-treated mice, 20-month-old mice displayed cognitive impairments in Y-maze and passive avoidance tests. NXP032 treatment contributed to reducing the BBB damage by attenuating the fragmentation of microvessels and reducing PDGFR-β, ZO-1, and laminin expression, thereby mitigating astrocytes and microglia activation during normal aging. Based on the results, we suggest that NXP032 reduces vascular aging and may be a novel intervention for aging-induced cognitive impairment.

Link: https://doi.org/10.1038/s41598-023-35833-x

Researchers here show that a mouse model of accelerated aging lives considerably longer when in a low-oxygen atmosphere for most of its life span. This is quite interesting, even given that large effect sizes in accelerated aging models should be taken with a grain of salt. It is most likely that any effect on normal mice would be smaller, and also likely that any form of life extension achieved through manipulation of stress responses, such as the response to hypoxia, will produce much smaller effects in long-lived mammals than in short-lived mammals.

As is always the case, recall that when we say "accelerated aging" what we really mean is that the mouse lineage in question exhibits some deficiency that allows one specific form of cellular dysfunction to accumulate rapidly. These models can appear a little like accelerated aging, but they are not actually exhibiting accelerated aging, just the accumulation of one form of damage. Normal aging is a mix of numerous different types of cellular dysfunction and damage, and that difference matters. In this case, the model has a mutation that impairs DNA repair. The large effect size for hypoxia in this model in turn might imply that hypoxic stress is good at improving DNA repair efficiency, but more research would be needed to confirm that hypothesis.

Hypoxia extends lifespan and neurological function in a mouse model of aging

To the best of our knowledge, the current study is the first to report that hypoxia extends lifespan in a mouse model of aging. We have demonstrated that continuous hypoxia (11% oxygen) - or "oxygen restriction" - significantly extends lifespan of Ercc1 Δ/- mice and delays neurologic morbidity. In this model, hypoxia appears to be the second strongest intervention to date, second only to dietary restriction.

Our findings add to a nascent but burgeoning literature on the beneficial effect of hypoxia in a wide variety of neurologic disease models. Chronic continuous hypoxia has been reported as beneficial in at least three other mouse models of neurologic disease. In two mitochondrial disease models, hypoxia corrects defects that arise as a consequence of the genetic lesion. In the experimental autoimmune encephalitis model of multiple sclerosis, continuous 10% oxygen promotes vascular integrity and apoptosis of infiltrating leukocytes. The ability of hypoxia to alleviate brain degeneration in such diverse models points either to the pleiotropic effects of oxygen restriction, or alternatively, the existence of a downstream and convergent neuroprotective mechanism.

An important future goal is to define the mechanism by which chronic continuous hypoxia is extending lifespan in this model, and the extent to which this mechanism overlaps with that of pathways known to be involved in aging, such as mTOR and insulin signaling. Three plausible mechanisms are the following: (i) activation of the HIF pathway; (ii) diminution of oxidative stress; and (iii) interruption of the vicious cycle of neurodegeneration and neuroinflammation.

Epidemiologic evidence suggests that lifelong oxygen restriction might slow the aging process in humans. Though there are many potential confounders to this finding, recent cross-sectional studies in Bolivia have demonstrated significant enrichment for nonagenarians and centenarians at very high altitudes. There is also intriguing data that suggests there are potential benefits of moving to altitude in adulthood. In a longitudinal study of over 20,000 soldiers of the Indian Army assigned to serve at 2 to 3 mile elevations above sea level for 3 years between 1965 and 1972, their risk of developing the major sources of age-related morbidity in modern societies was a fraction of the risk of their comrades serving at sea level.

Early aging, in the 20s through 40s in our species, is poorly studied. This is likely because aging causes few serious problems and minimal mortality in this age range. Nonetheless, a 35 year old is not the same as a 25 year old, and visibly so in many cases. The same processes of damage accumulation that cause the dramatic mortality of late life are at work, slowly, in early life, but which of them are more significant, and how do they interact to produce the observed, often subtle changes of early aging? Studies such as the one here remind us that this early aging does exist, and that it sets the foundation for the accelerated process of late life aging that is to come.

Athleticism and the mortality rates begin a lifelong trajectory of decline during early adulthood. Because of the substantial follow-up time required, however, observing any longitudinal link between early-life physical declines and late-life mortality and aging remains largely inaccessible. Here, we use longitudinal data on elite athletes to reveal how early-life athletic performance predicts late-life mortality and aging in healthy male populations.

Using data on over 10,000 baseball and basketball players, we calculate age at peak athleticism and rates of decline in athletic performance to predict late-life mortality patterns. Predictive capacity of these variables persists for decades after retirement, displays large effect sizes, and is independent of birth month, cohort, body mass index, and height. Furthermore, a nonparametric cohort-matching approach suggests that these mortality rate differences are associated with differential aging rates, not just extrinsic mortality. These results highlight the capacity of athletic data to predict late-life mortality, even across periods of substantial social and medical change.

Link: https://doi.org/10.1126/sciadv.adf1294

Evidence exists for herpesvirus infection to increase the risk of suffering Alzheimer's disease. The evidence is mixed, however, with some studies showing no effect. There is some suggestion that the interaction of multiple viruses is the real contributing effect, which is why looking at just one virus type may produce problematic data. Researchers here show that vaccination against herpes zoster reduces Alzheimer's risk, though one might as to whether this is because of reduced viral impact, or because vaccinations can produce a trained immunity effect, reducing chronic inflammation in older people.

There is growing interest in the question if infectious agents play a role in the development of dementia, with herpesviruses attracting particular attention. To provide causal as opposed to merely correlational evidence on this question, we take advantage of the fact that in Wales eligibility for the herpes zoster vaccine for shingles prevention was determined based on an individual's exact date of birth. Those born before September 2 1933 were ineligible and remained ineligible for life, while those born on or after September 2 1933 were eligible to receive the vaccine. The percentage of adults who received the vaccine increased from 0.01% among patients who were merely one week too old to be eligible, to 47.2% among those who were just one week younger. No other interventions used the exact same date-of-birth eligibility cutoff as was used for the herpes zoster vaccine program.

This unique natural experiment allows for robust causal, rather than correlational, effect estimation. We show that receiving the herpes zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of seven years by 3.5 percentage points, corresponding to a 19.9% relative reduction in the occurrence of dementia. Besides preventing shingles and dementia, the herpes zoster vaccine had no effects on any other common causes of morbidity and mortality. In exploratory analyses, we find that the protective effects from the vaccine for dementia are far stronger among women than men. Our findings strongly suggest an important role of the varicella zoster virus in the etiology of dementia.

Link: https://doi.org/10.1101/2023.05.23.23290253

Setting oneself up as a spokesperson for "we will not achieve this goal", as the fellow noted here is choosing to do, is a bet against technological progress. A glance at any few decade period in the past two hundred years suggests that such a bet will almost certainly fail in time, sometimes quite rapidly. In highly regulated fields that move as slowly as is the case for medicine, however, one can profitably continue to be a skeptic for quite some time. While progress is rapid and impressive in the lab and in animal studies, a skeptic can continue to shrug and point to the lack of human therapies.

This is the result of an excessive burden of regulatory cost: rapid progress in the lab, in a revolutionary era of increasing capacity, improving tools, and falling costs, runs up against a wall of regulatory delay and vast expense. It takes twenty years to move from early research to mode of therapy to clinical approval, and few programs make it all the way, abandoned in the face of a cost that no-one is willing to pay. All skeptics setting themselves up in general opposition to technological progress will look silly at some point, it just takes longer when the state has decided that progress in a given field will be slow and burdened.

When selective and intelligent, skepticism serves a useful purpose, as every grand endeavor, every new field will attract a problematic minority of the fraudulent, the mistaken, the grandiose, and the rent-seekers. There certainly exist a handful of modern day alchemists and would-be demagogues who care little about scientific truth amidst the majority of earnest, scientifically-minded folk in the longevity community. But to set oneself up as a full-on skeptic of the ability to meaningfully extend human life span? That is just as bad, and for similar reasons.

The Longevity Skeptic

At the Longevity Investors Conference last October in Switzerland, speakers described breakthrough therapies being developed to manipulate genes for longer lifespans. Swag bags bestowed pill bottles promising super longevity, stirring hopes for centuries of youth. Then Charles Brenner took the stage. The biochemist from City of Hope National Medical Center, in Los Angeles, addressed these ideas and treatments one by one, picking them apart, explaining that they're based on faulty research. We can't stop aging, he told the crowd. We can't use longevity genes to stay young because getting older is a fundamental property of life.

Over the past year, Brenner has been challenging life-extension theories on Twitter, YouTube, and the conference circuit, where he's been introduced as the "longevity skeptic." Brenner tells people the reasons for suspicion date back to Herodotus' made-up account of the Fountain of Youth in 425 B.C. Some things never change, he says, even as the field of aging research has picked up scientific momentum in recent years. Investments in longevity startups are predicted to jump from $40 billion to $600 billion in the next three years. Lured by funding from digital age tycoons such as Jeff Bezos and Peter Thiel, top scientists are aligning with companies to advance their work.

Brenner is critical of several big promises emanating from these companies and researchers, such as claims that cellular reprogramming could halt aging. At best, Brenner says, scientists can develop therapies that maintain the health of older people and help keep them out of the hospital-an increasingly important goal as the average age in the United States and elsewhere keeps climbing. Brenner is tackling this problem as the chief scientific advisor of a bioscience company called ChromaDex, which markets supplements for "healthy aging." But believing we can rewrite the operating manual for lifespan itself, Brenner told me, is like "believing in the tooth fairy."

The better understanding developed in recent years of the harmful effects of lingering senescent cells in the tissues of older individuals has led to a burst of research into cellular senescence in many areas of medicine. One of the more active parts of the field of late, judging by number of publications, is degenerative disc disease. Therapies that can efficiently remove senescent cells may well turn out to greatly slow the widespread age-related dysfunction observed in intevertebral disc tissue.

Closely associated with aging and age-related disorders, cellular senescence is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors that hamper normal tissue homeostasis. Chronic accumulation of senescent cells is thought to be associated with intervertebral disc degeneration (IDD) in an aging population. IDD is one of the largest age-dependent chronic disorders, often associated with neurological dysfunctions such as, low back pain, radiculopathy, and myelopathy.

Senescent cells increase in number in the aged, degenerated discs, and have a causative role in driving age-related IDD. This review summarizes current evidence supporting the role of cellular senescence on onset and progression of age-related IDD. The discussion includes molecular pathways involved in cellular senescence such as p53-p21CIP1, p16INK4a, NF-κB, and MAPK, and the potential therapeutic value of targeting these pathways. We propose several mechanisms of cellular senescence in IDD including mechanical stress, oxidative stress, genotoxic stress, nutritional deprivation, and inflammatory stress. There are still large knowledge gaps in disc cellular senescence research, an understanding of which will provide opportunities to develop therapeutic interventions to treat age-related IDD.

Link: https://doi.org/10.3390/biom13040686

Ghrelin signaling is a part of being hungry. The cell signaling involved in the state hunger appears to be an important part of the process by which fasting and calorie restriction improve cell metabolism, tissue function, and long-term health. Researchers here investigate LEAP2, an inhibitor of ghrelin signaling, finding that more of it correlates with worse cognitive function with age. Given what we know of the way in which hunger affects health, LEAP2 may also prove to be yet another target for future therapies that can mimic some of the effects of calorie restriction.

Elderly individuals frequently report cognitive decline, while various studies indicate hippocampal functional declines with advancing age. Hippocampal function is influenced by ghrelin through hippocampus-expressed growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous GHSR antagonist that attenuates ghrelin signaling. Here, we measured plasma ghrelin and LEAP2 levels in a cohort of cognitively normal individuals older than 60 and found that LEAP2 increased with age while ghrelin marginally declined. In this cohort, plasma LEAP2/ghrelin molar ratios were inversely associated with Mini-Mental State Examination scores.

Studies in mice showed an age-dependent inverse relationship between plasma LEAP2/ghrelin molar ratio and hippocampal lesions. In aged mice, restoration of the LEAP2/ghrelin balance to youth-associated levels with lentiviral shRNA Leap2 downregulation improved cognitive performance and mitigated various age-related hippocampal deficiencies such as CA1 region synaptic loss, declines in neurogenesis, and neuroinflammation.

Our data collectively suggest that LEAP2/ghrelin molar ratio elevation may adversely affect hippocampal function and, consequently, cognitive performance; thus, it may serve as a biomarker of age-related cognitive decline. Moreover, targeting LEAP2 and ghrelin in a manner that lowers the plasma LEAP2/ghrelin molar ratio could benefit cognitive performance in elderly individuals for rejuvenation of memory.

Link: https://doi.org/10.1172/jci.insight.166175