Fight Aging!

Another year has passed, and here we find ourselves once again another twelve months deeper into the 21st century and all of its promised wonders. The Golden Age science fiction authors were gloriously wrong in their extrapolation of trends of energy use, computation, and medicine, predicting a 21st century of slide-rules, ubiquitous heavy lift capacity into orbit and beyond, and a world in which 60-year olds still had bad hearts and little could be done about it. Instead, energy turned out to be hard, while computation enabled the biotechnology revolution and the prospect of longer, healthier lives through radical advances in medicine. Expansion into space awaits while we focus instead on the small-scale of our cellular biochemistry.

The trend in human life expectancy over the long term continues upwards, despite the short term negative impacts of obesity. Yet there remains a strong need for advocacy for aging research and the development of novel therapies to target the mechanisms of aging, even as this field grows apace. The progression of aging remains incompletely understood and much debated even given the more extensive knowledge of fundamental forms of damage that cause aging. The mainstream of our culture has yet to adopt a war on aging as it adopted the war on cancer. The advocacy of the first two decades of this century continues, but changing over time. Noted advocacy organizations SENS Research Foundation and Lifespan.io announced that they would merge; the book "The Death of Death" is now available in English, finally.

In part there is change because, unlike the early 2000s, there is now a longevity industry worthy of the name. It is a part of the broader biotech industry, and subject to the same perverse incentives, direct costs of regulation, and other issues that ensure a very long, slow development cycle. The pace of progress is nowhere as fast as we'd like it to be, even setting aside the terrible biotech investment market of the past two years, and some advocates have shifted their focus to this problem. Nonetheless, the wheel turns. Some of us are even optimistic about the next few decades. Meanwhile, the more adventurous arms of various governments are starting to come to the table to support areas of development, such as better measurement of biological age via clocks and other means, that are well underway. Typically one should expect to see government support arrive late to the table, in low-risk, high-attention areas that are already a foregone conclusion and well on their way to that conclusion. Thus ARPA-H is now entering the field of measurement and clock development.

A growing list of therapies are in preclinical development, a few programs reaching into clinical trials. Even if too many of the therapies under development aim only to modestly slow the progression of aging, there are still a good many potential rejuvenation therapies focused on repair of damage. This year, Fight Aging! noted updates from Cyclarity and Repair Biotechnologies (a few times, including at the Rejuvenation Startup Summit 2024) on atherosclerosis, Mitrix Bio on mitochondrial transplantation, Kimer Med on their implementation of the DRACO antiviral technology, Lygenesis on human trials of liver organoid implants. If you're looking for a broad view of the longevity industry and its progress, Aging Biotech Info continues to be a great resource; see an early 2024 interview with the maintainer for some of the background.

Last year's retrospective focused on categories of age-related disease rather than the forms of age-related damage outlined in the Strategies for Engineered Negligible Senescence (SENS) proposals, and was both less helpful and much more onerous to assemble as a result, I feel. So this year it is back to the fundamental causative mechanisms of aging, plus a couple of extra categories to cover some areas of personal interest.

Cell Loss / Atrophy

One of the most evident, early examples of cell loss leading to atrophy is the aging of the thymus, and the consequent loss of immune function that follows. Efforts to produce regeneration of the thymus lapsed for some years in the mid to late 2010s, but are now a going concern once more - multiple biotechnology companies are working on thymic regrowth. Replacement of cells via transplantation is one of the plausible paths forward to comprehensive therapy addressing cell loss and tissue atrophy, even where these cell therapies are really just ways to deliver signal molecules that adjust the behavior of native cells to increase regeneration. Cost-effective cell therapies will need universal cells, however. Progress is occurring on this front, but it is slow. Cell therapy examples from recent years include the ongoing efforts to provide new motor neurons to Parkinson's patients, delivery of cardiomyocytes to the aging heart, and cell therapy to restore the aged and atrophied thymus.

Beyond cell therapy lies tissue engineering and transplantation of that engineered tissue. This is a field with great promise, but which continues to struggle with goals such as creating the vasculature needed to support tissues larger than a few millimeters in size and speeding up the process of bioprinting. Cells survive transplantation better when introduced as tissue or in artificial tissue-like structures; it is even possible to provide those structures alone without the cells. A liver patch of only extracellular matrix produces benefits, for example. Recent work on tissue transplants include: efforts to replace portions of the neocortex; a clinical trial using sheets of corneal cells to replace a damaged cornea.

The alternative is to provoke replication in existing populations, such as by increasing stem cell function, or reactivation of developmental processes for replication in cell populations that normally do not replicate all that much in adults. A better understanding of how aged stem cells become dysfunctional than is presently the case will almost certainly be needed. Inroads are made in model organisms, but this area of research has the look of a long way to go yet. Changes in the stem cell niche, the supporting cells surrounding stem cells, are likely important. From the past year, a few examples of producing new cells in situ: gene therapy to promote cardiomyocyte replication in a damaged heart; more gene therapy to promote regeneration of lost sensory hair cells; yet more gene therapy to trigger muscle growth via MYC-1 expression; upregulation of cyclophilin A and increased PF4 both improve hematopoietic stem cell function; efforts to discover regulators of stem cell exhaustion; a similar search for regulators of neural stem cell function.

Mutation and Other Damage to Nuclear DNA

Stochastic DNA damage is mostly harmless, taking place in cells with few replications left, or in unusued regions of the genome. But mutations to stem cells and progenitor cells can spread throughout a tissue, producing somatic mosaicism. It remains unclear as to how important this is to aging, but most of the evidence for some role emerges from clonal hematopoiesis of indeterminate potential, somatic mosaicism in immune cells. This may contribute to kidney disease and risk of stroke, for example. What can be done about DNA damage? This seems a tough problem, but some paths forward have been suggested. Recently, it was discovered that natural examples of very efficient DNA damage response mechanisms can feasibly be transferred between species.

Damage in the structure of nuclear DNA and its surrounding machinery may be more subtle overall than simply mutational alterations to DNA sequences. For example, DNA damage and the repair response to that damage can indirectly cause RNA polymerase II to stall more often in reading DNA, altering gene expression for the worse. A fair number of researchers remain skeptics as to whether random mutation contributes meaningfully to aging. But research in recent years now suggests that random DNA double strand breaks and the resulting repair processes may alter the epigenetic regulation of nuclear DNA structure to cause many of the characterisitc changes in gene expression observed in aged tissues. To the extent that this is the case, we might think of partial reprogramming, a way to reset epigenetic expression by exposing cells to the Yamanaka factors, as a rejuvenation therapy. Certainly, a steady flow of animal studies of targeted reprogramming appear to demonstrate benefits. In the vasculature, for example, reducing hypertension. Or in the brain, where it reverses loss of cognitive function and is protective in models of neurodegeneration.

Another interesting field of study involves transposons, DNA sequences left behind by ancient viral infections that are repressed in youth, but run amok in later life to copy themselves across the genome, causing mutational damage. It remains unclear as to what degree this mechanism contributes to aging, but the research community is in search of the causes of transposon activation in later life. Perhaps the most intriguing evidence supports an important role for degree of transposon activity to determine the differences in life span between breeds of dog.

Mitochondrial Dysfunction

The pure SENS view of mitochondrial dysfunction is that the important component of it arises from damage to mitochondrial DNA. Researchers recently built a new cell model to better assess this mechanism. This is distinct from a more general malaise of impaired mitochondrial function that arises from gene expression changes with age, impairing mitochondrial dynamics, function, and the quality control process of mitophagy. It also results in mislocalized mitochondrial DNA fragments that provoke a maladaptive inflammatory response. These changes may result from cycles of DNA double strand break repair and their effects on nuclear DNA structure, and thus are downstream of damage to nuclear DNA. It remains clear as to how far one can go in restoring lost mitochondrial function by only restoring youthful gene expression, or improving mitophagy. Improvement in mitophagy is actually quite hard to measure, and there is much debate over the existing data for age-related mitophagy decline. Mitophagy interacts with the fusion and fission of mitochondria, and researchers have shown that adjusting the balance of fusion and fission in either direction can extend life in nematode worms. Equally, greater fragmentation of mitochondria due to excessive fission appears pathological in mammalian tissue.

Mitochondrial dysfunction is known to be important in muscle aging, in the heart and elsewhere in the body, and may interact with chronic inflammation to produce sarcopenia. Failing mitophagy is implicated in neurodegeneration, as is the consequent loss of mitochondrial function, an important mechanism in the aging of the brain. Mitochondrial dysfunction is also implicated in atherosclerosis, making the vascular cell dysfunction characteristic of the condition that much worse. Mitochondrial dysfunction has a role in ovarian aging, and in dry eye disease.

Approaches to address age-related mitochondrial dysfunction include allotopic expression of mitochondrial genes in the cell nucleus, less vulnerable to damage, and a backup source of mitochondrial proteins to prevent mutational damage to mitochondrial DNA from affecting mitochondrial function. Progress on this is taking place, but slowly; most recently researchers have produced a mouse lineage to demonstrate that ATP8 allotopic expression safely rescues function in loss of function ATP8 mutants. Then there is also the prospect of transplantation of functional mitochondria harvested from cultured cells or donor cells, shown to improve muscle function. Partial reprogramming of cells from aged tissues via short-term exposure to the Yamanaka factors has also been shown to improve mitochondrial function in the course of resetting epigenetic patterns. In terms of more targeted approaches to upregulate mitophagy, researchers have looked for targets in the function of HKDC1 and TFEB, but most of the mitophagy-related effort is focused on supplement-like molecules and their derivatives, such as the various groups working on urolithin A. While there are potential ways to increase the manufacture of new mitochondria, it isn't clear that this sort of enhancement will help in the aged environment.

Extracellular Matrix Damage

Changes in the physical properties of tissue due to age-related damage to the molecules of the extracellular matrix can produce cascading consequences. This is particularly true of stiffening of blood vessel walls, a contributing cause of hypertension, which in turn damages the delicate tissues of the kidney. Relatively little work takes place on this aspect of aging, and this line item in the SENS list of forms of molecular damage that drive aging includes more than just changes in physical properties. Any change in the extracellular matrix might change cell behavior for the worse in some way. There is every reason to think that a lot of this sort of thing takes place in the aging body, and that we have only scratched the surface of an understanding of it.

Senescent Cells

Senescent cells accumulate with age. They produce inflammatory signaling that is harmful to cell and tissue function, and encourages other cells to become senescent. Replication stress in cell populations may be an underappreciated source of senescence in later life. It is possible to correlate mortality to circulating levels of some of those signal molecules. Researchers have connected this signaling to the cells's response to the mutational damage that occurs as cells enter the senescent state. The consensus in the research community is that senescence is a complex state, or collection of states, and we remain far from a complete understanding of senescence. There are debates over whether everything presently classed as a senescent cell is in fact a senescent cell, or whether most of what are currently thought to be senescent tissue cells are in fact senescent tissue resident immune cells.

Nonetheless, senescent cells are linked to many age-related conditions and declines, and a selection of research from just the last year is extensive: skin aging is always a popular topic, and worthy of many mentions in the context of the burden of senescent cells; osteoporosis, particularly following menopause; macrophage signaling induces senescence in aging bone tissues; the onset of Alzheimer's disease and, for different reasons, Parkinson's disease; neurodegeneration more generally, such as via an increase in senescent T cells, increase in dysfunctional microglia, or aged neurons re-entering the cell cycle to become senescent; the relevance to neurodegeneration is worth emphasizing twice, as there is considerable enthusiasm in the research community for the development of therapies targeting senescent cells in the brain; moving on, there is the impairment of chemotherapy effectiveness by senescent cells; loss of capillary density in aged tissues; endothelial dysfunction in the vasculature; impairment of macrophage tissue maintenance functions; disruption of adrenal gland function; declining kidney function; excess cholesterol inside macrophages in atherosclerotic plaque provokes their senescence, contributing to the formation of unstable plaques prone to rupture; macular degeneration of retinal tissue; the aging of the heart and vasculature leading to cardiovascular disease; the role of senescent cells in cancer is both positive and negative for the patient, making the use of senolytic therapies more challenging than in other contexts; senescent B cells affect the ability of the immune system to garden the body's microbiomes; the aging of the ovaries; liver aging; loss of capacity for hair regrowth; the development of osteoarthritis; the secondary harms that follow stroke.

The first senolytic therapy combining dasatinib and quercertin continues to produce mostly promising results in clinical trials, most recently in older women with osteoporosis. The variety of senolytic therapies under development continues to grow at a fair pace year over year. Senolytic CAR-T therapies and adoptive transfer of other immune cells will likely be too expensive to be practical in the broader aging population, but continue to demonstrate promise in animal models. The cancer field may adopt these immunotherapy approaches to target senescent cancer cells, however. Topical applications of senolytics for skin aging continue to be developed, including a topical formulation of navitoclax shown to clear senescent cells from skin in mice. Novel biochemistry potentially relevant to therapies targeting senescence continues to be uncovered: PKM2 aggregation; that senescent cells use immune checkpoints to evade attention from immune cells; further, high mobility group proteins may turn out to be good targets to suppress senescence; and PAI-1 appears important in the creation of senescent cells.

A range of flavonoids are senolytic to varying degrees, and new ones are discovered on a regular basis, such as 4,4′-dimethoxychalcone. Researchers would like to improve the efficiency of flavonoid senolytics via delivery in nanocarriers, or by engineering better versions of molecules such as fisetin. Further, attempts are underway to find other natural compounds that can replace the chemotherapeutic drug dasatinib in the dasatinib and quecertin senolytic combination. The class of PI3K inhibitors continues to produce senolytic compounds. More diligent mapping of the surface features of senescent cells also continues to yield new targets for new selective ways to kill these errant cells. Researchers have proposed searching for senolytic lipids, and discovered a few that kill senescent cells via ferroptosis. Antidiabetic SGLT2 inhibitors are senolytic in overweight mice, but this seems likely to have little effect outside the context of obesity and the pathological diabetic metabolism. High intensity exercise is technically senolytic, but at the point at which we are calling lifestyle interventions senolytic, I feel the word begins to lose its meaning. At the end of the day, senolytics are just one part of a greater toolkit of rejuvenation therapies that will have to be used in combination.

An alternative approach to senolytics, less well developed, is to find ways to shut down the inflammatory signaling produced by senescent cells. It isn't clear that this is going to be as useful or progress as rapidly, given the incompletely understood complexity of the mechanisms by which senescent cells generate inflammation - but people are certainly working on it! Approaches to this end from the past year include CISD2 upregulation and selective sabotage of citrate metabolism.

Intracellular and Extracellular Waste, Including Amyloids

The amyloid-β that accumulates with age in the brain is an antimicrobial protein. This may explain associations between persistent viral infection and Alzheimer's disease, in that greater production of amyloid-β allows more of it to misfold and aggregate to contribute to Alzheimer's pathology. Other causes of amyloid-β aggregation may include the metabolic disruption produced by excess visceral fat. Amyloid-β may cause blood-brain barrier leakage, and this might be as important as other aspects of its pathology, such as provoking chronic inflammation and inhibiting synaptic proteasome function. While the amyloid cascade hypothesis remains firmly in the driver's seat of research strategy in the matter of Alzheimer's disease, one still finds fundamental debates taking place, such as whether it is the amyloid-β or other proteins that coincide with amyloid-β causing pathology, and the degree to which significant harms precede evident symptoms. More positively, it seems that loss of brain volume resulting from anti-amyloid therapies is not actually harmful, but results from clearance of amyloid. After amyloid-β in the progression of Alzheimer's disease comes tau aggregation and more severe harm to brain tissue. Tau aggregation induces inflammatory dysfunction in supporting cells in the brain, and consequent damage to synapses.

TDP-43 aggregation is a more recently discovered form of proteopathy relevant to neurodegeneration, and is more common than previously thought. It may also contribute to Huntington's disease pathology. Researchers continue to delve into the mechanisms of TDP-43 pathology. Attention has been given to NPTX2 as a link between TDP-43 aggregates and cell death. Like amyloid aggregation, TDP-43 aggregation may extend beyond brain tissue into the vasculature. Harm resulting from TDP-43 is not the only recent discovery! DDX5 also appears capable of forming prion-like aggregates.

The misfolding and aggregation of α-synuclein causes Parkinson's disease. α-synuclein pathology appears to interact with lipid metabolism in the brain, a bidirectional relationship shaping the spread of a synucleinopathy such as Parkinson's disease. As is the case for other protein aggregates associated with neurodegenerative conditions, α-synuclein aggregates can be found outside the brain - in skin, for example, or in exosomes in blood, opening the possibility of early detection. Outside the brain, researchers also see amyloid aggregates encouraging calcification in the heart. While thinking of the whole body, I should also note what would in a better world be a large area of research, into clearing out the various forms of lingering molecular waste, some of it altered proteins, that accumulate in the lysosomes of long-lived cells to cause dysfunction in normal recycling processes. Very little work takes place here, however; a few research teams, a few preclinical programs. In some years nothing comes to notice. This was one of those years.

In terms of approaches to clear protein aggregates, manipulating the behavior of microglia in the brain seems promising. Inhibition of p16 works, for example, perhaps by reducing the degree of senescence in this cell population. Also interfering in the LILRB4-APOE interaction, or upregulation of CCT2 to promote aggrephagy. Alternatively, there is the approach of preventing astrocytes from crowding out microglia and blocking access to amyloid plaques. Amyloid-targeting anticalins have been suggested as a strategy. Amyloid-β clearance via immunotherapy (with meaningful risk of unpleasant side-effects) is now a going concern, with enough data for meaningful commentary on what it might imply. It continues to appear that the amyloid cascade hypothesis is correct, and clearing amyloid in late disease stages doesn't help all that much. There, the target protein aggregate is hyperphosphorylated tau, and numerous approaches are under development. A more recent example is a clever evolution of proteolysis targeting chimera (PROTAC) technology that encourages the dephosphorylation of hyperphosphorylated tau, reducing the pace of aggregration. Another approach is delivery of anti-tau intrabodies via mRNA therapies. Others are investigating TYK2 inhibition as a way to slow the pace of pathological tau phosphorylation. For α-synuclein pathology, researchers are exploring use of a bacterial peptide that inhibits aggregate formation and antisense oligonucleotides to inhibit α-synuclein protein expression.

Gut Microbiome

Age-related alterations to the gut microbiome might arguably be added to the existing categories of SENS as another form of damage. This could occur independently of other mechanisms of aging, existing as a fundamental form of damage, even given that it is likely largely downstream of immune aging when it does occur over time. Loss of anti-microbial peptides may be important in reducing the ability of the immune system to garden the gut microbiome, for example. The gut microbiome is noted to be distinct in long-lived individuals. Harmful changes to the microbiome can be catalogued, but are far from fully understood. Nonetheless, these changes can be reversed independently of other aspects of aging by fecal microbiota transplantation from young donors to old recipients, producing benefits such as extended life span in animal models - or the reverse when transplanting an old microbiome into a young animal. Icariin is another approach to improving the composition of the gut microbiome. Flagellin immunization also works, demonstrated to extend life in mice. Sustained calorie restriction and intermittent fasting may improve the gut microbiome, or at least slow its aging. It is possible that delivery of genetically engineered microbes may also achieve useful goals, but this is far from proven in practice.

Restoration of a youthful gut microbiome may treat neurodegenerative conditions such as Parkinson's disease, and mechanisms to explain that outcome include its effects on astrocytes in the brain. Importantly, a clinical trial showed no benefits of fecal microbiota transplantation to patient's with Parkinson's disease. While the misfolding of α-synuclein characteristic of the condition may start in the gut in many patients, induced by a dysfunctional microbiome before spreading to the brain, addressing the gut contribution is likely too little, too late once evident symptoms have started. Despite this data point, the limited clinical trial data in humans for modification the gut microbiome, even transiently, is generally supportive of greater efforts in this direction.

Evidence exists for the gut microbiome to contribute to life span and numerous specific aspects of aging via mechanisms such as increased chronic inflammation: longevity in rabbits correlates with the gut microbiome composition, as do physiological changes in aged mice; aging of the ovaries; aging of the musculoskeletal system; increased risk of arrhythmia; Alzheimer's disease, where a fair amount of effort is devoted to trying to identify distinct microbial populations in patients, which may include infectious pathogens; reduced grip strength indicative of sarcopenia and frailty; loss of hematopoietic stem cell function; old individuals exhibit a distinct fungal gut microbiome; aging of bone leading to osteoporosis, and identification of specific features of the microbiome that correlate with this aspect of aging; the lymphatic system likely plays an important role in trafficking microbes and microbial metabolites from the intestine to the brain to cause harm; a novel way in which the aging microbiome may cause harm is by increasing intestinal permeability, allowing digestive enzymes to leak into tissues; it may also promote thymic involution, accelerating immune aging; rheumatoid arthritis may be driven by a distinct gut microbiome; menopause and the composition of the gut microbiome have a bidirectional relationship.

Cryonics

At the present pace of development of rejuvenation therapies, every older adult is going to age to death. Cryonics, the low temperature preservation of the structure of the mind following clinical death, remains a necessary industry in waiting. It has yet to exist in any way meaningful to the vast majority of people. Yes, one can be cryopreserved. No, the protocols are nowhere near as robust as we'd like them to be, and there are too few cryopreservation organizations to save more than a tiny handful of people.

There is a clear and well-defined roadmap for the technological capabilities needed to reach the fully developed, vast cryonics industry of the future. The road to turning the present small non-profit cryonics organizations into a full-fledged industry to compete with the grave and oblivion most likely starts with reversible cryopreservation of organs for the transplant industry. Solve that problem, and there is an engine to bring funds and interest into tissue preservation more generally. We will find ourselves half-way to convincing the world that the same can and should be done for people on the verge of death, to preserve them for a future in which both the technology and the will exist to safely restore a body and brain from both crypreservation and the damage of aging.

Aging Clocks

While not under the SENS heading, it is interesting to keep an eye on the development of clocks to assess biological age - or at least which are claimed to assess biological age. It may be fair to say that meaningful progress towards rejuvenation therapies can only occur to the degree to which we can effectively measure aging. This, at least, is a consensus sentiment in the research community. That community produces new clocks at quite the pace. In just the last year: a novel proteomic clock; an aging clock built from the senescence-associated secretory phenotype of senescent monocytes; a clock built from the metabolome called MileAge; a clock built from cheek swab DNA methylation data; a clock built from brain MRI imaging data; more novel transcriptomic clocks; the development of organ-specific proteomic clocks; a clock based on retrotransposon DNA methylation; aging clocks built from retinal imaging data; a clock based on protein aggregation; a physiological aging clock using clinical biomarker data.

A growing body of clinical trial data includes clock measures, enough now to start to say something about how useful the mainstream clocks are in practice. Some would argue it is time to stop building new clocks and standardize on the best of the established clocks. While epigenetic age acceleration in many clocks correlates well with age-related disease and mortality, a fair number of issues remain to be overcome. Existing clocks have many quirks, such as being responsive to psychological stress or time of day. Clock data is obtained from immune cells in a blood sample, and different immune cell populations exhibit different patterns of epigenetic aging, biasing results. This is also true when considering differences between mammalian species. Work on correcting this issue has led to the concept of intrinsic epigenetic age. Nonetheless, blood sample clocks do not generalize well to other tissues. The greatest challenge, however, is how to understand how the measured changes making up the clock actually relate to underlying processes of aging and disease. Some inroads are being made, such as separating harmful from adaptive changes and understanding how much of what is measured is epigenetic drift.

Other novel work on clocks this past year included: improvements to the Pace of Aging clock; advocacy for clocks built on clinical biomarkers and risk factors; a better grasp as to how lifestyle choices affect epigenetic age; demonstrating that modern clocks do show a slowing of aging for people exhibiting greater physical fitness; continued research into glycosylation clocks; quantifying the level of uncertainty we should expect from clocks that assess biological age; noting that chronic liver disease accelerates epigenetic aging in other organs; the negligibly senescent axoltl exhibits little alteration in the methylome over its lifespan, making it hard to construct something resembling the epigenetic clocks established for mammals; relating the existence of epigenetic clocks to theories of programmed aging; demonstrating that acccelerated aging correlates with cardiometabolic disease; Olympic medal winners exhibit slower expigenetic aging in comparison to other competitors; a demonstration that more recent epigenetic clocks do correlate with Alzheimer's disease risk.

Articles

Every year I note that I am not writing as much as I used to, or at least not directing said writing in the direction of the Fight Aging! audience as much used to be the case. There are more demands on my time than there used to be, or so it seems. Still, a few items from the past year are noted below.

• Predicting the Order of Arrival of the First Rejuvenation Therapies
• Reporting on a Nine Month Self-Experiment in Taurine Supplementation
• Request for Startups in the Rejuvenation Biotechnology Space, 2024 Edition
• Notes from the Rejuvenation Startup Summit in Berlin, May 2024

At the End, the Wheel Turns

The more involved one is in the field of aging and longevity, the more one feels that the tremendously important work of building therapies to treat aging as a medical condition is crawling along at a very slow pace indeed. But step back, look in only every five years or so, and change is rapid. Progress is made. The wheel turns. It can never be fast enough in a world in which so very many people suffer and die from age-related disease each and every day, but this is a very different environment when compared to the state of affairs twenty years past. The 2040s will be amazing.

Bone is constantly remodeled by the activities of osteoclasts and osteoblasts. Osteoclasts break down the extracellular matrix of bone, while osteoblasts create it. These activities are balanced in youth, but with advancing age a range of mechanisms operate to create a growing imbalance favoring osteoclasts. This steadily reduces bone density leading to osteoporosis and eventually life-threatening fracture risk. In principle any compensatory therapy should be beneficial, any way to suppress osteoclast or enhance osteoblast populations and activity regardless of whether or not underlying causes are targeted. In practice, finding good paths forward has been challenging, but researchers here report on their investigation of one potential new approach.

A CpG oligodeoxynucleotide (CpG-ODN), iSN40, was originally identified as promoting the mineralization and differentiation of osteoblasts, independent of Toll-like receptor 9 (TLR9). Since CpG ODNs are often recognized by TLR9 and inhibit osteoclastogenesis, this study investigated the TLR9 dependence and anti-osteoclastogenic effect of iSN40 to validate its potential as an osteoporosis drug.

The murine monocyte/macrophage cell line RAW264.7 was treated with the receptor activator of nuclear factor-κB ligand (RANKL) to induce osteoclast differentiation, then the effect of iSN40 on was quantified by tartrate-resistant acid phosphatase (TRAP) staining and real-time RT-PCR. iSN40 completely inhibited RANKL-induced differentiation into TRAP+ multinucleated osteoclasts by suppressing osteoclastogenic genes and inducing anti-/non-osteoclastogenic genes. Treatment with a TLR9 inhibitor or a mutation in the CpG motif of iSN40 abolished the intracellular uptake and anti-osteoclastogenic effect of iSN40.

These results demonstrate that iSN40 is subcellularly internalized and is recognized by TLR9 via its CpG motif, modulates RANKL-dependent osteoclastogenic gene expression, and ultimately inhibits osteoclastogenesis. Finally, iSN40 was confirmed to inhibit the osteoclastogenesis of RAW264.7 cells cocultured with the murine osteoblast cell line MC3T3-E1, presenting a model of bone remodeling. This study demonstrates that iSN40, which exerts both pro-osteogenic and anti-osteoclastogenic effects, may be a promising nucleic acid drug for osteoporosis.

Link: https://doi.org/10.3390/life14121572

Researchers here argue for lithocholic acid, a bile acid produced when the gut microbiome processes bile, to be a player in the ability of calorie restriction to slow aging and extend life in short-lived species. Researchers have in the past noted that providing lithocholic acid to yeast slows cell aging, while centenarians exhibit a gut microbiome that produces more lithocholic acid. While reading this, it is worth remembering that while the mechanisms described exist, it is ever challenging to determine how much of the benefits of calorie restriction or an altered gut microbiome derive from pathways involving lithocholic acid. Therapies that target this could be interesting, or could be poor options. It is hard to tell without trying.

Generally speaking, bile is less interesting than is longevity, but that might soon change. Consisting mainly of water, bilirubin (a breakdown product of haemoglobin), cholesterol, and bile acids, this yellow-green fluid is synthesized in the liver, stored in the gallbladder and released into the small intestine to emulsify dietary fats and increase the absorption of fat-soluble vitamins. Gut-resident bacteria, such as species of Clostridium and Lactobacillus, convert primary bile acids into the secondary bile acids deoxycholic acid and LCA, some of which is reabsorbed into the bloodstream.

Previous work has identified bile acids as health-promoting compounds. Dafachronic acids, which are structurally related to LCA, extend the lifespans of nematode worms (Caenorhabditis elegans) and LCA extends the lifespans of yeast (Saccharomyces cerevisiae) and fruit flies. In mammals, LCA is not known to extend lifespan, but it does alter physiology in ways that are consistent with improved health, such as lowering levels of liver triglycerides, blood glucose, and systemic inflammation - in part, by activating the bile-acid receptor TGR5. LCA is also implicated in the lifespan-extending effects of transplanting gut microbiota from young mice into old mice, but how the bile acid might impart health benefits is unclear.

In a recent study researchers gave LCA to old mice for a month. These mice experienced health benefits reminiscent of those induced by calorie restriction, including improved muscle regeneration, grip strength, and sensitivity to insulin. These effects were dependent on AMPK. Interestingly, LCA raised levels of the hormone GLP-1 without causing muscle loss, unlike today's popular weight-loss drugs that bind to the GLP-1 receptor. In nematodes and flies, LCA activated AMPK, increased stress resistance and extended lifespan - benefits that were negated when the gene encoding AMPK was deleted in the animals.

After ruling out TGR5 as the mediator of LCA's effects, the researchers turned their attention to the enzyme SIRT1. They demonstrated that LCA stimulates SIRT1 to upregulate AMPK. The involvement of gut microbiota in the production of LCA and the benefits of calorie restriction might explain why faecal transplants from young animals improve the health and increase the lifespans of older animals, and why some mice do not respond to calorie restriction.

Link: https://doi.org/10.1038/d41586-024-04062-1

Regular readers will know that I'm not in favor of the present state of medical regulation. In this I am not alone. Many people think that some fraction of the cost of obtaining regulatory approval of new therapies is entirely unnecessary, some fraction of the degree of rigor imposed on manufacture and clinical trials is entirely unnecessary. Clinical trials conducted in Australia cost half of those conducted in the US or Europe, because the Australian community has declared that full Good Manufacturing Practice (GMP) procedures mandated by the FDA in the US and EMA in the EU are in fact unnecessary. Something like 10% of all early stage clinical trials worldwide take place in Australia. In that country the government has delegated ethics and assessment of risk to their equivalent of competing institutional review boards, each associated with a specific clinical trial center. It is a good example of the way in which centralization and diminished competition penalizes progress.

Do you think that the right number for the degree of waste currently imposed by regulators is half? More than half? Less than half? It is a huge cost in a world in which $30M to $40M is needed to move from preclinical proof to completing a phase 1 safety trial in a small number of volunteers in the US or EU. That cost means that a sizable fraction of potential medicines are never developed. Halve that cost and more medicines will be developed. Yet those within the system are very quick to defend the excess: regulatory capture rules, and the established pharma industry uses the regulatory system in order to reduce competition from upstate therapeutic developers. None of this is to the benefit of humanity as a whole.

Since the turn of the century, the cost of developing new therapies has more than doubled. The regulators ask for ever more proof, ever more tests, ever more rigor, never strongly penalized for the invisible graveyard of therapies and patients that results. This is how complex systems trapped in the later stages of regulatory capture move forward. The dominant players retain their dominance by becoming a part of the system that suppresses the potential for progress. This is widely recognized, and numerous patient advocacy groups have come, tried to change the system from within, largely failed, and vanished. The Clinical Trials Abundance project is one such, and by no means the most radical. I think their proposals change too little to make a difference even if implemented. I believe that the only path likely to lead to radical change is the development of a robust clinical development ecosystem outside the FDA, EMA, and related regulatory systems, built atop the present medical tourism infrastructure. Something to compete at a much lower price point.

The Case for Clinical Trial Abundance

The need to make drug development more efficient has become increasingly pressing. US healthcare spending growth is predicted to reach nearly 20% of GDP by 2032 and exceed GDP growth itself for structural reasons, like an aging society. Meanwhile, given high medication prices and little political appetite to cut Medicare spending, there is mounting pressure to reduce drug development costs. In the face of these cross-pressures, the best policy approach is a supply-side innovation agenda, aimed at lowering the costs of trials.

We have several reasons to be optimistic about our ability to cut clinical trial costs and timelines. One proof-of-concept is the RECOVERY trial, which cost about 1/80th of a traditional randomized controlled trial (RCT) and likely saved hundreds of thousands of lives by demonstrating the efficacy of steroids for COVID-19. RECOVERY showed the enormous cost and time savings possible if trials are kept tightly focused on important questions and trial enrollment/organization is made as easy as possible. We can also look at historic examples of large trials (e.g., the polio vaccine field trials) that ran on time and answered important questions, by avoiding cumbersome and unnecessary administrative delays.

Many stakeholders agree on the urgency of the problem, often framed as clinical trial modernization. Reducing the cost and difficulty of generating high-quality medical evidence is a rare area where most experts agree on the goals. Beyond these specifics, many of our memos follow the guiding question: "What would a permanent, US-scale RECOVERY trial look like and accomplish?" With dramatically cheaper trials, we would more quickly sift through poorly evidenced clinical practice. New therapies would cost less to test in humans, and we would have answers and innovation sooner. Beyond speeding up the approval of new drugs, cheaper and faster trials would also allow more kinds of questions to be asked. When a large trial costs $100 million to carry out, some questions simply don't get asked.

While there seems to be no firmly established mechanism by which urolithin A acts to modestly improve mitochondrial function, it seems presumed that this (and a number of other compounds, such as mitoQ) largely function via improving the operation of mitophagy. Mitophagy, mitochondrially targeted autophagy, is a maintenance process that removes damaged and worn mitochondria. Too little of that and the mitochondrial population in a cell become incrementally more dysfunctional. Impaired mitophagy and mitochondrial dysfunction are features of aging, while improved autophagy is a feature of cell stress responses and many interventions known to modestly slow aging in animal studies.

Vandria is one of a number of companies attempting to make therapies for age-related conditions based on novel modifications of established autophagy or mitophagy promoting compounds. Here, Vandria is noted to have started an initial clinical trial for a urolithin A derivative. So far, efforts in this direction have failed to improve on calorie restriction, and only the rapalogs have done better in some aspects than exercise. It remains to be seen as to how this line of work will fare. Certainly, the original urolithin A compound isn't all that impressive in animal studies.

Vandria SA, a company at the vanguard of mitochondrial therapeutics developing first-in-class small molecule mitophagy inducers, today announces that the first subjects have been dosed in its first-in-human clinical trial of its lead Central Nervous System (CNS) compound VNA-318. Readout of this combined single and multiple ascending dose trial is expected in the summer of 2025.

VNA-318 is an orally available first-in-class small molecule against a novel target to rejuvenate cells and treat age-related diseases through the induction of mitophagy. The target has strong genetic links to several human diseases including Alzheimer's disease. It has a dual mode of action with an immediate improvement of memory, learning, and cognitive function, paired with long-term disease-modifying effects such as reduced neuroinflammation, less toxic protein aggregation, and improved mitochondrial function, as shown in pre-clinical models of Alzheimer's and Parkinson's disease. Toxicity studies have demonstrated VNA-318 has a wide safety window. A composition of matter patent covering VNA-318 and other compounds has been issued by the US Patent Office.

This Phase 1 randomized, double-blind trial is a combined single and multiple ascending dose trial of VNA-318, designed to assess safety, tolerability, pharmacokinetic, and pharmacodynamic parameters in healthy male subjects.

Link: https://vandria.com/press-release-16122024/

Mitochondria are the power plants of the cell, the distant descendants of symbiotic bacteria that carry their own small circular genome, distinct from that of the cell nucleus. The mitochondrial genome is more prone to damage and less well repaired than the nuclear genome, and mitochondrial DNA mutations are thought to be important in aging. Deletion mutations can create broken mitochondria that outcompete undamaged peers to take over a cell, creating a small number of harmfully dysfunctional cells. Less severe point mutations are more commonplace, but evidence is contradictory regarding the degree to which this form of damage contributes to mitochondrial dysfunction in aging. Hence the value of generating a cell model of aging-like mitochondrial damage, to better enable studies of the dysfunction it generates.

The consequences of heteroplasmic mitochondrial mutations have been challenging to study as genome editing for mitochondrial DNA (mtDNA) is limited and there are few established tools to alter heteroplasmy in vitro. Model systems such as the "mtDNA mutator" mouse containing a mutant polymerase gamma implicate mtDNA changes in many aging phenotypes. However, this mouse model induces a large mix of genome alterations often with mtDNA depletion in cells, yielding much more disruption than the clonally expanded heteroplasmic mutation events that occur in usual aging in vivo. Much of our current knowledge regarding heteroplasmy comes from comparisons of primary cells from patients with mtDNA mutations to controls, often with low mutant heteroplasmy and unmatched nuclear genetics, or from immortal "cybrid" cells, which have a malignant pathophysiology and limit the capacity to study the impact of heteroplasmy on cell fate and viability.

Reprogramming somatic cells to pluripotency has been shown to reverse some markers of aging, and expression of reprogramming factors is proposed as a potential rejuvenating therapy. However, the impact of mtDNA heteroplasmy on this process has not been queried. Although heteroplasmy of pathogenic mtDNA variants is typically stable for differentiated cells in culture, multiple recent studies established that heteroplasmy shifts significantly with reprogramming of primary cells to induced pluripotent stem cells (iPSCs). However, beyond this single-measure characterization, the impact of altered heteroplasmy on cell function, and particularly on the capacity for rejuvenation remains unexplored. This is a key area to understand as critical roles are rapidly evolving for mitochondrial metabolism in both maintenance of pluripotency and stem cell differentiation.

We note that the differential segregation of mtDNA heteroplasmy following iPSC generation offers a novel opportunity to understand the impact of clonal increases or decreases in mtDNA heteroplasmy on cellular function. We hypothesize that iPSCs with increased mtDNA heteroplasmy have functional adaptations consistent with cellular aging. Thus, we generated iPSC colonies from three primary fibroblast lines with known heteroplasmy of deleterious mtDNA mutations and quantified heteroplasmy of these mutations in resultant clones. We report that resultant clones displayed a primary bimodal distribution of mutation heteroplasmy. We determined that high-level mtDNA deletion mutant iPSCs exhibit distinct growth properties, metabolic profiles, and altered differentiation capacity, with growth and metabolic shifts mirroring a key subset of changes observed in aging-induced cell and tissue dysfunction.

Link: https://doi.org/10.1111/acel.14402

Any sufficiently large database of biological data obtained from individuals of different ages can be used to build an aging clock. Machine learning approaches can be used find algorithmic combinations of measures that, on average, map to chronological age, mortality risk, or a similar benchmark in the study population. Individuals with a clock age higher than their chronological age are then said to exhibit accelerated aging. The degree to which this approach actually produces good measures of biological age, meaning the burden of damage and dysfunction that causes eventual mortality, remains open to debate. It seems clear from the work conducted to date that some useful form of consensus assessment of aging will emerge eventually, and be used to speed up the development of therapies capable of reducing that measure of biological age.

New aging clocks are produced at a fair pace, a dozen or more every year at this point, even as many researchers are pushing for more of a focus on just a few specific clocks, trying to forge some consensus for a universally agreed upon clock to assess biological age. Today's open access paper is an example of yet another new clock. Here, researchers expand on recently published work to describe their metabolomic clock called MileAge, built on metabolite levels derived from blood samples in a human study population.

Metabolomic age (MileAge) predicts health and life span: A comparison of multiple machine learning algorithms

The increasing availability of high-dimensional molecular omics and neuroimaging data, for example, DNA methylation (DNAm) and magnetic resonance imaging, has enabled the development of biological aging clocks. These clocks are typically developed using statistical or machine learning algorithms that identify relationships between chronological age and molecular data. The difference between predicted age and chronological age can track with health outcomes. Aging clocks provide a more holistic view of a person's health and are more readily interpretable than many individual molecular markers, as they are expressed in units of years.

Metabolomics, the study of small molecules within cells, tissues, or organisms, is increasingly incorporated into biological aging research. Metabolites are the end products of metabolism, such as when food is converted to energy. Early metabolomics studies were limited to a few metabolites and small samples, but technological advancements have enabled the population-scale profiling of multiple molecular pathways. Quantifying hundreds or thousands of metabolites can provide detailed snapshots of an individual's physiological state. Metabolomic profiles can predict many common incident diseases and mortality risk.

This study aimed to benchmark machine learning algorithms for developing metabolomic aging clocks from nuclear magnetic resonance spectroscopy data. The UK Biobank data, including 168 plasma metabolites from up to N = 225,212 middle-aged and older adults (mean age, 56.97 years), were used to train and internally validate 17 algorithms. Metabolomic age (MileAge) delta, the difference between metabolite-predicted and chronological age, showed the strongest associations with health and aging markers. Individuals with an older MileAge were frailer, had shorter telomeres, were more likely to suffer from chronic illness, rated their health worse, and had a higher all-cause mortality hazard (hazard ratio = 1.51). MileAge can be applied in research and may find use in health assessments, risk stratification, and proactive health tracking.

Tau protein in the brain can become overly phosphorylated, and the resulting clumped proteins form solid aggregates that are disruptive to cell and tissue function. Clearing out this phosphorylated protein is one of the strategies under development for the treatment of Alzheimer's disease - without noteworthy clinical success so far, but recall that it took something like twenty years and innumerable clinical trials to produce a working approach to amyloid-β clearance. Many different therapeutic approaches to targeting specifically phosphorylated tau are presently at some stage of development, and here find a review of the current landscape.

Hyperphosphorylation of tau initiates the intracellular formation of neurofibrillary tangles, a hallmark of a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Pick's disease, multiple system atrophy, etc. Intracellular accumulation of hyperphosphorylated tau (pTau) decreases microtubule stability, induces protein aggregation, and impairs neuronal plasticity. Therefore, downregulation or removal of hyperphosphorylated tau (pTau) holds promise for the therapy of these diseases.

However, there remains a great challenge in the development of pTau-targeted drugs. For example, direct application of either tau kinase inhibitors or phosphatase activators may induce unacceptable toxic side effects, because the majority of these enzymes concurrently modulate numerous signaling pathways other than tau. Another way to eliminate pTau is immunotherapy, which employs tau-targeted antibodies to specifically facilitate tau degradation. Although these antibody drugs have shown moderate efficacy for alleviating cognitive impairment in AD patients, they are usually high-cost and it is generally difficult for antibodies to penetrate into the cells to bind tau.

A new kind of hetero-bifunctional molecule, namely targeting chimera, has attracted increasing attention in drug discovery in recent years for its ability to recognize and change the property of a certain protein of interest (POI), typically by enhancing the proximity between the POI and a specific effector, such as ubiquitin ligases for proteolysis targeting chimeras (PROTACs), and autophagosome protein LC3 for autophagy-tethering compounds (ATTECs). Several pTau targeting TACs have been developed in recent years, including dephosphorylation-targeting chimeras (DEPTACs), proteolysis targeting chimeras (PROTACs) for pTau, phosphorylation targeting chimeras (phosTACs), and affinity-directed phosphatase (AdPhosphatases) system.

In this review, we briefly introduce tau and its role in neurodegenerative diseases, provide progress in the development of pTau targeting therapies, and discuss their advantages and limitations.

Link: https://doi.org/10.1016/j.medp.2024.100060

Worse cardiovascular function is known to correlate with risk of neurodegenerative conditions. Evidence points to a range of mechanisms that include reduced cerebral blood flow, hypertension, atherosclerosis, and a dysfunctional blood-brain barrier. Here researchers use an aging clock based on analysis of brain imaging to compare the aging of the brain, as assessed this way, with various aspects of health and lifestyle. As might be expected, risk factors for cardiovascular disease are also correlated with accelerated brain aging.

This study investigated the associations of brain age gap (BAG) - a biological marker of brain resilience - with life exposures, neuroimaging measures, biological processes, and cognitive function. In this population-based cross-sectional study of septuagenarians, findings highlight that physical inactivity, diabetes, and stroke or transient ischemic attack (TIA) were independently associated with higher BAG, reflecting older-appearing brains. Conversely, prediabetes was associated with younger-appearing brains (lower BAG), but this became statistically not significant after adjustment for all risk factors simultaneously. Regular physical activity moderated the obesity-BAG relationship, yielding the lowest BAG in individuals with obesity who were physically active.

Greater cortical thickness, particularly in AD- and resilience-related regions, was linked to lower BAG. Conversely, a higher burden of small vessel disease, white-matter microstructural alterations, systemic inflammation, and high blood glucose levels were associated with a greater BAG, highlighting their influence on brain health in late life. Greater BAG was also related to poorer cognitive outcomes, particularly attention/speed and visuospatial abilities. Notably, sex-specific associations emerged, suggesting distinct pathological and resilience pathways to cognitive disorders between females and males. Together, these findings confirm that vascular-related lifestyles and health factors likely contribute to shaping the appearance of the brain during the aging process. The interplay between vascular brain injury, inflammation, and insulin-related dysregulations may be the key to understanding the neurobiological underpinnings of BAG, therefore, of resilience mechanisms in aging.

Link: https://doi.org/10.1002/alz.14435

The Advanced Research Projects Agency for Health (ARPA-H) is more or less intended to be a DARPA for medical research and development. Government bodies tend to present a view on aging that is very driven by current concerns surrounding entitlements and costs incurred by age-related disease. The entire diverse, distributed community aimed at the development of treatments for aging is viewed through the lens of its ability to reduce predicted budget issues. This perhaps biases government support for aging research towards less risky, more incremental gains that can be implemented broadly, such as cheap supplements, preventative programs based on better measurement of health, and the like, rather than more risky projects with a much greater potential payoff, such as the various rejuvenation biotechnologies.

The ostensible point of the DARPA-like parts of the US government, including ARPA-H, is to provide support for the riskier projects. How well that works out in practice is a matter for debate; ARPA-H is far too young as an entity to draw conclusions, and all arms of government are pressured to be risk averse regardless of stated mission. A few figures from the aging research community and longevity industry have transitioned into running or working at ARPA-H programs, and we shall see how they do in the years ahead. The ARPA-H program noted in today's publicity materials is less adventurous than it might be, essentially starting as a data gathering exercise at scale, to lend weight to efforts to measure biological age. A consensus, functional means of determining biological age is absolutely needed, true enough, but many groups are already working on this challenge. It is a well funded undertaking.

ARPA-H launches new program aimed at extending the healthspan of Americans

The Advanced Research Projects Agency for Health (ARPA-H), an agency within the U.S. Department of Health and Human Services (HHS) announced a new funding opportunity through the launch of the PROactive Solutions for Prolonging Resilience, or PROSPR, program. The big question that drives the program is, "What if we had therapies to extend healthspan and prevent the onset of age-related diseases?"

"The ultimate goal is to extend healthspan - meaning the number of years aging adults live healthy lives and enjoy overall well-being by compressing the frailty and disability that comes with aging, into a shorter duration of time near the end of life." The PROSPR program builds on foundational work by the National Institute of Aging and will work with industry and regulators to accelerate the testing and availability of new therapeutics targeted at healthspan.

The number of people 65 and older accounts for 18% of the US population and is projected to increase to 23% by 2054. Considering their increased care needs relative to younger ages, health care costs will increase by 75% if nothing is done to prevent the progressive loss of physical functioning during aging. It is estimated that increasing the average American healthspan would lessen health care costs due to a combination of fewer medical needs, less reliance on assistance by others, and increased potential for individuals and their family caregivers to remain in the workforce. Because of these and other factors, it is estimated that extending healthspan by one year in only 10 percent of the aging population would reduce costs of U.S. entitlement programs by $29 billion per year and increase value to the national economy by $80 billion per year.

PROSPR: Proactive Solutions for Prolonging Resilience

What if we had therapies to extend healthspan and prevent the onset of age-related diseases? The PROactive Solutions for Prolonging Resilience (PROSPR) program aims to identify biochemical and physiological markers and develop assessment tools that will allow researchers to better understand and target the underlying causes of age-related disease. To achieve this goal, PROSPR will pioneer in-home data collection and clinical trial protocols that can assess age-associated health outcomes in just three years instead of decades of study, accelerating the availability of new therapies. If successful, PROSPR will build a new therapeutic industry with interventions focused on maintaining health during aging.

Researchers here develop transcriptomic clocks for brain aging and use them to observe near neighbor effects between cell types in the brain. Neural stem cells reduce the pace of age-related changes in transcription in surrounding cells, whereas T cells of the adaptive immune system accelerate transcriptomic aging in neighboring cells, where they infiltrate the brain. While there are some paths for T cells to enter the brain in small numbers even in youth, the blood-brain barrier blocks the majority of routes. This barrier becomes dysfunctional with age, however, allowing inappropriate cells and molecules into the brain to cause inflammation and disrupted function. The work here is one viewpoint of that disruption.

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk. Brain ageing is complex and is accompanied by many cellular changes. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions - exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types.

Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell-cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

Link: https://doi.org/10.1038/s41586-024-08334-8

There is the suspicion that Alzheimer's disease, like Parkinson's disease, is in fact two or more distinct conditions with quite different root causes that converge on a similar outcome. Whenever there is a struggle to produce good correlations, with competing studies showing different results, it is plausible that the conflicting data arises because different subtypes of the condition are more or less prevalent in one study versus another. Here, researchers propose that one subtype of Alzheimer's disease arises from the persistent presence of cytomegalovirus (CMV) and its interaction with maladaptive innate immune responses. CMV is already implicated in age-related immune issues, so it would not be too surprising to find it causes other prevalent issues in old age.

The emergence of single nucleus RNA sequencing (snRNAseq) studies of Alzheimer's disease (AD) and aging-affected brain tissue has demonstrated the powerful opportunity for cell transcriptomics to illuminate and resolve disease mechanisms. Using 101 (AD n = 66, aged controls n = 35) exceptionally well-characterized, aged subjects from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND)/Brain and Body Donation Program (BBDP), We identified a differentially abundant AD-associated CD83(+) microglial subtype, detected in 47% of AD subjects and 25% of clinically and neuropathologically unaffected controls.

Given that CD83 is a marker of mature dendritic cells, with complex, bidirectional interactions with diverse pathogens and its role in activated microglia during neuroinflammation, we hypothesized that CD83(+) AD subjects may differ from CD83(-) AD subjects on the basis of a microbial or immunological perturbation. Mass spectrometry proteomics data from frozen transverse colon (TC) samples collected from a subset of 26 subjects revealed the most differentially abundant protein in subjects with CD83(+) microglia was immunoglobulin heavy constant gamma 4 (IGHG4) which forms the constant region of the immunoglobulin IgG4 antibody heavy chain. This observation was suggestive of increased IgG4 tissue response in the TC of AD subjects with CD83(+) microglia and more broadly, consistent with a potential microbial interaction between components of the gut microbiome and the presence of CD83(+) microglia.

We report a series of significant associations linking CD83(+) microglia in the superior frontal gyrus (SFG) with IgG4 and human cytomegalovirus (HCMV) presence in the TC, anti-HCMV IgG4 antibodies in the CSF, and both IgG4 and HCMV in the vagus nerve and SFG. HCMV histochemistry is consistent with an active HCMV infection. Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+) microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV infection.

Link: https://doi.org/10.1002/alz.14401

That medical science has been able to slightly compensate for the forms of cell and tissue damage characteristic of aging, without in any way deliberately targeting these causes of age-related disease, enough to keep people alive for longer in ill health, is an impressive feat. It is very hard to keep a damaged machine working without fixing the damage, and vast efforts have been devoted to this end in the case of the human machine. We can see the results in terms of increased human life expectancy, albeit life lived in the shadow of frailty and ill health.

Realistically, this vast expenditure of resources is a misguided effort, a wasted effort, that should instead be devoted to attempts to repair the damage of aging, the underlying causes of frailty and ill health. The immediate past seems fairly dismal, but we can be optimistic about the future. At this point it seems inevitable that a great realignment of goals and priorities will take place within the medical research and development community. Enough resources are now devoted to addressing the damage of aging that we should start to see the first high profile successes in the years ahead, and those successes will light the way to the better path to the treatment of aging as a medical condition.

Today's open access paper is a quantification of the present problem; that vast expenditure has led only to gains in the time spent in poor health and diminished function at the end of of life. Therapies that can repair the damage of aging will not produce outcomes that look like this; they will instead extend healthy life span.

Global Healthspan-Lifespan Gaps Among 183 World Health Organization Member States

To quantify the healthspan-lifespan gap across the globe, investigate for sex disparities, and analyze morbidity and mortality associations., this retrospective cross-sectional study used the World Health Organization (WHO) Global Health Observatory as the global data source and acquired national-level data covering all continents. The 183 WHO member states were investigated. Statistical analysis was conducted from January to May 2024.

Changes in life expectancy and health-adjusted life expectancy, as well as the healthspan-lifespan gap were quantified for all participating member states. Gap assessment was stratified by sex. Correlations of the gap with morbidity and mortality were examined. The healthspan-lifespan gap has widened globally over the last 2 decades among 183 WHO member states, extending to 9.6 years. A sex difference was observed with women presenting a mean (standard deviation) healthspan-lifespan gap of 2.4 (0.5) years wider than men. Healthspan-lifespan gaps were positively associated with the burden of noncommunicable diseases and total morbidity, and negatively with mortality. The US presented the largest healthspan-lifespan gap, amounting to 12.4 years, underpinned by a rise in noncommunicable diseases.

This study identifies growing healthspan-lifespan gaps around the globe, threatening healthy longevity across worldwide populations. Women globally exhibited a larger healthspan-lifespan gap than men.

The neuromuscular junction is a small, complex structure linking the nervous system to muscle fibers. A body of evidence suggests that degeneration of neuromuscular junctions is important in the age-related loss of muscle mass and strength leading to sarcopenia, though it remains unclear as to which mechanisms of aging are most important in causing this degeneration. Here, researchers provide a short overview of the problem and present thinking on therapeutic options to address it by provoking regeneration of lost structures and function.

The neuromuscular junction (NMJ) is an essential synaptic structure composed of motor neurons, skeletal muscles, and glial cells that orchestrate the critical process of muscle contraction. Degenerated NMJs exhibit smaller or fragmented endplates, partial denervation, reduced numbers of synaptic vesicles, abnormal presynaptic mitochondria, and dysfunctional perisynaptic Schwann cells.

Sarcopenia, a degenerative skeletal muscle disease characterized by the loss of muscle strength, muscle mass, and overall physical activity, is closely associated with aging. Although sarcopenia shares some pathological features with muscular dystrophy, the exact mechanisms underlying muscle weakness observed in aging populations are not fully understood. Aging muscles display a range of neural changes, including alterations in peripheral nerves and NMJs, which may initiate a cascade of muscle pathologies.

Aging negatively impacts axonal transport, thereby affecting the delivery of essential synaptic and energetic cargoes, and is accompanied by alterations in neurofilaments. NMJ changes such as axonal denervation, reinnervation, and remodeling are increasingly recognized as pivotal in the onset and progression of sarcopenia. Research in both animal models and human subjects has demonstrated age-related NMJ degradation with significant changes in synaptic transmission and a shift in the types of muscle fibers present. Interestingly, caloric restriction and exercise attenuated the alteration of NMJs by aging. These studies support the hypothesis that targeting NMJ pathology can be a viable therapeutic approach, as evidenced by the improvements in muscle weakness observed in sarcopenia models following NMJ intervention.

Regarding the assessment on whether these NMJ alterations are reversible, AAV-mediated gene therapy, which enhances the expression of NMJ proteins such as MuSK, Rapsyn, or Dok7, has improved NMJ structure and muscular function in models of muscular dystrophy and sarcopenia. These therapies are not yet ready for clinical trials. Glial cells, including perisynaptic Schwann cells and satellite cells, are proposed to play a crucial role in maintaining NMJs. Thus, developing therapies targeting these neurons and glial cells is essential, because focusing only on the NMJ may not achieve the best therapeutic outcomes. Owing to their multiple actions on NMJs and glial cells, supplementation with neurotrophic factors could be a promising approach.

Link: https://doi.org/10.4103/NRR.NRR-D-23-02055

A growing body of evidence correlates an altered gut microbiome with Alzheimer's disease. The gut microbiome changes with age in ways that provoke chronic inflammation and tissue dysfunction, but it isn't clear that alterations characteristic of Alzheimer's are contributing to the condition, versus being, say, a consequence of immune dysfunction. The study noted here is a recent example of this line of research, one again showing that the state of the gut microbiome can be correlated with Alzheimer's progression.

Accumulating evidence suggested that Alzheimer's disease (AD) was associated with altered gut microbiota. A total of 64 subjects (18 mild AD, 23 severe AD and 23 healthy control) were recruited in the study. 16s rDNA sequencing was performed for the gut bacteria composition, followed by liquid chromatography electrospray ionization tandem mass spectrometry (LC/MS/MS) analysis of short-chain fatty acids (SCFAs). The global cognition, specific cognitive domains (abstraction, orientation, attention, language, etc.) and severity of cognitive impairment, were evaluated by Montreal Cognitive Assessment (MoCA) scores. We further identified characteristic bacteria and SCFAs, and receiver operating characteristic (ROC) curve was used to determine the predictive value.

Our results showed that the microbiota dysbiosis index was significantly higher in the severe and mild AD patients compared to the healthy control (HC). Linear discriminant analysis (LDA) showed that 12 families and 17 genera were identified as key microbiota among three groups. The abundance of Butyricicoccus was positively associated with abstraction, and the abundance of Lachnospiraceae_UCG-004 was positively associated with attention, language, orientation in AD patients. Moreover, the levels of isobutyric acid and isovaleric acid were both significantly negatively correlated with abstraction, and level of propanoic acid was significantly positively associated with the attention. In addition, ROC models based on the characteristic bacteria Lactobacillus, Butyricicoccus and Lachnospiraceae_UCG-004 could effectively distinguished between low and high orientation in AD patients (area under curve is 0.891), and Butyricicoccus and Agathobacter or the combination of SCFAs could distinguish abstraction in AD patients (area under curve is 0.797 and 0.839 respectively).

These findings revealed the signatures gut bacteria and metabolite SCFAs of AD patients and demonstrated the correlations between theses characteristic bacteria and SCFAs and specific cognitive domains, highlighting their potential value in early detection, monitoring, and intervention strategies for AD patients.

Link: https://doi.org/10.3389/fnagi.2024.1478557

Stroke is the blockage or rupture of a blood vessel in the brain, leading to significant damage to brain tissue and consequent loss of function. Beyond the immediate harm it is now well known that stroke leads to accelerated cognitive decline over time following the event. This is perhaps mediated by increased inflammation leading to degeneration of the thalamus, a central node in communication between brain regions. This accelerated brain-wide neurodegeneration caused by stroke is not as well understood as the mechanisms driving the immediate damage and aftermath of a stroke, however.

In today's open access paper, researchers consider an increased burden of cellular senescence in the brain resulting from a stroke as a possible contributing factor to further declining function over time. Senescent cells cease to replicate and secrete a pro-inflammatory mix of signals. In the short term the presence of senescent cells and their signaling helps to coordinate regeneration from injury, to the degree that the brain is capable of such regeneration. Over the long term, however, the sustained inflammatory signaling generated by senescent cells is disruptive to tissue structure and function. In this way, lingering senescent cells are a cause of degenerative aging, in the brain and elsewhere in the body.

Cellular senescence as a key contributor to secondary neurodegeneration in traumatic brain injury and stroke

Traumatic brain injury (TBI) and stroke pose major health challenges, impacting millions of individuals globally. Once considered solely acute events, these neurological conditions are now recognized as enduring pathological processes with long-term consequences, including an increased susceptibility to neurodegeneration. However, effective strategies to counteract their devastating consequences are still lacking.

Cellular senescence, marked by irreversible cell-cycle arrest, is emerging as a crucial factor in various neurodegenerative diseases. Recent research further reveals that cellular senescence may be a potential driver for secondary neurodegeneration following brain injury. This review offers critical insights into the role of cellular senescence in secondary neurodegeneration following TBI and stroke. A growing body of evidence underscores a strong connection between cellular senescence, inflammation, and neurodegeneration. Notably, senescent cells, a common pathological feature, are present in the brain after TBI or stroke.

Although the precise vulnerability of different cell types to senescence and their interactions remain underexplored, the targeted elimination of these cells has yielded promising preliminary results in mitigating brain injury-induced neuronal degeneration. These findings highlight a novel therapeutic target for addressing secondary neurodegeneration following brain insult. From a translational standpoint, further rigorous investigation into the safety and efficacy of senolytic agents is imperative, as it holds the potential to open new avenues for managing the long-term consequences of brain injury.

The research noted here, showing that innate immune responses are regulated by circadian rhythm, is interesting in the context of aging. Aging is characterized by both a complex disruption of circadian rhythm, alongside a growing state of constant inflammation, some of which is generated by maldaptive innnate immune reactions to the molecular damage that becomes more prevalent with age, such as mislocalized mitochondrial DNA resulting from mitochondrial dysfunction. To what degree is the chronic inflammation of aging made worse by issues with regulation of circadian rhythm? This is a question yet to be definitively answered.

New research the link between the immune system and the body's circadian rhythms often referred to as the body clock. Macrophages, immune cells that detect and respond to harmful substances, are able to trigger inflammation as a defence mechanism by assembling large complexes known as inflammasomes. Inflammasomes could be compared to 'smoke detectors' that will then alert the immune system of danger.

Activation of an inflammasome called NLRP3 was not found to be constant throughout the day but was regulated by the body's 24-hour circadian clock. This daily rhythm determines when macrophages are most efficient at detecting threats and when their energy levels peak to mount a response. The research also highlights a key role for mitochondria, the cell's energy producers, in driving these daily changes in immune activity. The study has significant implications for understanding and treating inflammatory diseases, such as arthritis, where overactive inflammasomes play a key role. Symptoms of such diseases often worsen in the morning, something this research may help explain.

Link: https://www.rcsi.com/dublin/news-and-events/news/news-article/2024/12/rcsi-research-reveals-how-the-body-clock-regulates-inflammation

Early multicellular organisms must have fairly quickly evolved mechanisms to eliminate damaged or otherwise unfit cells during development. Some of those mechanisms continue throughout life. We might expect to find that genes involved in these elimination processes affect the pace of aging, as should anything that reduces damage and increases robustness. Here researchers show that the known longevity-associated gene FOXO3 is an important player in the processes of cell competition that operate during early development, removing unfit cells to ensure that viable, functional tissues are generated. One might look at analogous work on the role of azot in fruit flies, also a longevity-associated gene involved in elimination of unfit cells.

In this study, we identified a previously unknown universal cell competition marker in vertebrates and elucidated the novel roles and mechanisms of physiological cell competition during organogenesis - the Shh-unfitness-driven cell competition. In zebrafish spinal cord and muscle development regulated by Shh morphogen gradients, unfit cells with abnormal Shh activity spontaneously appear and distort the morphogen gradient. Subsequently, unfit cells alter membrane N-cadherin levels, activate the Smad-Foxo3-ROS axis, and undergo apoptosis through communication with neighbouring normal cells. In zebrafish and mouse, Foxo3 is upregulated in cells with abnormal morphogen signalling and in various less-fit cells, which are eliminated through cell competition. Thus, Foxo3 can be a common marker of cell competition in vertebrates.

Artificially introduced cells with abnormal Myc or Axin2 activity trigger competitive communication with neighbouring normal cells in developing mouse organs (i.e. the heart, skin, and brain). These facts suggest that developing tissues can eliminate unfit cells through cell competition. However, whether unfit cells are generated and drive cell competition during physiological organogenesis is poorly understood. This is partly due to the inherent difficulty in capturing spontaneously arising abnormal cells. In our zebrafish model, which is well-suited for imaging analyses, we previously captured the emergence of unfit cells during embryogenesis. In this study, we visualised abnormal cell appearance and endogenous cell competition in vertebrate organogenesis and elucidated their regulatory mechanisms. Furthermore, we demonstrated that eliminating these unfit cells is essential for proper organogenesis. Thus, we have revealed the physiological significance of cell competition during organogenesis.

Link: https://doi.org/10.1038/s41467-024-55108-x

Over the past fifteen years, studies emerging from work on heterochronic parabiosis, in which the circulatory systems of an old mouse and a young mouse are linked, have given rise to a busy and expanding portion of the field of aging research. At first, researchers focused on possible factors in young blood that might beneficially alter the aged environment. That side of the house gave rise to Elevian's focus on GDF-15, transfusion studies in which old people were given blood fractions from young donors, and ongoing work to try to find some form of blood fraction that produces meaningful benefits. Later, researchers focused more on harmful factors in old blood, and this led to efforts focused on blood dilution as a therapeutic strategy. Hybrid approaches to adjust specific connections of signals in the blood, such as increasing oxytocin while decreasing TGF-β, have also arisen.

Still, while one can certainly find ways to obtain blood dilution or plasma transfer treatments in the clinical marketplace, none of this has made much progress towards validation in clinical trials and consequent widespread use. In the case of plasma transfusions, this may be because it just isn't that great as a mode of therapy; those trials that have taken place did not produce great results. In the case of plasma dilution, we may just need to wait for longer for larger trials to take place and more than proof of concept data to emerge. Today's open access review of the state of development in the world of old blood versus young blood is very much on the side of plasma dilution as the right way forward, which is no surprise given the identity of the authors.

The dominance of old blood, and age-related increase in protein production and noise

Over the past 20 years research in aging and longevity has suggested that aging is caused by an excess of certain systemic proteins, which while at young levels are needed for healthy tissues, become counterproductive when persistently elevated. This work narrowed the effects of blood heterochronicity to dilution of old plasma being sufficient for tissue rejuvenation. Young blood or young blood factors, while potentially efficacious, do not seem to be necessary, because dilution of the age-elevated proteins breaks the inhibitory feed-backs in cell-cell signaling pathways, consequentially restoring the levels of the age-diminished proteins in tissues and systemically.

After neutral blood exchange (NBE), there is robust rejuvenation of old muscle with less fibrosis; in liver, fibrosis is also reduced, and adiposity diminished; in brain, hippocampal neurogenesis becomes increased, neuroinflammation and SA-βGal+ senescence decline, and cognitive capacity improves. Thus, this rejuvenation is to the whole body, simultaneously affecting multiple aspects of multiple tissues, in which for many parameters the old animals become statistically the same as young. In old people, an analogous procedure of therapeutic plasma exchange (TPE), resets to a younger state the blood proteins that control homeostasis and regeneration, immune responses, brain health and function, similar to the NBE effects in mice. Moreover, TPE rejuvenated the immune system and reduced measured human biological or health age.

In TPE and NBE, the red blood cells and white blood cells are returned to the patient, and the plasma is disposed, composed mostly of saline, albumin, immunoglobulins, fibrin, and soluble signaling factors. A replacement fluid is added back, consisting of a saline with added purified albumin, and immunoglobulins may also be added. Albumin itself interacts with or binds weakly to many circulating proteins and modulates their activity and specificity. The robust rejuvenation of multiple old tissues described above, is unlikely to be established by rare proteins bound to the introduced albumin, as this is a biochemically purified protein, it isn't "young" or "old". Yet, it might be that the purified albumin, cleaned of other interacting proteins, is now free to interact with endogenous blood proteins and modify their activity, e.g., attenuating the effects of age-elevated proteins.

In this review we emphasize the potential of diluting age-elevated proteins as the way to re-calibrate the systemic proteome to its younger state without donor blood. Furthermore, we introduce modulation of proteome noise, as an important part of understanding tissue aging and as a critical mechanism for tissue rejuvenation. We discuss studies on the dominance of aged systemic milieu in promoting progeric phenotypes in young cells, in vitro, and in multiple tissues of young animals, in vivo. We support our arguments with evidence showing a significant age-related increase in protein synthesis, in noise of newly synthesized proteomes, and in the rapid induction of these aging phenotypes in young muscle by exposure to aged tissue. We summarize the significance of these findings for future research on aging and longevity.

One prevalent viewpoint in the research and development community is that a great deal of work lies ahead merely to shift the priorities of the medical community towards prevention in the matter of aging, and that the failure of the medical community to be more prevention-focused is wasting most of the potential of existing approaches that can modestly slow aging. Here we are talking about diagnostics for early stage disease, exercise, calorie restriction mimetic supplements, and the like. This is in contrast to those who would rather push forward to more impressive biotechnologies of rejuvenation, assuming that the demonstration of rejuvenation and consequent demand for such therapies will cause the medical community to reorganize its own priorities without the need for outside pressure.

The primary focus of medicine in the late 19th and early 20th centuries was the management of communicable diseases. Today's healthcare systems confront a different landscape: the prevalence of chronic diseases, which often develop over extended periods, with the most critical being the "top four": cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes. Modern medicine has adapted various strategies in response to this shift, yet there is a tendency for chronic disease management to mirror approaches historically used for infectious diseases.

This has sometimes led to interventions being applied in the later stages of chronic diseases as symptom management becomes the predominant focus rather than early prevention. As a result, the healthcare stance today is often reactive, rather than proactive - addressing illness once it has already manifested. Without the adoption of new medical and wellness paradigms, the world is set to face an unsustainable burden of chronic diseases, which is already taking a substantial social and economic toll. To mitigate the age gradient in comorbidities, a health system focused on prevention rather than intervention is imperative. A shift in mindset is therefore needed, necessitating a transition toward long-term prevention strategies that align more appropriately with the gradual progression inherent to chronic diseases.

The present narrative review aims to provide insight into the "longevity pyramid" concept, a structure that effectively describes the various levels of longevity medicine interventions. At the base of the Longevity Pyramid lies the level of prevention, emphasizing early detection strategies and advanced diagnostics or timely identification of potential health issues. Moving upwards, the next step involves lifestyle modifications, health-promoting behaviors, and proactive measures to delay the onset of age-related conditions.

Link: https://doi.org/10.3389/fragi.2024.1495029

Telomeres are repeated DNA sequences at the ends of chromosomes. A little telomere length is lost with each cell division, a part of the machinery that limits the replication of somatic cells. Cells with very short telomeres become senescent or self-destruct. Stem cells and cancer cells employ telomerase to extend telomeres, evading the replication limit. The use of telomerase more broadly in the body has attracted attention, particularly given studies in mice demonstrating improved health and extended life span. One challenge here is that the telomere dynamics of mice are fairly different from those of humans, so it is unclear as to whether the benefits will be the same. In mice, it seems that any additional risk of cancer due to damaged cells being provided with telomerase is far outweighed by improvements to immune function and cancer suppression in later life. The only practical way to determine whether this is also true in humans is to attempt telomerase gene therapies and observe the results.

While previous research has demonstrated the therapeutic efficacy of telomerase reverse transcriptase (TERT) overexpression using adeno-associated virus and cytomegalovirus vectors to combat aging, the broader implications of TERT germline gene editing on the mammalian genome, proteomic composition, phenotypes, lifespan extension, and damage repair remain largely unexplored. In this study, we elucidate the functional properties of transgenic mice carrying the Tert transgene, guided by precise gene targeting into the Rosa26 locus via embryonic stem (ES) cells under the control of the elongation factor 1α (EF1α) promoter.

The Tert knock-in (TertKI) mice harboring the EF1α-Tert gene displayed elevated telomerase activity, elongated telomeres, and extended lifespan, with no spontaneous genotoxicity or carcinogenicity. The TertKI mice showed also enhanced wound healing, characterized by significantly increased expression of Fgf7, Vegf, and collagen. Additionally, TertKI mice exhibited robust resistance to the progression of colitis induced by dextran sodium sulfate (DSS), accompanied by reduced expression of disease-deteriorating genes. These findings foreshadow the potential of TertKI as an extraordinary rejuvenation force, promising not only longevity but also rejuvenation in skin and intestinal aging.

Link: https://doi.org/10.1111/acel.14445

T cell exhaustion is a poorly defined state in which these immune cells become ineffective, less responsive to antigens. It is seen most evidently in the contexts of persistent viral infection and cancer, but exhausted T cells are also present in older people. A common theme in all of these situations is replication stress, T cells forced into greater replication in response to the circumstances they find themselves in. Replication stress also leads to greater numbers of senescent T cells, another noteworthy problem. In the context of aging replication stress occurs over time because the supply of new T cells is greatly reduced, a consequence of the atrophy of the thymus, while the body still tries to maintain the same overall population size of T cells.

At the end of the day, restoring the hematopoietic system and the thymus in order to produce a youthful supply of new T cells is probably a necessary component of any attempt to fix the issues of the aged immune system. Senescent T cells can be destroyed using senolytic drugs. But can anything be done regarding T cell exhaustion directly? In today's research materials, it is suggested that the exhausted state might be prevented or reversed by altering aspects of nutrient processing in T cells, though the best target mechanism to achieve results analogous to the genetic manipulations that postpone T cell exhaustion shown here remains to be determined.

Your immune cells are what they eat

Nutrients provide the resources for all cellular activities, but they must first be broken down into smaller molecules called metabolites. Metabolites have many uses, including promoting epigenetic regulation, a process that changes the shape of a cell's DNA to alter the accessibility of different genes. Which genes are expressed in a cell at any given time then determines the behavior and identity of the entire cell. Researchers wondered: Could this change in metabolism be responsible for the epigenetic changes that turn effector T cells into exhausted T cells? Is there a link between nutrition and exhausted T cell differentiation? One of the most important and common metabolites is acetyl-CoA, which both effector and exhausted T cells make - but with one interesting difference. Exhausted T cells tend to make their acetyl-CoA using a protein called ACLY that uses citrate, rather than using a protein called ACSS2 that uses acetate.

The preferential activity of citrate-using-ACLY in exhausted T cells and acetate-using-ACSS2 in effector T cells piqued the team's curiosity, leading them to genetically investigate the production of these metabolic proteins in both T cell subtypes. They found that ACSS2 gene expression was most highly expressed in functional T cells, but was drastically reduced in exhausted T cells in both mouse and human tissue samples. In contrast, ACLY genes were expressed similarly in both effector and exhausted T cells - with slightly greater expression in the exhausted cells. This suggested that T cells needed to express ACSS2 to maintain a functional state and that with exhaustion comes a greater reliance on ACLY.

To verify their findings, they went into the T cells and deleted ACLY and ACSS2 genes one at a time - discovering that the loss of ACLY boosted anti-tumor T cell activity, while the loss of ACSS2 did the opposite and reduced T cell efficacy. Upon closer inspection, the researchers noticed that two distinct pools of otherwise identical acetyl-CoA were piling up in different locations in the nucleus - where the cell's DNA is stored - based on whether it was derived from acetate via ACSS2 or from citrate via ACLY. Each nutrient-specific pile was then linked to unique histone acetyltransferases, which are proteins that reshape DNA and influence which genes are expressed to change cellular behavior and identity. This novel link between nutrition and cell identity offers a new explanation for exhausted T cell identity and in turn offers a multitude of new targets for future therapeutics that could keep T cells turned "on" longer.

Nutrient-driven histone code determines exhausted CD8+ T cell fates

Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.

Researchers here report that the amount of visceral fat carried by an individual correlates with the burden of Alzheimer's-related pathological protein aggregation in the brains of people in middle age prior to the development of any neurodegenerative condition. It is at this point well known that visceral fat specifically is metabolically active, promoting chronic inflammation and in at least some aspects literally accelerating aging. The study population was largely obese, so this study tells us little regarding whether this relationship extends into much lesser degrees of being overweight. Past data has suggested that any amount of excess visceral fat tissue produces dysfunction, scaling up with the size of the excess, however.

Researchers focused on the link between modifiable lifestyle-related factors, such as obesity, body fat distribution and metabolic aspects, and Alzheimer's disease pathology. A total of 80 cognitively normal midlife individuals (average age: 49.4 years) were included in the study. Approximately 57.5% of participants were obese, and the average body mass index (BMI) of the participants was 32.31. The participants underwent brain positron emission tomography (PET), body MRI, and metabolic assessment (glucose and insulin measurements), as well as a lipid (cholesterol) panel. MRI scans of the abdomen were performed to measure the volume of the subcutaneous fat (the fat under skin) and visceral fat (deep hidden fat surrounding the organs). Thigh muscle scans were used to measure volume of muscle and fat. Alzheimer's disease pathology was measured using PET scans with tracers that bind to amyloid plaques and tau tangles that accumulate in the brains of people with Alzheimer's disease.

Our study showed that higher visceral fat was associated with higher PET levels of the two hallmark pathologic proteins of Alzheimer's disease - amyloid and tau. To our knowledge, our study is the only one to demonstrate these findings at midlife where our participants are decades out from developing the earliest symptoms of the dementia that results from Alzheimer's disease." The study also showed that higher insulin resistance and lower HDL were associated with high amyloid in the brain. The effects of visceral fat on amyloid pathology were partially reduced in people with higher HDL.

Link: https://www.eurekalert.org/news-releases/1066063

The comparative biology of aging, using species with radically different life courses as a way to identify important mechanisms in the progression of aging, is an interesting area of research. Why do naked mole rats live nine times longer than mice? Why do whales live so much longer than humans? What are the largest determinants of species life span? And so forth. It remains to be seen as to whether potential therapies can be made in a reasonable span of time and effort by mining the biochemistry of long-lived species, but the real goal of the scientific community has always been understanding, not intervention. Here, researchers comment on the relevance of the hallmarks of aging to research into aging in different species, particularly those in which aging progresses very differently than is the case in mice and humans.

Since the first description of a set of characteristics of aging as so-called hallmarks or pillars in 2013/2014, these characteristics have served as guideposts for the research in aging biology. They have been examined in a range of contexts, across tissues, in response to disease conditions or environmental factors, and served as a benchmark for various anti-aging interventions. While the hallmarks of aging were intended to capture generalizable characteristics of aging, they are derived mostly from studies of rodents and humans. Comparative studies of aging including species from across the animal tree of life have great promise to reveal new insights into the mechanistic foundations of aging, as there is a great diversity in lifespan and age-associated physiological changes. However, it is unclear how well the defined hallmarks of aging apply across diverse species.

Here, we review each of the twelve hallmarks of aging defined in 2023 with respect to the availability of data from diverse species. We evaluate the current methods used to assess these hallmarks for their potential to be adapted for comparative studies. Not unexpectedly, we find that the data supporting the described hallmarks of aging are restricted mostly to humans and a few model systems and that no data are available for many animal clades. Similarly, not all hallmarks can be easily assessed in diverse species. However, for at least half of the hallmarks, there are methods available today that can be employed to fill this gap in knowledge, suggesting that these studies can be prioritized while methods are developed for comparative study of the remaining hallmarks.

Link: https://doi.org/10.1016/j.arr.2024.102616

Chronic, unresolved inflammation is a feature of aging. Many of the forms of molecular damage associated with aging provoke an inflammatory response from cells, including the signaling generated by senescent cells and mitochondrial dysfunction leading to mislocalized mitochondrial DNA. Short-term inflammation is necessary for regeneration and defense against pathogens, but inflammation becomes harmful when sustained for the long term. It is disruptive to tissue structure and function, and accelerates the onset and progression of age-related conditions.

In today's open access paper, researchers note one interesting example of the way in which chronic inflammation provokes maladaptive responses. GDF-15 is an immune regulator expressed in response to inflammation, and which can dampen excessive inflammation. This is normal and beneficial in the short term. When inflammation becomes lasting, however, the constant presence of GFD-15 becomes harmful to cell function. An important goal in the treatment of aging is to find ways to suppress unwanted, chronic inflammation without suppressing necessary, transient inflammation - so far a challenge, as it appears they depend on the same pathways and systems of regulation.

GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process

The GDF15 protein, a member of the TGF-β superfamily, is a stress-induced multifunctional protein with many of its functions associated with the regulation of the immune system. GDF15 signaling provides a defence against the excessive inflammation induced by diverse stresses and tissue injuries. Given that the aging process is associated with a low-grade inflammatory state, called inflammaging, it is not surprising that the expression of GDF15 gradually increases with aging.

In fact, the GDF15 protein is a core factor secreted by senescent cells, a state called senescence-associated secretory phenotype (SASP). Many age-related stresses, e.g., mitochondrial and endoplasmic reticulum stresses as well as inflammatory, metabolic, and oxidative stresses, induce the expression of GDF15. Although GDF15 signaling is an effective anti-inflammatory modulator, there is robust evidence that it is a pro-aging factor promoting the aging process.

GDF15 signaling is not only an anti-inflammatory modulator but it is also a potent immunosuppressive enhancer in chronic inflammatory states. The GDF15 protein can stimulate immune responses either non-specifically via receptors of the TGF-β superfamily or specifically through the GFRAL/HPA/glucocorticoid pathway. GDF15 signaling stimulates the immunosuppressive network activating the functions of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages and triggering inhibitory immune checkpoint signaling in senescent cells. Immunosuppressive responses not only suppress chronic inflammatory processes but they evoke many detrimental effects in aged tissues, such as cellular senescence, fibrosis, and tissue atrophy/sarcopenia. It seems that the survival functions of GDF15 go awry in persistent inflammation thus promoting the aging process and age-related diseases.

Abnormal localized excesses of lipids in tissues, particularly cholesterol, is a feature of aging. It is disruptive to cell function, such as via accumulation of intracellular free cholesterol when the cell's ability to safely store that cholesterol in the form of lipid droplets is overwhelmed. Cholesterol is essentially toxic in its unmodified form. Researchers here note another potential problem resulting from a local excess of lipids, which is the formation of lipid droplets in the cell nucleus rather than in the cytoplasm as is usually the case. Some work remains in order to determine exactly how this introduction of lipid droplets into the cell nucleus might cause harm, but we might hypothesize that it results in altered gene expression at the very least.

A prominent hallmark of ageing is the accumulation of dysfunctional cellular components, which disrupts tissue homeostasis, contributing to age-related pathologies. This feature includes the abnormal deposition of lipids in non-adipose tissues, known as ectopic fat, which is highly associated with metabolic syndrome and various age-related conditions, including cardiovascular disease, type 2 diabetes, and neurodegenerative disorders, among others.

Lipid droplets (LDs) are primarily recognized as cytoplasmic organelles and have a pivotal role in energy storage, lipid metabolism, and cellular homeostasis. Traditionally, LDs presence has been confined to the cytoplasm, where they serve as reservoirs of neutral lipids, supporting energy balance and membrane biosynthesis. For a long time, the association between LDs and the nucleus was under-investigated. However, recent studies have unveiled an unexpected aspect of lipid biology demonstrating that LDs can also exist within the nucleus, forming nuclear lipid droplets (nLDs).

Interventions known to extend lifespan, such as caloric restriction and reduced insulin signaling, significantly reduce both the rate of accumulation and the size of nLDs. The triglyceride lipase ATGL-1, which localizes to the nuclear envelope, plays a critical role in limiting nLD buildup and maintaining nuclear lipid balance, especially in long-lived mutant nematode worms. These findings establish excessive nuclear lipid deposition as a key hallmark of aging, with profound implications for nuclear processes such as chromatin organization, DNA repair, and gene regulation. In addition, ATGL-1 emerges as a promising therapeutic target for preserving nuclear health, extending organismal healthspan, and combating age-related disorders driven by lipid dysregulation.

Link: https://doi.org/10.18632/aging.206175

Interfering in growth hormone signaling has been shown to extend life considerably in mice. Unfortunately, the analogous human populations with Laron syndrome resulting from loss of function mutations in the growth hormone receptor gene do not live notably longer than the rest of us. Thus the most important mechanisms linking growth hormone metabolism to longevity must produce smaller effects as species life span increases. Here, researchers suggest that growth hormone shortens life because it produces greater chronic inflammation in old age. Inflammation is known to drive age-related disease and mortality, which adds to the puzzle of why it is that the effects of growth hormone metabolism on life span are so small in humans versus mice.

While inflammation is a crucial response in injury repair and tissue regeneration, chronic inflammation is a prevalent feature in various chronic, non-communicable diseases such as obesity, diabetes, and cancer and in cardiovascular and neurodegenerative diseases. Long-term inflammation considerably affects disease prevalence, quality of life, and longevity. Our research indicates that the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is a pivotal regulator of inflammation in some tissues, including the hypothalamus, which is a key player in systemic metabolism regulation.

Moreover, the GH/IGF-1 axis is strongly linked to longevity, as GH- or GH receptor-deficient mice live approximately twice as long as wild-type animals and exhibit protection against aging-induced inflammation. Conversely, GH excess leads to increased neuroinflammation and reduced longevity. Our review studies the associations between the GH/IGF-1 axis, inflammation, and aging, with a particular focus on evidence suggesting that GH receptor signaling directly induces hypothalamic inflammation. This finding underscores the significant impact of changes in the GH axis on metabolism and on the predisposition to chronic, non-communicable diseases.

Link: https://doi.org/10.7570/jomes24032

What can we learn about aging from mutations that alter longevity? Rather than examining single biomarkers of aging to compare the effects of mutations, in today's open access paper the authors instead report on a comparison of the shift in all gene expression. The researchers measured the whole transcriptome across the life span of nematode worms, comparing worms with long-lived and short-lived gene variants, commenting on the results. The data supports the view that favorable gene variants literally slow aging: the same transcriptomic trajectory is observed in all worms, but stretched out over a longer period of time in the longer-lived individuals.

Is it actually helpful to examine the biochemistry underlying natural variations in life span? If the goal is to chip away at the massive undertaking of developing an complete understanding of how aging progresses at the detail level, then most likely yes. All data is useful. From the point of view of building meaningful therapies to treat aging, then most likely no. Researchers have a good map of important mechanisms in aging. The best way forward to is target those mechanisms, producing results that have no analogy in natural variations in aging. Looking at differences in how humans age will not inform us as to how good it is to entirely remove senescent cells, or entirely replace damaged mitochondria with fresh mitochondria - only actually building the therapies will answer the question of how good they are, how many years of healthy life might be added via their use.

Similarities and differences in the gene expression signatures of physiological age versus future lifespan

In contrast to chronological age, which is measured simply by the ticking of a clock, defining physiological age is a much more complex task. To deal with this complexity, we use biomarkers of aging as proxy measurements to determine how physiologically young or old an individual is. However, this requires that we understand what "young" and "old" look like for a given biomarker. Using the average biomarker levels over chronological time to build a trajectory from a youthful to aged state, we can then place an individual on this trajectory and compare whether it is physiologically older or younger than its actual chronological age would suggest. This works because biomarkers of aging vary over time in each individual at a faster or slower rate depending on each individual's rate of aging. Here, we expanded this logic by building a trajectory of aging using the whole transcriptome and comparing the transcriptomes of subpopulations predicted to be long- or short-lived by the expression of four different biomarkers of aging. In doing so, we identified a class of genes which separate along this trajectory of physiological age and another which separates orthogonally to it.

That biomarkers of aging correlate with a common physiological age state is also consistent with results suggesting that various interventions which affect population longevity, such as long-lived mutants, "rescale" lifespan and healthspan relative to the wildtype population. Researchers have shown, for instance, showed that several interventions which lengthen or shorten lifespan rescale the hazard curve of the wildtype population, and more recently it was shown that several long-lived mutants have proportionally-scaled healthspan relative to wildtype controls. Other researchers performed a meta-analysis of several RNA-seq studies of long-lived mutants and similarly found that the transcriptomic age of these populations was scaled primarily along a single axis in a manner correlated with lifespan extension. Our results suggest a similar phenomenon occurring among untreated individuals of the same population, whereby long- and short-lived individuals undergo, in large part, temporally-scaled versions of the same transcriptional trajectory. While our interpretations are limited by sorting and sequencing populations only at one time-point, future work could confirm whether differently-fated individuals continue to follow this common trajectory by sequencing at later timepoints post-sorting.

While the finding that a difference in predicted lifespan largely resembles a difference in apparent age may be intuitive, the consistency of this signature across each biomarker tested is notable. One could imagine an alternate model in which each biomarker correlates with a specific age-related etiology, resulting in several different ways to be healthy or unhealthy - instead, we find the transcriptomic differences underlying high versus low expression of each biomarker tested to be remarkably similar. This result lends further support to previous findings that certain transcriptional biomarkers of aging, even when expressed in different tissues, appear to correlate with some common underlying state related to future lifespan.

Platelet factor 4 (PF4) has been the subject of interesting research in recent years. Researchers have found that delivery of PF4 can dampen neuroinflammation in old animals and restore cognitive function. PF4 doesn't cross the blood-brain barrier to enter the brain, and the effect appears mediated by changes in the immune system. Here, researchers show that PF4 is involved in the regulation of hematopoietic stem cell function, and delivery of PF4 thus rejuvenates the generation of immune cells in aged animals. This seems promising for other strategies that also improve hematopoietic stem cell function, such as use of CASIN and derived compounds under development at Mogling Bio.

Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs.

Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.

Link: https://doi.org/10.1101/2024.11.25.625252

Researchers here provide evidence for circulating GDF-15 to increase with age and correlate with aging clock assessments of biological age. In the long term, more biomarkers can only help to improve our understanding of aging and the ability to measure aging sufficiently well to guide research and development to the most effective therapies. In the short term, the proliferation of interesting biomarkers is outpacing the exploration of their value. Considerable work and expense lies between where we stand now and a good understanding of how and why aging clocks work, and perhaps more importantly, how specific underlying processes of aging map to specific components of the clock measurements.

Growth differentiation factor 15 (GDF-15) has emerged as a significant biomarker of aging, linked to various physiological and pathological processes. This study investigates circulating GDF-15 levels in a cohort of healthy individuals from the Balearic Islands, exploring its associations with biological age markers, including multiple DNA methylation (DNAm) clocks, physical performance, and other age-related biomarkers. Seventy-two participants were assessed for general health, body composition, and physical function, with GDF-15 levels quantified using ELISA.

Our results indicate that GDF-15 levels significantly increase with age, particularly in individuals over 60. Strong positive correlations were observed between GDF-15 levels and DNAm GrimAge, DNAm PhenoAge, Hannum, and Zhang clocks, suggesting that GDF-15 could serve as a proxy for epigenetic aging. Additionally, GDF-15 levels were linked to markers of impaired glycemic control, systemic inflammation, and physical decline, including decreased lung function and grip strength, especially in men. These findings highlight the use of GDF-15 as a biomarker for aging and age-related functional decline. Given that GDF-15 is easier to measure than DNA methylation, it has the potential to be more readily implemented in clinical settings for broader health assessment and management.

Link: https://doi.org/10.1007/s10522-024-10165-z

Progressive heart failure is at presently largely irreversible, though there is suggestive evidence for senolytic therapies to clear senescent cells from cardiac tissue to be capable of reversing at least some of its aspects, such as ventricular hypertrophy, the enlargement and weakening of heart muscle. Heart failure can arise from a combination of several underlying causes leading to some combination of structural alteration of the heart or loss of function independently of altered structure, and so there are many different classifications of heart failure based on specific outcomes.

One of the possible approaches to the treatment of age-related disease is to compensate for a specific failure, rather than trying to address its root causes. Sometimes this can be worth the effort. For example, present treatments that control blood pressure in no way address the root causes of age-related hypertension, but produce a fair-sized reduction in mortality because the raised blood pressure of hypertension is very damaging in and of itself.

In today's open access paper, researchers use a gene therapy approach to compensate for a maladaptive reduction in the expression of a gene involved in regulating heart tissue structure and function. This change in expression that occurs in the environment of heart failure is not a root cause of heart failure, just as hypertension is nowhere near the root causes of aging. It is sufficiently problematic in and of itself, however, that a compensatory therapy may be able to produce enough benefit to be worth the effort.

New Gene Therapy Reverses Heart Failure in Large Animal Model

A new gene therapy can reverse the effects of heart failure and restore heart function in a large animal model. The researchers were focused on restoring a critical heart protein called cardiac bridging integrator 1 (cBIN1). They knew that the level of cBIN1 was lower in heart failure patients - and that, the lower it was, the greater the risk of severe disease. To try and increase cBIN1 levels in cases of heart failure, the scientists turned to a harmless virus commonly used in gene therapy to deliver an extra copy of the cBIN1 gene to heart cells. They injected the virus into the bloodstream of pigs with heart failure. The virus moved through the bloodstream into the heart, where it delivered the cBIN1 gene into heart cells.

For this heart failure model, heart failure generally leads to death within a few months. But all four pigs that received the gene therapy in their heart cells survived for six months, the endpoint of the study. Importantly, the treatment didn't just prevent heart failure from worsening. Some key measures of heart function actually improved, suggesting the damaged heart was repairing itself. Previous attempted therapies for heart failure have shown improvements to heart function on the order of 5-10%. cBIN1 gene therapy improved function by 30%.

Cardiac bridging integrator 1 gene therapy rescues chronic non-ischemic heart failure in minipigs

Heart failure (HF) is a major cause of mortality and morbidity worldwide, yet with limited therapeutic options. Cardiac bridging integrator 1 (cBIN1), a cardiomyocyte transverse-tubule (t-tubule) scaffolding protein which organizes the calcium handling machinery, is transcriptionally reduced in HF and can be recovered for functional rescue in mice. Here we report that in human patients with HF with reduced ejection fraction (HFrEF), left ventricular cBIN1 levels linearly correlate with organ-level ventricular remodeling such as diastolic diameter.

Using a minipig model of right ventricular tachypacing-induced non-ischemic dilated cardiomyopathy and chronic HFrEF, we identified that a single intravenous low dose (6 × 10^11 vg/kg) of adeno associated virus 9 (AAV9)-packaged cBIN1 improves ventricular remodeling and performance, reduces pulmonary and systemic fluid retention, and increases survival in HFrEF minipigs. In cardiomyocytes, AAV9-cBIN1 restores t-tubule organization and ultrastructure in failing cardiomyocytes. In conclusion, AAV9-based cBIN1 gene therapy rescues non-ischemic HFrEF with reduced mortality in minipigs.

There is the suspicion that the aging of the immune system into incapacity, inflammation, and malfunction includes a meaningful degree of low-grade autoimmunity, pathological and disruptive attacks by the immune system on the body's own structures, but not evidently rising to the level of a well-defined autoimmune condition. This is perhaps less well researched that it might be, given the many other far more evident ways in which an aged immune system becomes harmful. That the immune system does fall apart in a very complex set of ways is a strong argument for blunt approaches that involve destruction and then replacement of existing immune populations. Where this can be accomplished in a limited way in animal models, cell type by cell type, such as for microglia or for B cells, it appears to be a beneficial strategy.

Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood.

Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance.

Furthermore, the cumulative exposure to antigens and cellular debris during obesity and aging perpetuates pro-inflammatory pathways, linking immunosenescence with other aging hallmarks, such as proteostasis loss and mitochondrial dysfunction. This review examines the mechanisms driving autoantibody generation during obesity and aging and discusses key putative antigenic targets across these conditions. We also explore the therapeutic potential of emerging approaches, such as CAR-T/CAAR-T therapies, vaccines, and bispecific T cell engagers (BiTEs), to tackle autoimmune-related conditions in aging and obesity.

Link: https://doi.org/10.1186/s12979-024-00489-2

One of the classes of potential regenerative medicine for hair regrowth is the transplantation of cells that will provoke skin into forming new hair follicles. Dermal papilla cells are one population that might be considered in this context. Here, researchers discuss the challenge of cellular senescence in cell therapy, as it applies to dermal papilla cells and the goal of hair growth. Cultured cells will become senescent at some pace; senescent cells when transplanted may be anything from useless to actively harmful, and variation in the proportion of cultured cells that become senescent under a given protocol may be a major issue for present stem cell therapies, accounting for a wide variation in outcomes from patient to patient and clinic to clinic.

Senescent cells secrete a senescence-associated secretory phenotype (SASP), which can induce senescence in neighboring cells. Human dermal papilla (DP) cells lose their original hair inductive properties when expanded in vitro, and rapidly accumulate senescent cells in culture. Protein and RNA-seq analysis revealed an accumulation of DP-specific SASP factors including IL-6, IL-8, MCP-1, and TIMP-2. We found that combined senolytic treatment of dasatinib and quercetin depleted senescent cells, and reversed SASP accumulation and SASP-mediated repressive interactions in human DP culture, resulting in an increased Wnt-active cell population.

In hair reconstitution assays, senolytic-depleted DP cells exhibited restored hair inductive properties by regenerating de novo hair follicles (HFs) compared to untreated DP cells. In 3D skin constructs, senolytic-depleted DP cells enhanced inductive potential and hair lineage specific differentiation of keratinocytes. These data revealed that senolytic treatment of cultured human DP cells markedly increased their inductive potency in HF regeneration, providing a new rationale for clinical applications of senolytic treatment in combination with cell-based therapies.

Link: https://doi.org/10.1111/acel.14353

Every cell contains hundreds of mitochondria, vital to cell function. These are the evolved descendants of ancient symbiotic bacteria, and contain a small remnant genome, the mitochondrial DNA. Most of the original mitochondrial DNA has migrated to the cell nucleus to be incorporated into the nuclear DNA, but a few genes remain. Unfortunately mitochondrial DNA is less well protected and more prone to damage than nuclear DNA, and loss of function can lead to malfunctioning mitochondria that harm the cell. This is thought to be an important contribution to age-related loss of mitochondrial function, one of the contributing causes of degenerative aging.

Scientists at the SENS Research Foundation, now the Longevity Research Institute since the merger with Lifespan.io, have long been working on allotopic expression of mitochondrial genes, meaning to place a copy of these genes into the nuclear DNA, suitably altered such that the proteins can find their way back to the mitochondria. A backup source of necessary proteins would render mitochondrial DNA damage irrelevant to cell function. This is a challenging project, and given the limited funds available to date, has been achieved for only a few of the thirteen remaining mitochondrial genes. But progress has been made, and today's research materials describe an important step forward. Researchers have created a genetically engineered mouse lineage in which allotopic expression of ATP8 clearly works to provide the ATP8 protein needed in mitochondria.

Nuclear Expression of a Mitochondrial Gene in Mice

Previously, the same team had achieved promising results in vitro, but finding a suitable animal model proved difficult: mitochondrial DNA (mtDNA) genes are so essential that mutations in them usually render mice non-viable. However, a particular strand of mice exists that harbors a relatively benign mutation in ATP8, a gene encoding a subunit of the ATP synthase complex, which causes only a mildly pathologic phenotype. Alongside those mutants, wild-type mice were used as controls.

The team synthesized a nuclear-compatible version of ATP8 and inserted it into the ROSA26 locus, a well-characterized "safe harbor" site in the mouse genome. This locus is widely used in genetic engineering because it allows stable organism-wide expression of inserted genes without interfering with other essential genomic functions. The researchers had to overcome significant technical challenges to achieve nuclear expression of a gene that is normally expressed in mitochondria (allotopic expression) and to make the protein transferrable to mitochondria. Eventually, their efforts paid off: allotopic ATP8 was able to compete with mitochondrial ATP8 even in wild-type mice and outperformed the mutant ATP8. The allotopic gene was expressed in all the tissues that the researchers tested, and the protein successfully integrated into the mitochondrial machinery.

Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo

Replicative errors, inefficient repair, and proximity to sites of reactive oxygen species production make mitochondrial DNA (mtDNA) susceptible to damage with time. We explore in vivo allotopic expression (re-engineering mitochondrial genes and expressing them from the nucleus) as an approach to rescue defects arising from mtDNA mutations. We used a mouse strain C57BL/6J(mtFVB) with a natural polymorphism in the mitochondrial ATP8 gene that encodes a protein subunit of the ATP synthase. We generated a transgenic mouse with an epitope-tagged recoded mitochondrial-targeted ATP8 gene expressed from the ROSA26 locus in the nucleus and used the C57BL/6J(mtFVB) strain to verify successful incorporation.

The allotopically expressed ATP8 protein in transgenic mice was constitutively expressed across all tested tissues, successfully transported into the mitochondria, and incorporated into ATP synthase. The ATP synthase with transgene had similar activity to non-transgenic control, suggesting successful integration and function. Exogenous ATP8 protein had no negative impact on measured mitochondrial function, metabolism, or behavior. Successful allotopic expression of a mitochondrially encoded protein in vivo in a mammal is a step toward utilizing allotopic expression as a gene therapy in humans to repair physiological consequences of mtDNA defects that may accumulate in congenital mitochondrial diseases or with age.

Atherosclerosis is the formation of fatty plaques in blood vessel walls that grow to obstruct blood flow. The degree to which the plaque is dangers isn't just a matter of size, it is also the composition. A softer, more lipid-laden plaque is more prone to rupture, leading to a heart attack or stroke when a downstream vessel is blocked. Plaques with more fibrotic or calcified structures are less dangerous in this sense. Here, researchers provide evidence suggesting that metabolic disease makes cardiovascular disease worse by altering the structure of plaques in favor of less stability, and thus greater risk of rupture.

Type 2 diabetes is associated with cardiovascular disease, possibly due to impaired vascular fibrous repair. Yet, the mechanisms are elusive. Here, we investigate alterations in the fibrous repair processes in type 2 diabetes atherosclerotic plaque extracellular matrix by combining multi-omics from the human Carotid Plaque Imaging Project cohort and functional studies. Plaques from type 2 diabetes patients have less collagen.

Interestingly, lower levels of transforming growth factor-ß distinguish type 2 diabetes plaques and, in these patients, lower levels of fibrous repair markers are associated with cardiovascular events. Transforming growth factor-ß2 originates mostly from contractile vascular smooth muscle cells that interact with synthetic vascular smooth muscle cells in the cap, leading to collagen formation and vascular smooth muscle cell differentiation. This is regulated by free transforming growth factor-ß2 which is affected by hyperglycemia. Our findings underscore the importance of transforming growth factor-ß2-driven fibrous repair in type 2 diabetes as an area for future therapeutic strategies.

Link: https://doi.org/10.1038/s41467-024-50753-8

It is becoming clear that the gut microbiome plays an important role in health and aging, perhaps as influential as exercise and diet. The composition of the gut microbiome shifts in unfavorable ways with advancing age, promoting chronic inflammation and reducing the generation of beneficial metabolites. Concretely demonstrating specific mechanistic connections to specific diseases, and definitive proof for specific bacterial species to be the problem, is still a work in progress, however.

The gut microbiota (GM) plays a critical role in regulating human physiology, with dysbiosis linked to various diseases, including heart failure (HF). HF is a complex syndrome with a significant global health impact, as its incidence doubles with each decade of life, and its prevalence peaks in individuals over 80 years. A bidirectional interaction exists between GM and HF, where alterations in gut health can worsen the disease's progression.

The "gut hypothesis of HF" suggests that HF-induced changes, such as reduced intestinal perfusion and altered gut motility, negatively impact GM composition, leading to increased intestinal permeability, the release of GM-derived metabolites into the bloodstream, and systemic inflammation. This process creates a vicious cycle that further deteriorates heart function. GM-derived metabolites, including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids (BAs), can influence gene expression through epigenetic mechanisms, such as DNA methylation and histone modifications. These epigenetic changes may play a crucial role in mediating the effects of dysbiotic gut microbial metabolites, linking them to altered cardiac health and contributing to the progression of HF. This process is particularly relevant in older individuals, as the aging process itself has been associated with both dysbiosis and cumulative epigenetic alterations, intensifying the interplay between GM, epigenetic changes, and HF, and further increasing the risk of HF in the elderly.

Despite the growing body of evidence, the complex interplay between GM, epigenetic modifications, and HF remains poorly understood. The dynamic nature of epigenetics and GM, shaped by various factors such as age, diet, and lifestyle, presents significant challenges in elucidating the precise mechanisms underlying this complex relationship.

Link: https://doi.org/10.1186/s13148-024-01786-9

Cells become senescent on reaching the Hayflick limit to replication, or in response to stress and damage. A senescent cell ceases replication and generates pro-inflammatory signals. In the short term this is usually helpful, attracting the immune system to assist in issues such as regeneration following injury or cells with potentially cancerous DNA damage. When sustained for the long term, however, the signaling of senescent cells is harmful. Following the realization that senescent cells accumulate with age and that their inflammatory signaling contributes to degenerative aging, assessments of the burden of senescence used a few consensus markers, such as β-galactosidase and p16 expression.

As time went on, it became clear that senescence is more varied a state than first appreciated, differing by cell type, cause of senescent, time spent senescent, and no doubt other factors. While the initial consensus markers for senescence continue to be used, it is now generally accepted that these markers might not be capturing the picture originally thought to be the case. Today's open access paper is an example of the sort of research into the burden of senescence and its relationship to aging presently taking place in this new context. Researchers provide evidence for p16 expression in tissues to be a marker of resident or infiltrating immune cell senescence, not tissue cell senescence. Their interpretation is that this puts more of an emphasis on the aging of the immune system as a driver of systemic aging throughout the body.

Distribution and impact of p16INK4A+ senescent cells in elderly tissues: a focus on senescent immune cell and epithelial dysfunction

Cellular senescence, as a major player among hallmarks of aging, has been reported as being able to accumulate senescent cells in various tissues during aging process. Cellular senescence can cause a halt in the proliferation of functional cells, ultimately resulting in organic dysfunction and induce sterile chronic inflammation through the secretion of senescence-associated secretory phenotypes (SASPs), which are known as 'inflammaging'. Previous studies applying senolytics or selective cytotoxicity in p16INK4A-overexpressed cells in aged mice have been supported the notion that removal of senescent cells can be alleviate not all but many aging-related phenotypes and lead to the prolongation of life span. Although the final phenotypes resulting from the removal of senescent cells have been confirmed in multiple previous studies, information about the specific cell types that accumulate as senescent cells and their removal remains scarce.

Organs are composed of two major components: the parenchyma and the stroma. Parenchymal cells, responsible for executing organ-specific functions, often exhibit rapid proliferation and turnover rates. Examples include gastrointestinal tract epithelial cells and skin keratinocytes. Conversely, the tissue stroma can be further categorized into cells providing structural support and immune cells. Cells providing structural support (hereinafter referred as structural stromal cells), such as fibroblasts and smooth muscle cells produce extracellular matrix (ECM) components and maintain tissue structures. The remaining stromal cells are immune cells, which may be resident, such as liver Kupffer cells and skin Langerhans cells, or infiltrating, such as bone marrow-derived cells and lymphocytes. These cells are involved in protecting organs from foreign invaders, chronic inflammation, and tissue regeneration related to the aging process.

Our research indicates that fully senescent p16INK4A+ cells are rarely identified in the parenchyma of organic tissues and in the stromal cells crucial for structural maintenance, such as fibroblasts and smooth muscle cells. Instead, p16INK4A+ cells are more commonly found in immune cells, whether they reside in the organ or are infiltrating. Notably, p16INK4A+ senescent T cells have been observed to induce apoptosis and inflammation in colonic epithelial cells through Granzyme A / protease-activated receptor signaling, compromising the integrity of the epithelial lining. This study showed that the senescence of immune cells could affect the phenotypical change of the parenchymal cells in the elderly and suggests that targeting immunosenescence might be a strategy to control functional decline in this population.

As knowledge grows regarding the age-related accumulation of senescent cells in tissues throughout the body, researchers are establishing a role for senescent cells in many conditions already known to be characterized by the presence of chronic, unresolved inflammatory signaling. When cells become senescent, they cease to replicate and instead devote their energies to secreting inflammatory signals. As the immune system slows down in its clearance of senescent cells with age, their numbers grow and their signaling becomes constant. This is disruptive to tissue structure and function, altering the behavior of surrounding cells in harmful ways and accelerating the onset and progression of age-related conditions.

Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation.

We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.

Link: https://doi.org/10.1038/s41413-024-00375-z

Every cell contains hundreds of mitochondria, descended from ancient symbiotic bacteria. Mitochondrial dynamics are like those of bacteria, in that they constantly divide, fuse together, and swap component parts. Mitochondria are vital to cell function, their primary purpose being to manufacture the chemical energy store molecule adenosine triphosphate (ATP) that powers cell processes. The balance between fission and fusion of mitochondria is known to alter with age, and imbalance generates inflammation and is associated with loss of mitochondrial function. In tissues that require a great deal of energy, such as muscle, mitochondrial dysfunction is likely important in age-related declines.

Ageing substantially impairs skeletal muscle metabolic and physical function. Skeletal muscle mitochondrial health is also impaired with ageing, but the role of skeletal muscle mitochondrial fragmentation in age-related functional decline remains imprecisely characterized. Here, using a cross-sectional study design, we performed a detailed comparison of skeletal muscle mitochondrial characteristics in relation to in vivo markers of exercise capacity between young and middle-aged individuals.

Despite similar overall oxidative phosphorylation capacity (young: 99 ± 17 vs. middle-aged: 99 ± 27 pmol O2/s/mg) and intermyofibrillar mitochondrial density (young: 5.86 ± 0.57 vs. middle-aged: 5.68 ± 1.48%), older participants displayed a more fragmented intermyofibrillar mitochondrial network (young: 1.15 ± 0.17 vs. middle-aged: 1.55 ± 0.15 A.U.), a lower mitochondrial cristae density (young: 23.40 ± 7.12 vs. middle-aged: 13.55 ± 4.10%) and a reduced subsarcolemmal mitochondrial density (young: 22.39 ± 6.50 vs. middle-aged: 13.92 ± 4.95%). Linear regression analysis showed that 87% of the variance associated with maximal oxygen uptake could be explained by skeletal muscle mitochondrial fragmentation and cristae density alone, whereas subsarcolemmal mitochondrial density was positively associated with the capacity for oxygen extraction during exercise. Intramuscular lipid accumulation was positively associated with mitochondrial fragmentation and negatively associated with cristae density.

Collectively, our work highlights the critical role of skeletal muscle mitochondria in age-associated declines in physical function.

Link: https://doi.org/10.1111/acel.14386

The composition of the gut microbiome is influential on health, perhaps to a similar degree as diet and exercise. Unfortunately this composition, the relative numbers of different microbial species, changes with age in ways that promote chronic inflammation and reduce the generation of beneficial metabolites necessary to tissue function. Researchers have shown that it is possible to rejuvenate an aged gut microbiome, producing a lasting reset to a more youthful configuration with a single intervention. Approaches include flagellin immunization to guide the immune system into destroying harmful microbiomes, and fecal microbiota transplantation from a young donor. While in principle one could achieve similar outcomes using tailored high dose probiotics, at this time available forms of probiotic therapy produce only short-term alterations to the gut microbiome.

In today's open access paper, researchers discuss fecal microbiota transplantation as an approach to treat aging as a medical condition. Adjusting the aged gut microbiome to a youthful configuration is a form of rejuvenation therapy, repairing a type of damage in order to remove the downstream consequences of this damage. Fecal microbiota transplantation from young donors to old recipients works well in animal studies, improving health and extending life. There is some use in human medicine, but the inability to completely control outcomes resulting from fecal microbiota transplantation suggests that the field will probably ultimately favor efforts to develop forms of analogous high dose probiotic therapy.

Fecal microbiota transplantation, a tool to transfer healthy longevity

The gut microbiome has emerged as an important contributor influencing host aging. The gut microbiome comprises an extensive population of microorganisms, predominantly different phyla of bacteria and, to a lesser degree, also viruses, protozoa, and fungi. Among other physiological roles, the gut microbiome supports the digestion and absorption of food, generates vitamins and nutrients, exerts a positive effect on lipid metabolism, maintains intestinal integrity, and metabolizes fibers into bioactive short-chain fatty acids (SCFAs), which have immunomodulatory, anti-inflammatory, and anti-cancer capabilities.

Microbe-derived SCFAs also play an important role in gut-brain intercommunication, with gut microbiota imbalances promoting brain alterations and neurodegeneration. Since these microorganisms play significant roles in immunological, metabolic, and physiological functions of host health, increasing evidence demonstrate that shifts in host-microbiome balance have a clinical impact in the pathogenesis of several metabolic disorders, age-related diseases, and other major conditions. In this scenario, personalized gut microbiome remodeling is evolving as a promising new era of therapeutic interventions against age-associated chronic diseases.

Interestingly, exceptional longevity of centenarians and semi-supercentenarians, who are less susceptible to inflammation, infectious diseases, and many other aging-associated dysfunctions, is also associated to the maintenance of a higher gut microbiome diversity of core microbiota species and a higher prevalence of health-associated gut-microorganisms compared to younger individuals. For example, Akkermansia muciniphila is present at higher abundance in centenarians. Conversely, progeria patients and progeroid mouse models exhibit a significant loss of this particular strain.

Gut microbiome from centenarians also presents high capacity for central metabolism, including glycolysis, amino acid metabolism and fermentation to SCFAs. Likewise, microbiome-related gene pathways related to bile acid metabolism - including secondary bile acid with antimicrobial activity - are suggestive of reduced levels of infections among centenarians. Furthermore, administration of A. muciniphila by oral gavage is sufficient to enhance healthspan and to promote lifespan in progeroid mice models, partially by the restoration of correct secondary bile acid metabolism and other metabolites (arabinose, ribose, inosine) in the intestinal tract of these animals.

Restoring a healthy gut microbiome via Fecal Microbiota Transplantation (FMT) is receiving extensive consideration to therapeutically transfer healthy longevity. Herein, we comprehensively review the benefits of gut microbial rejuvenation - via FMT - to promote healthy aging, with few studies documenting life length properties. Throughout this review, we examine the impact of gut microbiome on host aging, and we address the potential therapeutic advantages of modulating gut microbiome via FMT. Preclinical and clinical research, along with current gaps, including safety and risks associated to FMT, are thoroughly examined. By addressing these objectives, this manuscript enhances our understanding of FMT-based interventions aimed at promoting healthier longevity.

The brain stores the data of the mind. Restoration of the aged brain will be the most challenging portion of the development of a comprehensive toolkit of rejuvenation therapies, if only because we (largely) cannot resort to outright replacement of component parts, as is the case for the rest of the body. So it is interesting to keep an eye on research into the degree to which the brain can be induced to adapt to damage, to shift and repurpose neural networks to restore lost function. Here, researchers find that stimulating the hypothalamas can enable repurposing of the remaining connections in a damaged but not severed spinal cord.

A spinal cord injury (SCI) disrupts the neuronal projections from the brain to the region of the spinal cord that produces walking, leading to various degrees of paralysis. Here, we aimed to identify brain regions that steer the recovery of walking after incomplete SCI and that could be targeted to augment this recovery. To uncover these regions, we constructed a space-time brain-wide atlas of transcriptionally active and spinal cord-projecting neurons underlying the recovery of walking after incomplete SCI. Unexpectedly, interrogation of this atlas nominated the lateral hypothalamus (LH). We demonstrate that glutamatergic neurons located in the LH (LHVglut2) contribute to the recovery of walking after incomplete SCI and that augmenting their activity improves walking.

We translated this discovery into a deep brain stimulation therapy of the LH (DBSLH) that immediately augmented walking in mice and rats with SCI and durably increased recovery through the reorganization of residual lumbar-terminating projections from brainstem neurons. A pilot clinical study showed that DBSLH immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBSLH was turned off. There were no serious adverse events related to DBSLH. These results highlight the potential of targeting specific brain regions to maximize the engagement of spinal cord-projecting neurons in the recovery of neurological functions after SCI.

Link: https://doi.org/10.1038/s41591-024-03306-x

Chronic, unresolved inflammation is a feature of aging. It arises from a varied set of causes, including a growing presence of senescent cells, excess visceral fat tissue in those who are overweight, and mislocalization of mitochondrial DNA that triggers responses evolved to detect bacteria. The end result is disruptive inflammatory signaling that alters cell behavior for the worse, harming tissue structure and function, and accelerating the onset and progression of all of the common age-related conditions. Here, researchers propose that the problem is a more a case of too little anti-inflammatory signaling than too much inflammatory signaling. Can the maladaptive reactions to age-related damage be effectively dampened without also suppressing necessary immune signaling though? Immune suppression remains an unfortunate side-effect of the anti-inflammatory strategies developed to date.

Acute inflammation is elicited by lipid and protein mediators in defense of the host following sterile or pathogen-driven injury. A common refrain is that chronic inflammation is a result of incomplete resolution of acute inflammation and behind the etiology of all chronic diseases, including cancer. However, mediators that participate in inflammation are also essential in homeostasis and developmental biology but without eliciting the clinical symptoms of inflammation. This non-inflammatory physiological activity of the so called 'inflammatory' mediators, apparently under the functional balance with anti-inflammatory mediators, is defined as unalamation. Inflammation in the absence of injury is a result of perturbance in unalamation due to a decrease in the anti-inflammatory mediators rather than an increase in the inflammatory mediators and leads to chronic inflammation.

This concept on the etiology of chronic inflammation suggests that treatment of chronic diseases is better achieved by stimulating the endogenous anti-inflammatory mediators instead of inhibiting the 'inflammatory' mediator biosynthesis with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Furthermore, both 'inflammatory' and anti-inflammatory mediators are present at higher concentrations in the tumor microenvironment compared to normal tissue environments. Since cancer is a proliferative disorder rather than a degenerative disease, it is proposed that heightened unalamation, rather than chronic inflammation, drives tumor growth. This understanding helps explain the inefficacy of NSAIDs as anticancer agents. Finally, inhibition of anti-inflammatory mediator biosynthesis in tumor tissues could imbalance unalamation toward local acute inflammation triggering an immune response to restore homeostasis and away from tumor growth.

Link: https://doi.org/10.3389/fimmu.2024.1460302

A stroke is caused by rupture or blockage of a blood vessel in the brain. Rupture of blood vessels in the brain can occur due to the combination of (a) mechanisms that weaken blood vessel walls and (b) raised blood pressure, both of which are commonplace in older individuals. Blockage arises due to the breakup of an unstable atherosclerotic plaque, sending debris downstream. This is by far the most common cause of stroke, and one of the leading forms of human mortality. Since plaque rupture can also causes heart attack and fatal embolism elsewhere in the body, we should perhaps all pay more attention to atherosclerosis and the development of means to reverse its progression.

In an environment in which atherosclerosis cannot be reversed reliably or to any great degree, as is presently the case, a great deal of attention goes instead to coping with the aftermath of blocked blood vessels. Researchers try to find ways to repair some of the damage done to survivors, or as in today's open access paper, better understand how it is that a stroke occurring in a small part of the brain can produce lasting dysfunction throughout the brain. The answer appears to be that stroke provokes degeneration of the thalamus, a part of the brain thought to act as a form of relay, central to the flow of information between many different areas of the brain. Why this degeneration occurs following a stroke is an open question: one might suspect the usual culprit of excessive inflammatory signaling, disruptive to function in so very many ways.

Study uncovers promising new target for stroke treatment

Strokes leave behind an area where brain cells have died, called a lesion. However, this cannot explain the widespread consequences of stroke, limiting scientists' and clinicians' ability to treat them. A new study reveals that degeneration of the thalamus - an area of the brain distinct from the stroke lesion - is a significant contributor to post-stroke symptoms. "This is both good and bad news. The bad news is the impact to the brain caused by stroke is not limited to the lesion seen on a brain scan. The good news is the area that shows abnormal electrical activity outside the lesion might be treatable with innovative new therapies."

Damage to brain tissue near the stroke lesion was not the primary cause of abnormal brain electrical activity. Instead, these abnormalities were related to the thalamus, a structure located deep in the brain's centre that acts like a hub connecting numerous brain areas and activities. More than the lesion alone, the amount of degeneration in the thalamus predicted the amount of abnormal brain electrical activity measured using magnetoencephalography (MEG), and the individual's language and cognitive deficits.

Secondary thalamic dysfunction underlies abnormal large-scale neural dynamics in chronic stroke

Stroke causes pronounced and widespread slowing of neural activity. Despite decades of work exploring these abnormal neural dynamics and their associated functional impairments, their causes remain largely unclear. To close this gap in understanding, we applied a neurophysiological corticothalamic circuit model to simulate magnetoencephalography (MEG) power spectra recorded from chronic stroke patients. Comparing model-estimated physiological parameters to those of controls, patients demonstrated significantly lower intrathalamic inhibition in the lesioned hemisphere, despite the absence of direct damage to the thalamus itself. We hypothesized that this disinhibition could instead be related to secondary degeneration of the thalamus, for which growing evidence exists in the literature.

Further analyses confirmed that spectral slowing correlated significantly with overall secondary degeneration of the ipsilesional thalamus, encompassing decreased thalamic volume, altered tissue microstructure, and decreased blood flow. Crucially, this relationship was mediated by model-estimated thalamic disinhibition, suggesting a causal link between secondary thalamic degeneration and abnormal brain dynamics via thalamic disinhibition. Finally, thalamic degeneration was correlated significantly with poorer cognitive and language outcomes, but not lesion volume, reinforcing that thalamus damage may account for additional individual variability in poststroke disability. Overall, our findings indicate that the frequently observed poststroke slowing reflects a disruption of corticothalamic circuit dynamics due to secondary thalamic dysfunction, and highlights the thalamus as an important target for understanding and potentially treating poststroke brain dysfunction.

Loss of muscle mass is a universal issue in aging, leading a degree that leads to physical frailty. Beyond this, muscle is also metabolically active, such as via the production of myokines, and loss of muscle mass is harmful to the rest of the body via these and other signaling mechanisms that remain to be fully explored. Researchers here note the transcription factor MYC as a target for the development of enhancement therapies producing muscle growth. Overexpression of the Yamanaka factor MYC is something to be careful with, given its role in cancer and reprogramming. The classes of therapy presently explored by the reprogramming community, intended to produce repeated short-term expression of Yamanaka factors, seem needed here. Many of the same challenges and caveats will likely apply, such as those regarding targeting to specific cell types and the different cell populations in a tissue requiring different timing and levels of expression for optimal effect.

Several seminal and recent studies suggest that the transcription factor c-Myc (referred to as Myc or MYC for mouse and human genes, respectively) is a key component of skeletal muscle hypertrophic adaptation to loading in animals. Our work using human skeletal muscle biopsies after a bout of resistance exercise (RE), as well as meta-analytical information that combines numerous human muscle gene expression datasets during the recovery period after exercise, indicates that MYC is highly responsive to hypertrophic loading. MYC protein accumulates in human muscle following a bout of RE as well as in response to chronic training. Its expression may also differentiate between low and high hypertrophic responders.

The current investigation details the global gene expression response to a bout of RE after 30 minutes, 3-, 8-, and 24-hours using RNA-sequencing (RNA-seq) in skeletal muscle biopsy samples from healthy untrained humans. Molecular and computational analyses identified MYC as an influential transcription factor controlling the exercise transcriptome throughout the time course of recovery after a bout of RE. Muscle-specific Myc overexpression data from the plantaris and soleus of mice reinforced the human exercise data.

We employed a genetically modified mouse model to induce MYC in a pulsatile fashion specifically in skeletal muscle over 4 weeks to determine if MYC is sufficient for hypertrophy. Our genetically driven pulsatile approach avoids potential negative effects of chronically overexpressing a hypertrophic regulator and more closely mimics the transient molecular response of exercise in skeletal muscle. Pulsed MYC induction resulted in a larger absolute mass (+12.5%) and normalized mass (+20.7%) of the soleus muscle relative to controls. This magnitude of soleus muscle growth is similar to what is observed after 4 weeks of progressive weighted wheel running.

Link: https://doi.org/10.1038/s44319-024-00299-z

3-D tissue printing has been a work in progress for going on twenty years at this point. The biggest challenges are (a) that it remains slow and expensive, and (b) producing sufficient microvasculature to support the printed tissue. Inroads are being made on both of these issues, such as the work noted here, but progress is incremental. It remains to be seen as to when the much anticipated 3-D printed organs made from a patient's own cells and ready for transplantation will emerge - at this point, the creation of functional tissues much larger than a few millimeters is not a practical proposition for most use cases.

Bioprinting allows researchers to build 3D structures from living cells and other biomaterials. Living cells are encapsulated in a substrate like a hydrogel to make a bioink, which is then printed in layers using a specialized printer. These cells grow and proliferate, eventually maturing into 3D tissue over the course of several weeks. However, it's difficult to achieve the same cell density as what's found in the human body with this standard approach. That cell density is essential for developing tissue that's both functional and can be used in a clinical setting. Spheroids, on the other hand, offer a promising alternative for tissue bioprinting because they have a cell density similar to human tissue.

While 3D printing spheroids offers a viable solution to producing the necessary density, researchers have been limited by the lack of scalable techniques. Existing bioprinting methods often damage the delicate cellular structures during the printing process, killing some of the cells. Other technologies are cumbersome and don't offer precise control of the movement and placement of the spheroids needed to create replicas of human tissue. Or the processes are slow.

To address these issues, researchers developed a new technique called High-throughput Integrated Tissue Fabrication System for Bioprinting (HITS-Bio). HITS-Bio uses a digitally controlled nozzle array, an arrangement of multiple nozzles that moves in three dimensions and allows researchers to manipulate several spheroids at the same time. The team organized the nozzles in a four-by-four array, which can pick up 16 spheroids simultaneously and place them on a bioink substrate quickly and precisely. The nozzle array can also pick up spheroids in customized patterns, which can then be repeated to create the architecture found in complex tissue. To test the platform, the team set out to fabricate cartilage tissue. They created a one-cubic centimeter structure, containing approximately 600 spheroids made of cells capable of forming cartilage. The process took less than 40 minutes, a highly efficient rate that surpasses the capacity of existing bioprinting technologies.

Link: https://www.psu.edu/news/research/story/new-bioprinting-technique-creates-functional-tissue-10x-faster

The lack of consensus on aging is well known within the field of aging research and the longevity industry - good luck in trying to get any two research groups to agree on any specific declaration regarding the causes and progression of aging! That there are few points of consensus on aging is perhaps less well appreciated outside the field. Yet this seems inevitable for any very complex area of study. Researchers have produced an immense and growing body of data, but connecting these pieces together into a coherent map of cause and consequence remains a work in process, and will likely continue for decades yet.

We live in an era in which one can measure gene expression throughout the body and show how it changes with age, but we struggle to turn this data into an understanding of cause and effect. It seems likely that the fastest path forward to building that map of cause and consequence in aging is the direct one: produce therapies that repair and reverse specific age-related changes, and observe the results. Therapies targeting causes will do well. Therapies targeting consequences, not so well.

Disagreement on foundational principles of biological aging

While the field of aging has seen major advances, e.g. extending the lifespan of all major model organisms through genetic, pharmacological, and dietary interventions, there is no convincing evidence of the exact causes and mechanisms of aging, and no effective treatment proved to slow down or reverse the aging process in humans. Even the definitions of aging in the published literature are widely different and not easily reconcilable. Understanding how scientists who study aging view this process could help bridge this gap and accelerate progress in the field. With this in mind, we conducted a survey on the most basic features of aging with the participants of the 2022 Systems Aging Gordon Research Conference.

Notwithstanding the broad disagreement revealed by this survey, the answers nevertheless show elements of shared thinking, with most respondents aligning on certain principles and features of aging, as well as on what aging is not. First, there is a general consensus that aging - however it is defined - exists, has identifiable causes and effects, and can be studied experimentally. These views may be compared with the idea that aging as a unified phenomenon does not exist. Second, most scientists agree that aging is inherently deleterious, involving the accumulation of harmful changes, damage, degeneration, and loss of function. Third, aging is widely regarded as a process, with most respondents explicitly referring to it as such. It has certain characteristics, manifestations, a rate of progression, and outcomes - most notably, leading to death. Fourth, aging may be targeted, modulated, regulated, accelerated, and decelerated. Fifth, the aging process has a definable starting time or period within an organism's life. Sixth, rejuvenation is acknowledged as a real phenomenon (in that it can be defined), implying that aging can theoretically be reversed, not just slowed - though this does not imply feasibility. Seventh, a clear distinction exists between chronological age and biological age.

It is clear from the responses that aging remains an unsolved problem in biology. Scientists disagree over whether it is a universal property of life, whether it is pathological or normal, whether it is subject to natural selection, and whether it has a particular purpose. Interestingly, almost all respondents answered all questions, suggesting that they have a clear opinion on the subject. Yet, their responses were widely different. So, while most scientists think they understand the nature of aging, apparently their understanding differs. It is also clear from the responses that scientists working in the aging field have mixed opinions on the most fundamental definitions and mechanisms in the biology of aging. In the whole survey, no question received more than 50% of common responses. When discussing the biology of aging with colleagues, we often assume we are talking about the same process, but clearly, we are not. Some of us consider aging to be a loss of function, some accumulation of damage, some an increase in mortality rate, etc. While these and other features often go hand in hand, they are fundamentally different and therefore may be targeted differently.

Despite the importance of foundational issues in the biology of aging and the clear lack of consensus on these issues, little effort is being placed into directly addressing them. Moreover, there is a clear disconnect between what respondents think are the most important unanswered questions in the field and the ongoing research in the field. It is not necessarily because scientists are biased toward what they do. It is more likely that this is because these are very difficult questions to answer or to even design proper experiments and statistical treatments to address them. A part of the problem is also that most terms in the field are ill-defined, causing confusion due to different emphasis in different contexts and due to the variable use of the terms, including the term aging. For example, aging can be described as normal, normative, successful, healthy, pathological, premature, accelerated, etc., but what exactly all these terms mean is rarely discussed.

More generally, it is clear from the survey that in the most commonly referenced sequence of events - damage causes functional decline causes age-related disease causes mortality - different events are viewed as aging by different respondents. This may present a critical impediment to developing the most effective strategies to target aging. Depending on what one considers the essence of aging, experimental strategies may be disconnected from aging and directed either to the causes of aging and other upstream events or to the consequences and associations of aging.

The incidence and progression of many specific diseases and declines of aging correlate with one another. Insofar as aging as a whole emerges from a shared set of underlying forms of cell and tissue damage, one would expect this to be the case. Still, some consequences of aging feed into other consequences, making them worse. The challenge lies in teasing out the differences between these two classes of mechanism from human epidemiological data. The research noted here looks at muscle loss and dementia. Aging leads to chronic inflammation and mitochondrial dysfunction, both of which independently negatively impact the ability to maintain muscle mass and the function of the brain. Equally, loss of muscle mass implies loss of myokine signaling and lower levels of activity, both of which could speed neurodegeneration. Which is more important? That is a hard question to answer given only human study data to work with.

As people grow older, they begin to lose skeletal muscle mass. Because age-related skeletal muscle loss is often seen in older adults with Alzheimer's disease (AD) dementia, this study aimed to examine whether temporalis muscle loss (a measure of skeletal muscle loss) is associated with an increased risk of AD dementia in older adults. The temporalis muscle is located in the head and is used for moving the lower jaw. Studies have shown that temporalis muscle thickness and area can be an indicator of muscle loss throughout the body.

Researchers used baseline brain MRI exams from the Alzheimer's Disease Neuroimaging Initiative cohort to quantify skeletal muscle loss in 621 participants without dementia (mean age 77 years). The researchers manually segmented the bilateral temporalis muscle on MRI images and calculated the sum cross-sectional area (CSA) of these muscles. Participants were categorized into two distinct groups: large CSA (131 participants) and small CSA (488 participants). Outcomes included subsequent AD dementia incidence, change in cognitive and functional scores, and brain volume changes between the groups. Median follow-up was 5.8 years.

Based on their analysis, a smaller temporalis CSA was associated with a higher incidence risk of AD dementia. Furthermore, a smaller temporalis CSA was associated with a greater decrease in memory composite score, functional activity questionnaire score and structural brain volumes over the follow-up period. "We found that older adults with smaller skeletal muscles are about 60% more likely to develop dementia when adjusted for other known risk factors."

Link: https://www.eurekalert.org/news-releases/1066226

There are a great many theories of aging. This is in part because it is easier to theorize than to develop concrete proof linking root causes to downstream effects in the biochemistry of aging. Cells are enormously complex systems, and tissues made up of cells are even more complex. Vast mountains of data relating to aging have been produced, layer upon layer of data, from changes in transcription to changes in cell behavior to changes in organ function to visible manifestations of age-related disease. Everything in the body interacts with everything else. Determining what is cause and what is effect is very challenging. So there is plenty of room for hypothesis, and most of those hypotheses will turn out to be wrong in some way.

Despite recent progress in understanding the biology of aging, the field remains largely fragmented due to the lack of a central organizing hypothesis that could provide a framework for investigating how fundamental upstream biological processes regulate the timing of age onset and progression. While numerous theories on aging have been proposed and efforts have been made to create unifying theories that incorporate various aging-related phenotypes and mechanisms, none of them constitutes a fully comprehensive doctrine for understanding the aging process in its entirety. There are ongoing debates on whether the aging process is programmed or stochastic. The programmed theory views aging as a continuation of the orderly genetic program that guides early growth and development, while the stochastic hypothesis considers aging to be a result of the accumulation of random errors. However, neither theory can independently explain the complexity of aging.

The Pro-aging metabolic reprogramming (PAMRP) theory proposed here posits that aging is determined by degenerative changes in cellular metabolism that occur over time. Specifically, aging has both a programmed and stochastic nature, with its onset requiring both the preexistence of pro-aging substrate (PAS) buildup through degenerative metabolic alterations and the emergence of pro-aging triggers (PAT) induced by stochastic events. The convergence of PAS and PAT initiates metabolic reprogramming (MRP), predisposing the body to cellular reprogramming (CRP) and genetic reprogramming (GRP) and ultimately leading to a self-perpetuating progression of the aging process governed by the genetic program.

The human body's metabolism is genetically preprogrammed but can be epigenetically reprogrammed for good or bad outcomes depending on the specific context. As organisms age, there are significant alterations in metabolic pathways within cells, including shifts in energy production, nutrient utilization, and waste-management processes. Initially, this MRP serves as an adaptive mechanism to cope with varying stress conditions. However, these adaptations come at the cost of accumulating molecular damage, including oxidative stress-induced DNA mutations, protein aggregation, and mitochondrial dysfunction, which are hallmarks of and substrates for aging. Over time, this MRP becomes maladaptive, contributing to a self-perpetuating cycle that maintains the altered metabolic state and exacerbates degenerative changes in gene expression and regulatory mechanisms. Ultimately, once a threshold level is reached, MRP triggers the genetic aging program, impacting cellular function, tissue homeostasis, and overall organismal health.

Link: https://doi.org/10.1016/j.eng.2024.09.010

Healthy, cognitively normal older people are called healthy and cognitively normal because their degeneration is not yet severe enough to be called disease. Whether or not one has an age-related disease isn't as binary as the regulators would like it to be, however. Loss of function is a progression, growing over time, and disease status is just a line in the sand drawn somewhere along that path. The average healthy older person is impaired to some measurable degree in comparison to their younger self, and that impairment derives from the accumulation of damage and dysfunction in cells and tissues throughout the body.

As an illustration of this point, today's open access paper provides data on cognitively normal older people. The researchers show that measurable dysfunction in the blood-brain barrier correlates with loss of memory function. When the blood-brain barrier leaks, it allows unwanted molecules and cells into the brain, where they can provoke chronic inflammation. This is harmful to brain function. This damage and cognitive decline definitively exist, and yet these people are considered healthy and cognitively normal in the present system of medicine. One might hope that this way of looking at things will change dramatically as the first rejuvenation therapies emerge into widespread use.

Cross-sectional and longitudinal relationships among blood-brain barrier disruption, Alzheimer's disease biomarkers, and cognition in cognitively normal older adults

The deposition of amyloid-beta (Aβ) plaques and neurofibrillary tau tangles has been the focus of Alzheimer's disease (AD) research. Both Aβ and tau show relationships with cognition that are particularly malignant when the two proteins occur together. Recent research suggests that neurovascular factors including blood-brain barrier disruption (BBBd) may be an early biomarker of human cognitive dysfunction and possibly an underlying mechanism of age-related cognitive decline or AD. BBBd is implicated in both aging and AD, with BBBd observed in regions susceptible to neurodegeneration and important for cognitive function. Studies have also identified that BBBd is associated with cognitive deficits, independent of AD pathology and atrophy. However, there is also evidence that pathological protein aggregation may be related to BBBd. These findings highlight the need to further consider relationships between BBBd and pathological protein aggregation, and to examine in greater depth the likely complex processes that drive age related cognitive decline and perhaps AD.

The current model of AD is a sequential cascade: first Aβ deposition, then tau pathology, neurodegeneration, and eventually dementia. Some research points to BBBd as a potential early biomarker and underlying mechanism of cognitive decline. The BBB is essential for brain homeostasis, and its disruption has been implicated in AD pathogenesis. BBBd may facilitate the entry of neurotoxic substances into the brain and impair Aβ clearance, contributing to plaque accumulation. This raises critical questions about how BBBd fits into the current AD model and whether it acts as an early or parallel process that exacerbates neurodegeneration and cognitive decline.

We used dynamic contrast-enhanced MRI (DCE-MRI) and positron emission tomography (PET) imaging in cognitively normal older adults to explore how BBBd correlates with brain atrophy and cognitive function, and whether these relationships are influenced by Aβ or tau. We found that greater BBBd in the hippocampus (HC) and an averaged BBBd-susceptible region of interest (ROI) were linked to worse episodic memory, with interactions between BBBd and atrophy influencing this relationship, independent of Aβ and tau. However, there were no significant relationships between BBBd and non-memory cognitive performance. In participants with longitudinal AD biomarker and cognitive data acquired prior to DCE-MRI, faster longitudinal entorhinal cortex (EC) tau accumulation and episodic memory decline were associated with greater HC BBBd, independent of global Aβ changes and regional atrophy.

Taken together, both our cross-sectional and longitudinal findings suggest that BBBd may play a role in the early stages of cognitive decline, independent of the key biomarker of AD, Aβ. The significant relationships among HC BBBd, atrophy, and memory performance point to the potential of BBBd as an early indicator of cognitive decline.

Researchers here produce a map of transcription in muscle regeneration in mice of various ages, separated by cell type and time following muscle injury. The results are interesting, and show that the participation of the immune system in regeneration becomes dysregulated in older animals. Muscle stem cell function also declines, as might be expected. Restoring the aged immune system and aged stem cell populations are both sizable challenges facing those intent on developing the first rejuvenation therapies, but clearly very important.

The immune, stromal, and myogenic cells found in skeletal muscle contribute to muscle maintenance and regeneration by regulating muscle stem cell (MuSC) quiescence, proliferation, and differentiation. It has been shown that an imbalance in immune cell populations during injury response can disrupt proper muscle repair. To investigate this, we compared the change in cell-type abundances over our regeneration time course between young, old, and geriatric muscles. As expected, neutrophils are one of the first immune cell types to peak in abundance. We also observe monocyte and macrophage populations that express pro-inflammatory markers like Ccr2 and patrolling markers like Ctsa responding soon after injury (days 1-2) when we expect the muscle environment to be enriched with pro-inflammatory cytokines. Monocytes and macrophages that express pro-inflammatory markers clear cellular debris and promote myogenic cell proliferation. There should be a shift to monocytes and macrophages that express anti-inflammatory marker C1qa at days 4-7 following injury.

We do broadly observe a shift from monocytes and macrophages that express pro-inflammatory markers to anti-inflammatory markers, but there are significant differences by age. This difference in monocyte and macrophage dynamics could explain the age-related decline in muscle repair because if macrophages do not clear cellular debris or promote myogenic cell proliferation and differentiation, the muscle remains inflamed and there are repeated cycles of necrosis and regeneration. The damaged myofibers are then replaced with adipose tissue, fibrotic tissue or bone, instead of new myofibers. In addition to age-specific differences in the dynamics of the monocyte and macrophage populations, we observe age-specific differences in the T cell dynamics. There is miscoordination of the T cell response, which in turn could impact the ability of aged muscle to repair itself.

One factor that has been shown to contribute to the reduced functionality of MuSCs in aged tissues is the establishment of senescent MuSCs. Our data is supportive of a senescent-like MuSC and progenitor population that is more abundant in the geriatric mice, suggesting stalled stem cell self-renewal in mouse muscle aging. Together, these observations point to a transitory senescent-like cell population that is abundant at the self-renewing MuSC stage during regeneration across all ages of mice. This population of senescent-like MuSCs increases within the injury zone and in older mice, suggesting that a stalled stem cell self-renewal state underlies the regenerative dysfunction in mouse aging.

Link: https://doi.org/10.1038/s43587-024-00756-3

Epidemiological data consistently shows that professional athletes live longer than the rest of the population. Here, researchers compare top tier professional athletes with other athletes, and find that those who succeed in competition appear to show slowed epigenetic aging. If we believe that epigenetic clocks are a decent measure of biological age, and that winning is a decent proxy for degree of physical fitness, then this seems a reasonable outcome, given what is known of the dose-response curve for exercise effects on mortality.

The lifestyle patterns of top athletes are highly disciplined, featuring strict exercise regimens, nutrition plans, and mental preparation, often beginning at a young age. Recently, it was shown that physically active individuals exhibit slowed epigenetic aging and better age-related outcomes. Here, we investigate whether the extreme intensity of physical activity of Olympic champions still has a beneficial effect on epigenetic aging. To test this hypothesis, we examined the epigenetic aging of 59 Hungarian Olympic champions and of the 332 control subjects, 205 were master rowers.

We observed that Olympic champions exhibit slower epigenetic aging, applying seven state-of-the-art epigenetic aging clocks. Additionally, male champions who won any medal within the last 10 years showed slower epigenetic aging compared to other male champions, while female champions exhibited the opposite trend. We also found that wrestlers had higher age acceleration compared to gymnasts, fencers, and water polo players. We identified the top 20 genes that showed the most remarkable difference in promoter methylation between Olympic champions and non-champions. The hypo-methylated genes are involved in synaptic health, glycosylation, metal ion membrane transfer, and force generation. Most of the hyper-methylated genes were associated with cancer promotion. The data suggest that rigorous and long-term exercise from adolescence to adulthood has beneficial effects on epigenetic aging.

Link: https://doi.org/10.1007/s11357-024-01440-5

Any sufficiently complex set of biological measures can be used to produce an aging clock: researchers establish a database of the measures in people of different ages and apply machine learning techniques to produce an algorithm that maps an individual's measured data to a predicted age. That doesn't mean it is a good clock, however. One then has to validate the algorithm against data from other populations and see how well it does in predicting disease, mortality, and other outcomes of interest. Much of the development of clocks is focused on epigenetic data, but distinctly from that line of research, the scientific community is also exploring clocks built on clinical measures, such as blood chemistry, physical performance, and so forth.

Of the clinical measure clocks, PhenoAge is probably the most widely used, both inside and outside the scientific community. Its popularity may derive from ease of use, as it employs only 9 parameters that can be obtained from a complete blood count and a couple of other blood chemistry measures. If proposing a new, more complicated clinical measure clock, one would have to demonstrate that it improves on PhenoAge to a meaningful degree. In today's open access paper, researchers fail to achieve this goal. Their Physiological Aging Index uses 17 parameters and only marginally improves on PhenoAge. It is perhaps interesting to consider why it is that clocks with fewer parameters can still perform well, even in diverse populations.

Estimation of physiological aging based on routine clinical biomarkers: a prospective cohort study in elderly Chinese and the UK Biobank

It has been known that for individuals of the same chronological age (CA), those with obesity, long-term nicotine exposure, or lower socioeconomic status are more likely to experience adverse health outcomes and increased mortality risk. Thus it is important to measure one's biological age (BA) to identify individuals with accelerated aging and to develop precision prevention and intervention strategies for major chronic diseases in an aging population. To date, researchers have developed a variety of predictors of BA using biomarkers such as telomere length, DNA methylation, gene expression, metabolites, or clinical biomarkers. While BA indices based on genomic data, such as DNA methylation, are accurate in predicting CA, clinical biomarkers are generally more affordable, interpretable, and modifiable. However, existing clinical biomarker predictors were primarily based on supervised models with CA as the training label and thus may have limited value to predict disease risks independent of CA.

In this study, we propose a physiological aging index (PAI) based on 36 clinical biomarkers from the Dongfeng-Tongji (DFTJ) cohort of elderly Chinese. In the DFTJ training set (n = 12,769), we identified 25 biomarkers with significant nonlinear associations with mortality, of which 11 showed insignificant linear associations. By incorporating nonlinear effects, we selected CA and 17 clinical biomarkers to calculate PAI. PAI aims to measure an individual's BA based on routine clinical biomarkers in the blood. We use restricted cubic spline (RCS) Cox models to capture potential U-shaped relationships between clinical biomarkers and mortality, and determine the optimal value of each biomarker for subsequent piece-wise linear transformation. We define PAI as a linear combination of CA and the transformed biomarkers, as well as ΔPAI as the residual of PAI after regressing on CA. Thus, ΔPAI measures physiological aging acceleration independent of CA.

In the DFTJ testing set (n = 15,904), PAI predicts mortality with a concordance index (C-index) of 0.816, better than CA (C-index = 0.771) and PhenoAge (0.799). ΔPAI was predictive of incident cardiovascular disease and its subtypes, independent of traditional risk factors. In the external validation set of the UK Biobank (n = 296,931), PAI achieved a C-index of 0.749 to predict mortality, remaining better than CA (0.706) and PhenoAge (0.743). In both DFTJ and UK Biobank, PAI calibrated better than PhenoAge when comparing the predicted and observed survival probabilities. Furthermore, ΔPAI outperformed any single biomarker to predict incident risks of eight age-related chronic diseases.

The nucleolus resides in the cell nucleus, and is where ribosomes are assembled. It is known that the nucleolus grows larger with age, and in cells that have undergone a sufficient number of divisions to approach the Hayflick limit. Here, researchers provide evidence for harms caused by enlargement of the nucleolus in aging, using a novel approach that prevents the nucleous from enlarging without manipulating other aspects of cell function. It remains to be seen as to how one might progress from this engineering exercise to interventions that target the nucleolus, and whether other approaches to rejuvenation might prevent this from being needed in the first place. Enlargement of the nucleolus may be a downstream consequence of molecular damage that is easier to fix than the nucleolus itself.

The nucleus holds the cell's chromosomes and the nucleolus where the ribosomal DNA (rDNA) is housed. The nucleolus isolates the rDNA which encodes the RNA portions of the ribosomes, the protein-building machinery. The rDNA is one of the most fragile parts of the genome, due to its repetitive nature making it more difficult to maintain and fix if damaged. If damage in the rDNA is not accurately repaired, it can lead to chromosomal rearrangements and cell death. In organisms from yeast to worms to humans, nucleoli expand during aging. On the flip side, anti-aging strategies like calorie restriction result in smaller nucleoli.

Researchers suspected that keeping nucleoli small could delay aging. To test this idea, they engineered an artificial way to secure rDNA to the membrane surrounding the nucleus of yeast cells so they could control when it was anchored and when it was not. The researchers discovered that tethering the nucleolus was enough to keep it compact, and small nucleoli delayed aging to about the same extent as calorie restriction.

Interestingly, nucleoli did not expand at the same rate during the entire lifespan as cells aged. They remained small for most of the yeast's life, but at a nucleolar size threshold, the nucleoli suddenly began to grow quickly and expand to a much larger size. Cells only survived for an average of about five more cell divisions after hitting this threshold. Passing the threshold appears to serve as a mortality timer, ticking down the final moments of a cell's life. During aging, DNA accumulates damage, some of which can be devastating to the cell. In tests, researchers found that large nucleoli had less stable rDNA than smaller ones. Also, when the structure is large, proteins and other factors that are usually excluded from the nucleolus are no longer kept out. It's as if the nucleolus becomes leaky, letting in molecules that can wreak havoc on the fragile rDNA.

Link: https://news.weill.cornell.edu/news/2024/11/fighting-aging-by-staying-compact

Researchers here report that more recently developed second generation epigenetic clocks do in fact demonstrate correlations between accelerated epigenetic age and risk of Alzheimer's disease. Clocks are developed from databases of the status of DNA methylation sites on the genome in people of various ages. Some of these sites tend to become more or less methylated with advancing age, allowing machine learning approaches to derive algorithms that match a pattern of methylation to a chronological age. An accelerated epigenetic age implies that an individual's epigenetics look more like those of someone with an older chronological age. The implication is that such an individual suffers a greater burden of age-related damage and dysfunction, and will thus have a higher risk of disease and mortality going forward.

Transgenic mouse models of Alzheimer's disease (AD) demonstrate unique epigenetic alterations associated with AD pathology and studies of human brain tissue show marked DNA methylation differences in AD when compared to normal aging brain. By contrast, data from clinical studies has been mixed. For example, a recent systematic review largely using cross-sectional studies found no strong evidence that epigenetic age estimates were associated with risk for dementia or mild cognitive impairment (MCI), while other smaller studies have suggested a limited though promising relationship with risk for AD or related disease biomarkers.

There are multiple possible explanations for these surprisingly discrepant findings as insights from mouse models and postmortem human tissue are translated into clinical settings, and, taken together, these findings suggest the need for additional studies using more sensitive longitudinal and biomarker data paired with well-established and validated epigenetic clocks. Therefore, we investigated the relationship between two well-validated second-generation epigenetic clocks, DNAmPhenoAge and DNAmGrimAge, and risk for MCI or AD using longitudinal analyses and multimodal neuroimaging. Specifically, we analyzed the rate of progression from cognitively normal (CN) aging to either MCI or AD, cortical thinning and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI), and longitudinal cognitive changes.

Using survival analyses, we found that DNAmPhenoAge and DNAmGrimAge predicted progression from cognitively normal aging to mild cognitive impairment or AD and worse longitudinal cognitive outcomes. Epigenetic age was also strongly associated with cortical thinning in AD-relevant regions and white matter disease burden. Thus, in contrast to earlier work suggesting limited applicability of blood-based epigenetic clocks in AD, our novel analytic framework suggests that second-generation epigenetic clocks have broad utility and may represent promising predictors of AD risk and pathophysiology.

Link: https://doi.org/10.21203/rs.3.rs-5273529/v1

A cell is a bag of molecules, all constantly slamming into each other at high speed. Damage to intricate structures such as the packaged DNA of the cell nucleus occurs all time. Most of it is fixed immediately by the highly efficient DNA repair machinery, but a tiny fraction slips through to produce mutations in the sequences describing proteins. In general, even this mutational damage is mostly harmless, except when it hits exactly the right gene to produce a cancerous cell. The damage usually occurs in regions of DNA not used in that cell, or in genes that are used but are not all that important to cell function, or it occurs in a cell that has only a few replications left before reaching the Hayflick limit, and thus any consequences are quite limited.

However, some mutational damage occurs in stem cell and progenitor cell populations, and this ensures that a mutation spreads throughout a tissue over time, present in every daughter somatic cell produced by the mutated stem cell. A layered spread of mutations throughout a tissue, occurring slowly over time as damage accrues in stem cells, is called somatic mosaicism. Researchers consider that this likely contributes to aging by spreading dysfunction, but connecting specific harms to the specific presence of somatic mosaicism has proven challenging.

The one form of somatic mosaicism for which researchers are finding connections is clonal hematopoiesis of indeterminate potential (CHIP), mosaicism in the populations of immune cells generated in the bone marrow. The immune system is influential on health, declines with age, and it seems plausible that one might see widespread effects resulting from significant mutational change in a sizable fraction of circulating immune cells. Today's open access paper is one of a number of examples in which CHIP correlates with unfavorable outcomes, likely because it is giving rise to greater inflammatory behavior in the aged immune system.

Impact of Clonal Hematopoiesis of Indeterminate Potential on the Long-Term Risk of Recurrent Stroke in Patients with a High Atherosclerotic Burden

Clonal hematopoiesis of indeterminate potential (CHIP), which has recently been shown to be an age-related phenomenon, is associated with cardiovascular diseases, including atherosclerosis and stroke. This study focused on the association between CHIP and short- and long-term stroke recurrence in patients with acute ischemic stroke and intracranial atherosclerotic stenosis (ICAS).

This study included 4,699 patients with acute ischemic stroke based on data from the Third China National Stroke Registry (CNSR-III), a nationwide prospective hospital-based registry. The ICAS assessment followed the criteria established by the Warfarin-Aspirin Symptomatic Intracranial Disease Study and Brain Imaging. Atherosclerosis Scores (AS) were used to assess the atherosclerosis burden, as determined by the number and severity of steno-occlusions in the intracranial arteries. The primary outcome was stroke recurrence three months and one year after the event.

Among the 4,699 patients, 3,181 were female, and the median age was 63.0 years. We found that CHIP significantly increased the risk of stroke recurrence at the 1-year follow-up in patients with ICAS (adjusted hazard ratio [HR] 2.71). Our results revealed that CHIP might have a significant impact on the long-term risk of recurrent stroke, particularly in patients with a higher atherosclerotic burden.

The composition of the gut microbiome changes with age in ways that contribute to loss of function and inflammation throughout the body. Evidence from animal studies suggests that the influence of the gut microbiome on long-term health may be similar to that of lifestyle choices such as exercise and diet. Here, researchers discuss what is known of the relationship between menopause and the gut microbiome. As is the case for immune aging, this is likely a bidirectional relationship, each side negatively impacting the other.

The oral and gut microbiota, constituting the largest ecosystem within the human body, are important for maintaining human health and notably contribute to the healthy aging of menopausal women. This paper presents the current understanding of the microbiome during menopause, with a particular focus on alterations in the oral and gut microbiota.

While sex hormones shape the gut microbiome, resulting in sexual differences in microbial composition, the gut microbiome also participates in regulating sex hormone levels, indicating a bidirectional relationship. Glucuronic acid conjugation marks estrogens for biliary excretion through urine and feces, and the removal of glucuronic acid releases estrogens to reabsorb into the circulation. Some gut bacteria, such as Clostridium, Bifidobacterium, and Lactobacillus, yield β-glucuronides and β-glucuronidases, which deconjugate or conjugate estrogens. These gene products from gut bacteria that metabolize estrogens are termed the estrobolome. The proportion of β-glucuronides and β-glucuronidases in the gut regulates the quantity of circulating estrogens. Some gut bacteria produce enzymes that can selectively deconjugate certain estrogens, thus changing the profile of circulating estrogens. In addition to estrogens, other sex hormones, including androgens and progesterone, are similarly metabolized by the gut microbiota.

Studies suggest a bidirectional interplay between the gut microbiome and sex hormones during menopause. Estrogens and progesterone act as substrates for several bacterial species and therefore may contribute to elevated gut microbial diversity; moreover, the increased diversity and deconjugation activity of certain bacteria help to recycle sex hormones. Without production from the ovary, the estrogen and progesterone levels remain low in postmenopausal women; hence, the recycling of sex hormones by the gut microbiome may become a significant source of circulating estrogens and progesterone.

Link: https://doi.org/10.1016/j.jgg.2024.11.010

Researchers here suggest that one of the issues arising from oxidative stress in a cell is a reduced ability for critical proteins to move about the cell to where they are needed. It is an interesting concept, but quite unclear as to what one might do about it beyond alleviating the issues that caused the oxidative stress in the first place. This is the case for much of the cellular dysfunction of aging - it is more practical to focus on the causes of dysfunction than to try to patch over it.

Many chronic diseases have a common denominator that could be driving their dysfunction: reduced protein mobility. Normally, most proteins zip around the cell bumping into other molecules until they locate the molecule they work with or act on. The slower a protein moves, the fewer other molecules it will reach, and so the less likely it will be able to do its job. Researchers found that such protein slow-downs lead to measurable reductions in the functional output of the proteins. When many proteins fail to get their jobs done in time, cells begin to experience a variety of problems.

The researchers studied proteins involved in a broad range of cellular functions, including MED1, a protein involved in gene expression; HP1α, a protein involved in gene silencing; FIB1, a protein involved in production of ribosomes; and SRSF2, a protein involved in splicing of messenger RNA. They used single-molecule tracking and other methods to measure how each of those proteins moves in healthy cells and in cells in disease states. All but one of the proteins showed reduced mobility (about 20-35%) in the disease cells.

Researchers suspected that the defect had to do with an increase in cells of the level of reactive oxygen species (ROS), molecules that are highly prone to interfering with other molecules and their chemical reactions. Many types of chronic-disease-associated triggers, such as higher sugar or fat levels, certain toxins, and inflammatory signals, lead to an increase in ROS, also known as an increase in oxidative stress. The researchers measured the mobility of the proteins again, in cells that had high levels of ROS and were not otherwise in a disease state, and saw comparable mobility defects, suggesting that oxidative stress was to blame for the protein mobility defect.

The final part of the puzzle was why some, but not all, proteins slow down in the presence of ROS. SRSF2 was the only one of the proteins that was unaffected in the experiments, and it had one clear difference from the others: its surface did not contain any cysteines, an amino acid building block of many proteins. Cysteines are especially susceptible to interference from ROS because it will cause them to bond to other cysteines. When this bonding occurs between two protein molecules, it slows them down because the two proteins cannot move through the cell as quickly as either protein alone.

Link: https://wi.mit.edu/news/cellular-traffic-congestion-chronic-diseases-suggests-new-therapeutic-targets

Many forms of mild stress produce a corresponding increase in cell maintenance activities that lasts for a while longer, improving cell function, improving tissue and organ function, and over time extending life by slowing the accumulation of some of the forms of damage that drive aging. Low nutrient availability, cold, heat, toxins, all of these can be beneficial at some level and duration of exposure. For example, the practice of calorie restriction produces an upregulation of the cell maintenance processes of autophagy, and this appears to be the crucial outcome that drives improved health and a slowed progression of aging.

It is unfortunate that these effects have a much smaller effect on aging in long-lived species versus short-lived species. It means that most of the interventions discovered to influence the pace of aging turn out to be a poor basis for human enhancement therapies to extend healthy life span. In the case of nutrient sensing and its ability to extend life past a season of famine, there are sound evolutionary reasons as to why short-lived species undergo a greater extension of life relative to their life span - a season is a long time for a mouse, not so long for a human. But it isn't all that clear as to why this should also apply to, say, the heat shock response, other than it potentially using many of the same underlying mechanisms as the calorie restriction response. In today's open access paper, researchers find that this assumption may not be correct, or at least that matters are more complex than this, leading by a winding and indirect path to the mitochondria.

HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling

Cells possess an array of protein quality control mechanisms collectively referred to as the proteostasis network (PN), which act to preserve proteome integrity. The PN coordinates protein synthesis, folding, disaggregation and degradation and integrates components of the translational machinery, molecular chaperones and co-chaperones and the proteolytic systems - the ubiquitin-proteasome system (UPS), and autophagy-lysosomal system - to ensure cell viability.

The cytosolic/nuclear arm of the PN is subject to regulation by heat shock transcription factor 1 (HSF-1), which protects the proteome by driving the expression of heat shock proteins (HSPs) that function as molecular chaperones. In line with its function, the knockdown of HSF-1 leads to increased protein aggregation, tissue dysfunction and decreased survival, whereas overexpression of HSF-1 maintains proteome integrity, promotes tissue health, and extends lifespan. While it is apparent that increasing HSF-1 activity is beneficial for longevity, our understanding of the mechanisms that act downstream of HSF-1 to prolong healthy tissue function remains limited.

It is widely believed that HSF-1 regulates ageing by upregulating the expression of HSPs. However, in addition to HSPs, HSF-1 also controls the expression of genes encoding cytoskeletal components, metabolic enzymes, ribosomal subunits, chromatin factors and components of the UPS. Moreover, recent work has demonstrated roles for autophagy, maintenance of the cytoskeleton and lipid regulation in HSF-1-mediated lifespan extension. These observations indicate that HSF-1 regulates longevity through mechanisms beyond HSP-mediated chaperoning of the proteome.

Here, we employ an RNA interference screen to identify the HSF-1 target genes that promote increased lifespan in C. elegans overexpressing HSF-1. We find that the sole worm ubiquilin, ubiquilin-1 (ubql-1), is necessary to increase lifespan. Ubiquilins are multifaceted, conserved shuttle proteins that localise to the cytoplasm and nucleus, where they function as chaperones that aid in the degradation of substrates through the ubiquitin-proteasome system and autophagy. Despite its central role in protein degradation, we find that ubiquilin-1 does not promote longevity by altering general proteostasis capacity. Instead it leads to transcriptional downregulation of all components of the CDC-48-UFD-1-NPL-4 complex, which is central to both endoplasmic reticulum and mitochondria associated protein degradation, and that this is complemented by UBQL-1-dependent turnover of NPL-4.1. As a consequence, mitochondrial network dynamics are altered, leading to increased lifespan.

Together, our data establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to down-tuning of components associated with organellar protein degradation pathways.

Many aspects of aging tend to progress in parallel, which is much as one might expect if considering aging to be a collection of outcomes that all arise from the same underlying forms of cell and tissue damage. So finding a correlation isn't always evidence that there is some link between outcomes in aging. Here, researchers note an association between physical capacity and autonomic nervous system function in late life. It is quite possible to theorize on cause and consequence, and the mechanisms involved, in this situation - but actually proving any of those connections is quite a different story.

The autonomic nervous system plays unique and pivotal roles in maintaining physiological homeostasis. These roles are mainly exerted through their effects on the function of multiple organ systems. Aside from its well-known effects on cardiovascular and metabolic systems, recent experimental research even showed the previously unexpected close connections of autonomic nervous system activity with inflammation, immune responses, and skeletal muscle physiology.

Here, we conducted a longitudinal study with repeated measurements of heart rate variability (HRV), a measure of autonomic nervous system function, and functional capacity. We aimed to examine the longitudinal association of heart rate variability and its change with changes in functional capacity over time in older adults.

A cohort of 542 adults (mean age of 70.1 years) received repeated measurements of heart rate variability, an autonomic nervous system function marker, and chair rise time, a functional capacity measure. Linear mixed models analysis showed that 1 standard deviation (SD) lower power in low-frequency range of heart rate variability at baseline was associated with a 0.11 second/year faster increase in chair rise time during the follow-up, whereas 1 SD increase in power in high-frequency range and 1 SD decrease in the ratio of power in low-frequency range to power in high-frequency range during the follow-up were associated with a 0.22 second and 0.17 second increase in chair rise time. In conclusion, autonomic nervous system function and its changes were longitudinally associated with changes in functional capacity in older adults.

Link: https://doi.org/10.1038/s41598-024-80659-w

The PAI-1 protein is generated by the SERPINE1 gene. You might recall the discovery of a small human population with a loss of function mutation in this gene and longer lives then peers without the mutation. Here researchers map the relationships between PAI-1 and cellular senescence; PAI-1 is important in enabling onset of the senescent state. The accumulation of senescent cells with age is thought to be a meaningful contribution to degenerative aging, and the longevity of the PAI-1 loss of function population provides another piece of evidence in support of that hypothesis - to go along with all of the biochemical data, evidence of rejuvenation in aged animals following clearance of senescent cells, and promising clinical trials of senolytic drugs.

In this study, we aim to illustrate a pathway map of PAI-1, highlighting its contributions to cellular senescence and aging. PAI-1 is a critical component in the iniation of cellular senescence, and our findings underscore the pivotal role of the SERPINE1 gene in this process. Targeting PAI-1 offers a promising strategy to mitigate cellular senescence and associated age-related conditions such as emphysema, arteriosclerosis, organ fibrogenesis, and thrombosis. The publicly available PAI-1 pathway map will aid researchers in understanding the various molecules involved in modulating this pathway in pathological and physiological contexts. This resource provides insights for identifying other related molecules participating in this signaling network and may lead to innovative pharmacological means for managing cellular senescence and addressing diseases linked to PAI-1.

Accumulating evidence, including our laboratory's research, positions PAI-1 as a molecular signature of cellular senescence and a potential inducer and mediator of maturation. Our research team is currently exploring the essential function of PAI-1 and the fibrinolytic system in age-related fibrotic lung conditions through pharmacological PAI-1 inhibitors. In our ongoing and future studies, we aim to further clarify the crucial function of PAI-1 in cellular senescence and its connections to the fibrinolytic system, particularly in age-associated mortality and morbidity.

Link: https://doi.org/10.1186/s12964-024-01910-5

The primary challenge in the matter of understanding aging is not the generation of data - there is far more data on any aspect of aging than any one research group is capable of assimilating. Production of data is a great deal easier than making something of that data, and so the databases continue to grow at a faster pace than the understanding of that data. The primary challenge is to build bridges of established, comprehensible cause and effect between the various bodies of data, to show that age-related biochemical change A causes unfortunate consequence B, and that A is more important in the progression of B than any of the countless other biochemical changes observed to correlate with B. This is hard.

One first step along this path is to take what is known of the causes of aging (such as those outlined in the SENS view of rejuvenation biotechnology) and try to fix them, observing the results. This is not as popular an approach as might be imagined! More effort goes instead to taking what is known of observed outcomes in aging, and attempting to gain insight into their relationships to to one specific age-related condition. Since the publication of the Hallmarks of Aging paper, a lot of this latter sort of exploration has been undertaken. Today's open access paper is one example of the type, in which researchers give direction for others to explore more deeply the links between specific hallmarks of aging and the age-related loss of muscle mass and strength that leads to sarcopenia.

Sarcopenia and the biological determinants of aging: A narrative review from a geroscience perspective

Research on how molecular and cellular processes - referred to as the hallmarks of aging - are linked to clinically diagnosed sarcopenia and its muscular components. Understanding the biological mechanisms underlying sarcopenia and identifying signature biomarkers are essential for developing preventive strategies that could delay its onset. Among aging hallmarks, mitochondrial dysfunction appears to be the most closely associated with sarcopenia. This dysfunction is characterized by decreased electron transport chain (ETC) expression and activities, changes in metabolites from the TCA cycle, compromised OXPHOS, heightened oxidative stress, and lower antioxidant defenses. These findings were consistently observed across various populations.

Additionally, sarcopenia was associated with deregulated nutrient sensing, indicated by lower IGF-1 and insulin levels in sarcopenic individuals, alongside diminished mTOR signaling and potential influences from specific amino acids. Inflammatory indicators included elevated cortisol levels and oxidative stress markers, while CRP and other cytokines were not consistently associated with sarcopenia. Direct muscle evaluation also revealed no significant increase in inflammatory pathways. Lastly, a decrease in butyrate-producing bacteria and an increase in pathogenic flora were indicatives of gut dysbiosis in individuals with sarcopenia.

Additional connections between sarcopenia and other aging hallmarks, though indicative of potential links, are based on limited or inconsistent evidence. This applies to most of the primary hallmarks. Indicators suggest that genomic instability occurs in sarcopenia, evidenced by increased levels of cell-free mitochondrial and nuclear DNA, as well as epigenetic alterations. However, a deeper understanding of the specific pathways influenced by methylation in various DNA regions and other epigenetic processes is essential. There is a rationale supporting the influence of proteostasis on muscle function, and evidence of transcriptional changes in sarcopenia is apparent. However, the available information is not sufficient to confirm their direct link to sarcopenia. Moreover, lower concentrations of circulating progenitor cells and reduced activation of myosatellite cells in sarcopenic individuals indicate that stem cell exhaustion may contribute to the disease. More research, including mechanistic preclinical investigations, as well as longitudinal human studies, is necessary to explore how these factors relate to the development of sarcopenia.

The field of sarcopenia has witnessed significant advancements, evolving from establishing disease criteria to deepening our understanding of its mechanisms and exploring potential interventions. Despite this progress, the primary management strategies for sarcopenia are solely strength exercise training and nutritional support, as current evidence does not support the efficacy of pharmacological treatments. A recent systematic review examining both current and investigational medications for sarcopenia found no conclusive evidence to support the effectiveness of testosterone replacement or vitamin D supplementation in improving sarcopenia outcomes, reinforcing the findings of our review, which also did not find a consistent relationship between these endocrine networks and sarcopenia. Current preclinical research is investigating the roles of exerkines - molecules secreted by skeletal muscle fibers - and senolytic drugs in muscle health. Based on our findings, enhancing oxidative phosphorylation pathways and restoring energetic balance are also promising future targets for developing treatment options for sarcopenia.

That loss of brain volume is a bad thing, resulting from the loss of necessary cells, is a concept central to the research and clinical fields. It occurs in the late stages of Alzheimer's disease as cells die and cognitive function is lost. So it is interesting to see this view challenged in the context of the recently approved amyloid-clearing immunotherapies. Is brain volume loss following treatment a function of mechanisms other than loss of cells? Is it actually a beneficial outcome? I can see it requiring a great deal more time, funding, and data to convince the broader field that this is the case.

Researchers analysed data from a dozen different trials of amyloid-targeting immunotherapy. While brain shrinkage is usually an undesirable outcome, the team found that the excess volume loss was consistent across studies and correlated with how effective the therapy was in removing amyloid and was not associated with harm. As a result, the researchers believe that the removal of amyloid plaques, which are abundant in Alzheimer's patients, could account for the observed brain volume changes. And, as such, the volume loss should not be a cause for concern.

To describe this phenomenon, the research team coined a new phrase: "amyloid-removal-related pseudo-atrophy" or ARPA. "Amyloid-targeting monoclonal antibodies represent a significant therapeutic breakthrough. One area of controversy has been the effect of these agents on brain volumes. Brain volume loss is a characteristic feature of Alzheimer's disease, caused by progressive loss of neurons. Amyloid immunotherapy has consistently shown an increase in brain volume loss - leading to concerns in the media and medical literature that these drugs could be causing unrecognised toxicity to the brains of treated patients. However, based on the available data, we believe that this excess volume change is an anticipated consequence of the removal of pathologic amyloid plaque. We are calling for better reporting of these changes in clinical trials."

Link: https://www.ucl.ac.uk/news/2024/nov/brain-shrinkage-associated-alzheimers-therapies-shows-effectiveness-rather-harm

Evidence strongly suggests that the inflammatory dysfunction of the innate immune cells of the brain known as microglia contributes to neurodegenerative conditions. There is a way to clear microglia from the brain, which is the use of CSF1R inhibitors such as PLX5622. A few weeks of treatment dramatically reduce the population of microglia, which will rebuild itself within a further few weeks after treatment has stopped. Researchers have observed that the new population is much less inflammatory than the old one. Researchers here note that this therapy fails to improve measures of Alzheimer's pathology in a mouse model by the end of a short ten day study - more time is required for effects to emerge.

While moderately activated microglia in Alzheimer's disease (AD) are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations reported that the elimination of ~80% of microglia through inhibition of the colony-stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglia are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition using PLX5622 in three-month-old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal Aβ plaques.

We observed ~65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia displayed a noninflammatory phenotype with reduced NLRP3 inflammasome complexes. Moreover, plaque-associated microglia were reduced with diminished Clec7a expression. Additionally, phosphorylated S6 ribosomal protein and the protein sequestosome 1 analysis suggested reduced mechanistic targets of rapamycin (mTOR) signaling and autophagy in microglia and neurons within the hippocampus and cerebral cortex. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling in the hippocampus and cerebral cortex, and enhanced autophagy in the hippocampus. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, astrocyte hypertrophy, or hippocampal neurogenesis.

Thus, short-term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.

Link: https://doi.org/10.1111/acel.14398

Blood clotting relies upon platelets and the reaction of those platelets to circumstances that indicate clotting is required: when suitably provoked platelets adhere to tissue, change shape, and bind to one another to form a clot. Platelets are essentially small slices of cell membrane and cytoplasm, shed by a specialized form of bone marrow cell called a megakaryocyte. Like all complex processes, clotting is impacted by age-related changes in cells and tissue. Platelets become more willing to clot, and can produce inappropriate clotting inside blood vessels, leading to thrombosis. We might ask how much of this problem is innate to platelets versus arising from damage to the vascular endothelium and an altered signaling environment.

In today's open access preprint, researcher suggest that the problem is innate to platelets. The authors provide evidence for a minority population of megakaryocytes to grow in number with age. This population produces overly reactive platelets, and as these problematic platelets grow as a proportion of all platelets, so the risk of inappropriate clotting rises. This is analogous to other similar issues in the production of blood cells and immune cells in the bone marrow, in which aging produces unfavorable shifts in relative numbers. Evidence to date suggests much of this is driven by chronic inflammation, but that is no doubt far from the only mechanism in play.

A rare HSC-derived megakaryocyte progenitor accumulates via enhanced survival and contributes to exacerbated thrombopoiesis upon aging

Distinct routes of cellular production from hematopoietic stem cells (HSCs) have defined our current view of hematopoiesis. Recently, we challenged classical views of platelet generation, demonstrating that megakaryocyte progenitors (MkPs), and ultimately platelets, can be specified via an alternate and additive route of HSC-direct specification specifically during aging. This "shortcut" pathway generates hyperactive platelets likely to contribute to age-related platelet-mediated morbidities.

Here, we used single-cell RNA/CITEseq to demonstrate that these age-unique, non-canonical (nc)MkPs can be prospectively defined and experimentally isolated from wild type mice. Surprisingly, this revealed that a rare population of ncMkPs also exist in young mice. Young and aged ncMkPs are functionally distinct from their canonical (c)MkP counterparts, with aged ncMkPs paradoxically and uniquely exhibiting enhanced survival and platelet generation capacity. We further demonstrate that aged HSCs generate significantly more ncMkPs than their younger counterparts, yet this is accomplished without strict clonal restriction.

Together, these findings reveal significant phenotypic, functional, and aging-dependent heterogeneity among the MkP pool and uncover unique features of megakaryopoiesis throughout life, potentially offering cellular and molecular targets for mitigation of age-related adverse thrombotic events.

One of the many interesting questions about Alzheimer's disease is why the relationship with being overweight or obese is tenuous in comparison to, say, type 2 diabetes. Why are there so many dramatically overweight people who do not develop Alzheimer's disease? As researchers here note, one can clearly point to Alzheimer's-adjacent mechanisms that obesity makes worse. Inflammatory dysfunction of the innate immune cells of the brain known as microglia has attracted a lot of attention in recent years, thought to contribute to all forms of neurodegeneration. Here, researchers look at one mechanism by which excess visceral fat tissue can harm microglia, giving rise to behaviors observed in the brains of Alzheimer's patients and animal models.

Increasing evidence suggests that metabolic disorders such as obesity are implicated in the development of Alzheimer's disease (AD). The pathological buildup of lipids in microglia is regarded as a key indicator in brain aging and the progression of AD, yet the mechanisms behind this process remain uncertain. The adipokine ANGPTL4 is strongly associated with obesity and is thought to play a role in the advancement of neurodegenerative diseases. This study utilized RNA sequencing to identify differential expression in lipid-accumulating BV2 microglia and investigated the potential mechanism through ANGPTL4 overexpression in BV2. Subsequently, animal models and clinical data were employed to further explore alterations in circulating ANGPTL4 levels in AD.

RNA sequencing results indicated a correlation between ANGPTL4 and microglial lipid accumulation. The overexpression of ANGPTL4 in microglia resulted in increased secretion of inflammatory factors, elevated oxidative stress levels, and diminished antiviral capacity. Furthermore, when simulating the coexistence of AD and obesity through combined treatment with Amyloid-Beta 1-42 peptide (Aβ) and Free Fatty Acids (FFA) in vitro, we observed a notable upregulation of ANGPTL4 expression, highlighting its potential role in the interplay between AD and obesity.

In vivo experiments, we also observed a significant increase in ANGPTL4 expression in the hippocampus and plasma of APP/PS1 mice compared to wild-type controls. This was accompanied by heightened microglial activation and reduced expression of longevity-related genes in the hippocampus. Clinical data from the UK Biobank indicated that plasma ANGPTL4 levels are elevated in patients with AD when compared to healthy controls. Moreover, significantly higher ANGPTL4 levels were observed in obese AD patients relative to their non-obese counterparts. Our findings suggest that ANGPTL4-mediated microglial aging may serve as a crucial link between AD and obesity, proposing ANGPTL4 as a potential biomarker for AD.

Link: https://doi.org/10.1016/j.nbd.2024.106741

Forms of fasting and calorie restriction all function to produce sweeping, favorable alterations to metabolism. In short-lived animals, these changes significantly extend healthy life span. In long-lived animals, the effects on life span are more muted. The challenge in understanding the interaction between reduced calorie intake and pace of aging is that near everything changes in response to diet. There is no firm understanding at the detail level to link the copious observations into a coherent explanation of how aging is slowed. While evidence points to upregulation of autophagy as the primary mechanism connecting reduced calorie intake to slowed aging, it seems clear that researchers will still be writing papers like this one for decades yet.

Dietary restriction (DR) has multiple beneficial effects on health and longevity and can also improve the efficacy of certain therapies. Diets used to instigate DR are diverse and the corresponding response is not uniformly measured. We compared the systemic and liver-specific transcriptional response to intermittent fasting (IF) and commercially available fasting-mimicking diet (FMD) after short- and long-term use in C57BL/6 J mice.

We show that neither DR regimen causes observable adverse effects in mice. The weight loss was limited to 20% and was quickly compensated during refeeding days. The slightly higher weight loss upon FMD versus IF correlated with stronger fasting response assessed by lower glucose levels and higher ketone body, free fatty acids, and especially FGF21 concentrations in blood. RNA sequencing demonstrated similar transcriptional programs in the liver after both regimens, with PPARα signalling as top enriched pathway, while on individual gene level FMD more potently increased gluconeogenesis-related, and PPARα and p53 target gene expression compared to IF. Repeated IF induced similar transcriptional responses as acute IF. However, repeated cycles of FMD resulted in blunted expression of genes involved in ketogenesis and fatty acid oxidation.

Link: https://doi.org/10.1186/s12915-024-02061-2