Fight Aging!

A number of proteins in the body are capable of misfolding or otherwise becoming altered in ways that allow the formation of aggregates, solid clumps that precipitate from solution to cause harm to the normal function of cells. Those harms might be direct, or result from a surrounding biochemistry of interactions with the aggregates that generates damaging molecules, or be driven by a maladaptive inflammatory response to the presence of the protein aggregates. Much of the research related to protein aggregates is focused on the aging brain and neurodegenerative conditions, as these are largely characterized by the formation of various forms of protein aggregate, such as amyloid-β, tau, and α-synuclein.

TDP-43 is a more recent addition to the established list of protein aggregates, with its own Alzheimer's-like condition called limbic-predominant age-related TDP-43 encephalopathy (LATE). As research into TDP-43 aggregation progresses, it is becoming clear that it is a common form of pathology, perhaps often misdiagnosed as Alzheimer's disease. TDP-43 aggregation is also important in amyotrophic lateral sclerosis (ALS) and potentially other conditions. Generally, one should expect all forms of protein aggregation to be present in the aging brain; the various named conditions develop when one or more of these protein aggregates pass the threshold needed to produce outright, evident pathology. Even prior to this, they cause harm, however. Protein aggregation should be treated as a form of damage, and therapies developed to minimize it as best possible.

Neurodegenerative disease ALS: Cellular repair system could prevent protein aggregation

In amyotrophic lateral sclerosis (ALS), poorly soluble protein aggregates accumulate in motor neurons. Among other proteins, these aggregates consist of TDP-43, which plays various critical roles in cellular RNA metabolism. While in healthy cells TDP-43 is mainly found in soluble form in the cell nucleus, in ALS patients it forms poorly soluble aggregates that mainly accumulate outside the cell nucleus. This means that TDP-43 loses its functionality, as well as ultimately leading to the death of the motor neurons.

Researchers exposed cells to stress, for example by increasing the temperature or using a chemical substance. As a result, some TDP-43 was released from the cell nucleus into the cytosol, where it accumulated in so-called stress granules. "The formation of such stress granules is a normal process and serves the cell as a temporary protective space for proteins so that they are immediately available to the cell once the stress has subsided. However, if TDP-43 is mutated, as it is in the cells of many ALS patients, the stress granules persist, increasingly solidify and ultimately damage the neurons."

The scientists successfully prevented TDP-43 from leaving the cell nucleus under stress by linking it with the cell's "roadside assistance" - a protein called SUMO - which directed TDP-43 to a cellular "mechanic", the so-called nuclear bodies. As a result, TDP-43 remains soluble, and the nuclear bodies - like a mechanic - ensure that harmful forms of TDP-43 are restored or broken down by the cellular recycling system. Insoluble protein aggregates that damage or even kill cells would therefore be prevented from forming in the first place. The team of researchers is now looking for future drug candidates in the form of chemical compounds that bring SUMO and TDP-43 together.

Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks

The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control.

We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation-ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that SUMO-ubiquitin networks protect cells from insoluble TDP-43 inclusions and propose the functionalization of PML as a potential future therapeutic avenue countering aggregation.

Coping with the damage and dysfunction of aging imposes a staggering cost. The funds dedicated to aging research are tiny compared to the funds spent on coping with the consequences of aging, and it is still the case that little of the activity taking place in the field of aging research is focused on establishing ways to slow or reverse aging. When looking a the consequences of aging category by category, the costs remain huge. Here, for example, find an estimate of the yearly costs imposed by the various forms of dementia in the United States alone.

The total economic burden of Alzheimer's disease and related dementias in the United States will reach $781 billion this year according to a newly developed model produced as a part of the U.S. Cost of Dementia Project. An estimated 5.6 million Americans are living with dementia this year, including 5 million who are 65 and older. Medical and long-term care for patients with dementia will cost the United States $232 billion this year, including $52 billion paid out of pocket by patients and their families. More than two-thirds of the total cost of care is paid for by Medicare ($106 billion) and Medicaid ($58 billion).

Dementia's societal costs are even more staggering, the model reveals. The largest share stems from a factor often not measured in other cost estimates: The significant decline in quality of life for patients ($302 billion) and care partners ($6 billion). Lost earnings among friends and family who forego work to provide care - another measure often not captured by other estimates - total $8.2 billion. Care partners provide 6.8 billion hours of unpaid care, valued at $233 billion.

Link: https://mann.usc.edu/news/u-s-dementia-costs-to-exceed-780-billion-this-year-usc-led-research-finds/

Senescent cells accumulate with age to cause cell and tissue dysfunction, and their clearance via varied forms of senolytic treatment has been shown to produce rapid rejuvenation in animal studies. Human clinical trials have provided initially promising results. Senescent cells also serve useful purposes in regeneration from injury and suppression of cancer, when present for only a short time. Researchers here assess changes in epigenetic age produced by senolytic treatment in aged and injured muscle tissue, and note that clearance of senescent cells actually aids regeneration in old mice. The senolytic in question inhibits p53-MDM2 binding, not as well studied as BCL2 family inhibitors in the context of clearance of senescent cells, though well explored in the context of cancer.

Senescent cells emerge with aging and injury. The contribution of senescent cells to DNA methylation age (DNAmAGE) in vivo is uncertain. Furthermore, stem cell therapy can mediate "rejuvenation", but how tissue regeneration controlled by resident stem cells affects whole tissue DNAmAGE is unclear. We assessed DNAmAGE with or without senolytics (BI01) in aged male mice (24-25 months) 35 days following muscle healing (BaCl2-induced regeneration versus non-injured). Young injured mice (5-6 months) without senolytics were comparators.

DNAmAGE was decelerated by up to 68% after injury in aged muscle. DNAmAGE was modestly but further significantly decelerated by injury recovery with senolytics. ~1/4 of measured CpGs were altered by injury then recovery regardless of senolytics in aged muscle. Specific methylation changes caused by senolytics included differential regulation of Col, Hdac, Hox, and Wnt genes, which likely contributed to improved regeneration. Altered extracellular matrix remodeling using histological analysis aligned with the methylomic findings with senolytics.

Without senolytics, regeneration had a contrasting effect in young mice and tended not to influence or modestly accelerate DNAmAGE. Comparing young to old injury recovery without senolytics using methylome-transcriptome integration, we found a more coordinated molecular profile in young mice and differential regulation of genes implicated in muscle stem cell performance: Axin2, Egr1, Fzd4, Meg3, and Spry1. Muscle injury and senescent cells affect DNAmAGE and aging influences the transcriptomic-methylomic landscape after resident stem cell-driven tissue reformation. Our data have implications for understanding muscle plasticity with aging and developing therapies aimed at collagen remodeling and senescence.

Link: https://doi.org/10.1111/acel.70068

Mutational damage to nuclear DNA occurs constantly throughout life, and is suspected to contribute to degenerative aging in ways other than risk of cancer. But most mutational damage occurs in somatic cells with few replications left before the Hayflick limit, and in DNA sequences that are not used in that cell type. So how can this damage cause significant disruption of metabolism? One recent idea is that repeated activation of DNA repair processes can deplete factors necessary to maintain correct DNA structure and gene expression, producing detrimental epigenetic changes characteristic of aging. Separately, perhaps only some mutations are meaningfully harmful, those that occur in stem cells. A mutated stem cell will spread that mutation throughout a tissue as it creates a steady supply of mutated daughter somatic cells. Over time, tissues will develop a patchwork of different combinations of mutations that originally occurred in specific stem cells, creating what is known as somatic mosaicism.

Clonal hematopoiesis of indeterminate potential (CHIP) is one of the better researched manifestations of somatic mosaicism, occurring in the hematopoietic cell populations in bone marrow responsible for generating immune cells. It is known to be a risk factor for leukemia, and also correlates with other conditions, possibly because of an increased propensity for chronic inflammation on the part of the immune system as its somatic mosaicism grows. In today's open access paper, researchers report on a specific connection between the aging gut microbiome and CHIP, showing that one specific metabolite produced by microbial populations can promote the expansion of populations of potentially harmful mutated hematopoietic cells, raising the risk of a resulting leukemia.

Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1

Clonal haematopoiesis of indeterminate potential (CHIP) involves the gradual expansion of mutant pre-leukaemic haematopoietic cells, which increases with age and confers a risk for multiple diseases, including leukaemia and immune-related conditions. Although the absolute risk of leukaemic transformation in individuals with CHIP is very low, the strongest predictor of progression is the accumulation of mutant haematopoietic cells. Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during ageing remains rudimentary.

Here we show that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes pre-leukaemic cell expansion. Specifically, ADP-d-glycero-β-d-manno-heptose (ADP-heptose), a metabolic specific to Gram-negative bacteria, is uniquely found in the circulation of older individuals and favours the expansion of pre-leukaemic cells. ADP-heptose is also associated with increased inflammation and cardiovascular risk in CHIP. Mechanistically, ADP-heptose binds to its receptor, ALPK1, triggering transcriptional reprogramming and NF-κB activation that endows pre-leukaemic cells with a competitive advantage due to excessive clonal proliferation.

Collectively, we identify that the accumulation of ADP-heptose represents a direct link between ageing and expansion of rare pre-leukaemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukaemia and immune-related conditions.

Many disparate aspects of aging correlate with one another, emerging from the same underlying processes of cell and tissue damage. Similarly, any one specific form of age-related damage will tend to correlate with outcomes in aging regardless of whether it makes a sizable contribution to those outcomes. There are so many bidirectional connections between forms of damage, and between consequent dysfunction and forms of damage, that excess in any one aspect of aging tends to drag along the others. Nonetheless, there are cases in which one can reasonably speculate about causation in a narrow sense of one mechanism and one outcome, as the contribution is likely large enough to consider in isolation. Here is one of them, the link between levels of the metabolic waste of advanced glycation endproducts and their relation to physical frailty.

Advanced glycation endproducts (AGEs) form non-enzymatic cross-links with proteins, thereby altering the structure of extracellular matrix proteins comprising muscles and skeletal tissues. These structural changes negatively affect tissue stiffness and elasticity. Consequently, the altered physical properties of musculoskeletal tissues reduce force transmission from the muscle fibers, resulting in a decline in muscle strength and function. Additionally, AGEs bind to the receptor for AGEs (RAGE), promoting inflammatory responses and oxidative stress, which contribute to muscle cell dysfunction and the aging of muscle cells. However, AGEs accumulation is likely a consequence rather than the initial trigger of oxidative stress and inflammation. Minor but chronic oxidative stress and proinflammatory conditions create a favorable environment for the formation of AGEs, nitrosylated proteins, and lipids, which in turn propagate oxidative damage through radical chain reactions. This bidirectional relationship between oxidative stress and AGEs suggests a reinforcing cycle rather than a one-way causative mechanism

This cross-sectional correlational study included 552 community-dwelling older adults. AGE accumulation was assessed using skin autofluorescence (SAF) measured using an AGE reader. Mobility decline factors were evaluated using the sit-to-stand (STS), gait speed (4 m walk tests), single-leg stance (SLS), and Timed Up and Go (TUG) tests. A comparison of the physical function across the quartile groups revealed that the group with the highest SAF values exhibited a general decline in STS, gait speed, SLS, and TUG performance when compared with the other groups. Spearman's correlation analysis revealed that the SAF-AGEs demonstrated significant negative correlations with STS, gait speed, and SLS. Additionally, TUG showed a significant positive correlation. In conclusion, this study has demonstrated that higher SAF values were associated with decreased lower-limb strength, gait speed, and balance, thereby suggesting that SAF may be a useful screening tool for predicting mobility decline in older adults.

Link: https://doi.org/10.3390/healthcare13060613

Senolytic drugs capable of selectively destroying senescent cells in aged tissues are probably the most immediately promising of present efforts to treat aging as a medical condition. It is unfortunate that so little work presently takes place to rigorously evaluate the well established low-cost generic drug and supplement senolytics in human patients, as the animal studies suggest that they could be very beneficial. Unfortunately the high costs of running clinical trials ensure that low cost treatments receive little attention from the biotech and pharmaceutical industry. The dasatinib and quercetin combination is at least demonstrated to reduce the burden of senescent cells in humans, and is prescribed off-label by some anti-aging physicians, but large clinical trials are needed to be able to say in certainty that human use produces some degree of rejuvenation.

Aging is a multifactorial process driven by various intrinsic and extrinsic factors, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These factors are closely related to organismal aging, and research has shown that inducing them can accelerate aging, while intervening in them can slow down, halt, or even reverse the aging process.

Among these factors, cellular senescence is a key contributor to organismal aging. Targeting senescent cells (SCs) holds promise for developing novel and practical anti-aging therapies. Cellular senescence is an irreversible state of cell cycle arrest caused by various factors, such as DNA damage and telomere shortening. Additionally, the process whereby immune system function gradually declines or becomes dysregulated with human aging is known as immunosenescence. Although considerable variability in aging exists among individuals, the aging process generally involves chronic inflammation, tissue homeostasis disorders, and dysfunction of the immune system and organ functions, readily causing cardiovascular, metabolic, autoimmune, and neurodegenerative diseases associated with aging.

Existing research indicates that transplanting SCs into young mice induces bodily dysfunction, while transplanting them into aged mice exacerbates aging and increases the risk of death. This suggests that SCs accelerate organismal aging. The specific reason is that SCs release the senescence-associated secretory phenotype (SASP) into the tissue, promoting chronic inflammation and inducing senescence in surrounding tissue cells and immune cells. SCs and chronic inflammation interact and crosstalk, forming a vicious cycle of inflammation and aging. Therefore, in-depth research into the key characteristics and underlying mechanisms of cellular senescence, immunosenescence, and inflammation, identifying drug intervention targets, and developing targeted interventions can help mitigate aging and aging-related diseases, thereby promoting healthy aging in the elderly.

Link: https://doi.org/10.3390/cells14070499

The consensus on the immune system and aging is that dysfunction in immune function is an important contribution age-related degeneration and disease. Firstly increased, constant inflammatory signaling drives harmful changes in cell and tissue function; all of the major age-related diseases are characterized by inflammation. Secondly, loss of immune capacity allows senescent cells, cancerous cells, and infectious pathogens to slip through the net and prosper. Senescent cell burden increases with age, cancer risk scales up with age, and infectious disease is far more a threat to older people than to younger people.

The two aspects of immune aging, chronic inflammation and a growing ineffectiveness, are aggregated under the single heading of loss of immune resilience. Immune resilience is defined as maintaining both an effective immune response to challenges while also controlling inflammation, though different researchers may use different ways of coming to a specific set of measures and numbers that represent immune resilience.

In this context, the authors of today's open access paper mount an interesting argument. They agree that loss of immune resilience to be an important aspect of aging, but, for the span of human age from the 40s to the 70s, suggest that it is only loosely coupled to what we might think of as the rest of aging, whether we think of that more as the accumulation of damage and dysfunction in non-immune cells and tissues after the SENS model, or in terms of the non-immune hallmarks of aging. Thus interventions specifically focused on immune aging may go a long way to reducing mortality in this age range, even if other aspects of aging are not addressed. In practice, whether this is in fact the case will only be established in certainty by developing and widely deploying therapies to restore lost immune function - which should be an important goal regardless!

The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging

Environmental factors, particularly infections, have fundamentally shaped human evolution by selecting for protective inflammatory response mechanisms that enhance survival. This evolutionary pressure has created a core biological paradox: inflammation is indispensable for host defense, yet its dysregulation significantly heightens disease and mortality risk. This fundamental tension raises three fundamental questions about human aging and immunity: (1) How have selective pressures driven the evolution of mechanisms to balance inflammation's protective benefits against its harmful consequences? (2) Why does substantial variability in healthspan persist despite historically stable rates of aging? (3) Does evolutionary prioritization of reproductive fitness inherently limit longevity?

To address these questions, we developed an integrated evolutionary framework comprising four interconnected dimensions. At its foundation lies immune robustness - the ability to neutralize pathogenic threats while minimizing collateral tissue damage. This capability represents a critical evolutionary adaptation balancing protection against immediate threats with long-term tissue integrity. The remaining dimensions include (1) inflammatory stressors (environmental challenges that activate immune responses), (2) salutogenesis (health-promoting processes derived from Latin roots meaning "the origin of health" - "salus" meaning "health"), and (3) immune resilience (the dynamic capacity to respond to and recover from immunological challenges).

When immune robustness fails, it triggers what we term the "pathogenic triad" - three interconnected processes that accelerate biological aging: (1) inflammaging (sterile, chronic low-grade inflammation), (2) immune senescence (progressive impairment of innate and adaptive immunity), and (2) accumulation of senescent cells through Senescence-Associated Secretory Phenotype-driven damage. Importantly, these processes do not simply correlate with aging-they actively accelerate age-related morbidity independent of chronological age and mirror the established molecular hallmarks of organismal aging. Environmental triggers can initiate this triad, thereby elevating the risk of infection, multimorbidity, and mortality.

Our framework posits that immune robustness - shaped by evolutionarily optimized strategies - provides the foundation for salutogenesis, supporting systemic resilience by counteracting the aging hallmarks encompassed in the pathogenic triad. These salutogenic mechanisms mitigate age-related pathologies and extend lifespan through what is conceptualized as a "biological warranty period" encompassing both reproductive and post-reproductive phases. This warranty period closely aligns with the 2024 global average life expectancy of 73.4 years. We propose that premature mortality (before approximately 70 years) likely reflects a failure to sustain salutogenic adaptations rather than representing inherent biological constraints of aging.

To empirically investigate these concepts, we conducted longitudinal multi-omics profiling in approximately 17,500 participants exposed to diverse inflammatory challenges across the lifespan, from birth to over 90 years of age. We specifically mapped immune resilience (IR) trajectories and the emergence of the pathogenic triad across health-to-disease transitions. Our findings demonstrate that maintaining optimal IR with elevated transcription factor 7 (TCF7) levels establishes a clinically actionable salutogenic trait. This TCF7-associated trait significantly reduces the emergence of the pathogenic triad. Mechanistically, TCF7 encodes TCF1, an evolutionarily conserved master regulator of T-cell immunity and stemness. Through genome-wide screening of 1380 transcription factors, we identified a TCF7-centered regulatory network governing IR mechanisms, alongside six co-regulated factors. This finding helps explain the substantial variability in healthspan despite stable aging rates by identifying specific biological mechanisms that can vary between individuals.

A great many ways to slow the progression of atherosclerosis have been demonstrated in mice, and some these have been shown to work in large mammals such as pigs and non-human primates. Slowing atherosclerosis isn't the hard problem; regressing existing atherosclerotic plaque so as to clear arteries and restore cardiovascular function is the outcome that the research and development community continues to struggle with. None of the existing approaches used in the clinic produce reliable, large regression of plaque, and only a few ways of achieving some degree of reliable plaque regression have been demonstrated in mouse studies. Here, researchers demonstrate yet another approach to slow plaque growth in large mammals, an orally delivered peptide that likely produces this outcome by reducing inflammatory signaling in the plaque environment.

Advanced atherosclerotic lesions and vascular calcification substantially increase the risk of cardiovascular events. However, effective strategies for preventing or treating advanced atherosclerosis and calcification are currently lacking. This study investigated the efficacy of DT-109 (Gly-Gly-Leu) in attenuating atherosclerosis and calcification in nonhuman primates, exploring its broader therapeutic potential. In this study, twenty male cynomolgus monkeys were administered a cholesterol-rich diet ad libitum for 10 months. Then, the animals were treated either orally with DT-109 (150 mg/kg/day) or a vehicle (water) for 5 months while continuing on the same diet. Plasma lipid levels were measured monthly and at the end of the experiment, pathological examinations of the aortas and coronary arteries and RNA sequencing of the coronary arteries were performed. To explore possible molecular mechanisms, the effects of DT-109 on smooth muscle cells (SMCs) were examined in vitro.

We found that DT-109 administration significantly suppressed atherosclerotic lesion formation in both the aorta and coronary arteries. Pathological examinations revealed that DT-109 treatment reduced lesional macrophage content and calcification. RNA sequencing analysis showed that DT-109 treatment significantly downregulated the pro-inflammatory factors NLRP3, AIM2, and CASP1, the oxidative stress factors NCF2 and NCF4, and the osteogenic factors RUNX2, COL1A1, MMP2, and MMP9, while simultaneously upregulating the expression of the SMCs contraction markers ACTA2, CNN1, and TAGLN. Furthermore, DT-109 inhibited SMC calcification and NLRP3 inflammasome activation in vitro.

These results demonstrate that DT-109 effectively suppresses both atherosclerosis and calcification. These findings, in conjunction with insights from our previous studies, position DT-109 as a novel multifaceted therapeutic agent for cardiovascular diseases.

Link: https://doi.org/10.1038/s41392-025-02201-2

Why does the ability to generate new blood vessels decline with age? One manifestation is a loss of capillaries, which become less dense in tissues with age. Another issue is that efforts to produce therapies that provoke the growth of new vessels, as a way to treat conditions such as peripheral artery disease results from reduced blood flow through vessels obstructed by atherosclerotic plaque, have struggled due to this age-related impairment of blood vessel growth processes. Here, researchers provide evidence for senescent macrophage cells to be an important contributing cause of dysfunction in blood vessel growth and maintenance in older people. This is yet another reason to push for more clinical trials and greater use of existing low-cost senolytic treatments such as the dasatinib and quercetin combination.

Peripheral arterial disease is a common vascular disease in the elderly. Therapeutic revascularization, including angiogenic and arteriogenic therapy, is a promising treatment approach for peripheral arterial disease. However, the progress of clinical trials is not ideal, possibly due to insufficiency of preclinical models, such as not taking into account the effect of aging on vascular regeneration. Macrophages are crucial in angiogenesis and arteriogenesis.

The aging microenvironment typically makes recruited monocytes and macrophages more susceptible to senescence. However, the feature of macrophages in ischemic muscle of old individuals and their underlying role remains unclear. In this study, we reveal that macrophages of ischemic skeletal muscle in old mice are more senescent and proinflammatory. By transplanting macrophages into mice following hindlimb ischemia, we find senescent macrophages inhibit revascularization.

Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing vascular endothelial growth factor A-165B (VEGF-A165B) expression and secretion, and eventually impair revascularization. Due to the presence of two splicing isoforms, the role of VEGF-A in revascularization is complex: VEGF-A165A is the the proangiogenic isoform, while VEGF-A165B is the antiangiogenic isoform. Notably, plasma VEGF-A165B levels are elevated in old patients with peripheral arterial disease and positively associated with a lower ankle brachial index, an assessment of disease severity. Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.

Link: https://doi.org/10.1111/acel.70059

Microglia are innate immune cells resident in the brain, somewhat analogous to macrophages elsewhere in the body. Like macrophages, microglia exhibit a diverse set of states, and can shift from one state to another in response to circumstances. At the high level, much of the literature focuses on the inflammatory M1 state, capable of hunting and destroying pathogens and errant cells, versus the anti-inflammatory M2 state, focused on regeneration and tissue maintenance. But, as the authors of today's open access paper point out, this is an oversimplification of a much more complex continuum of states, some of which don't fit well into the M1 or M2 buckets.

So while it is possible to argue that microglia are important in neurodegenerative conditions in large part because too many of them become inflammatory and dysfunctional in response to the aged tissue environment in the brain, the fine details do matter. Some microglia are more harmful than others, some are more helpful than others, and attempts to broadly adjust the state of microglia may be less helpful than hoped. The suspicion is that more of the panoply of states must be understood in greater detail, and targeted distinctly.

The dual role of microglia in Alzheimer's disease: from immune regulation to pathological progression

Despite extensive research, the role of microglia in Alzheimer's disease (AD) remains complex and dual. The aim of this review is to summarize the most recent advances in research regarding the dual role of microglia in AD concerning both immunomodulation and pathological progression by considering mechanisms of activation of microglia, effects on amyloid-β (Aβ) clearance, tau pathology, and impacts due to genetic variations on microglial functions.

The functional state of microglia, the principal immune cells of the central nervous system (CNS), is far more complex than the traditional M1 and M2 phenotype polarization. Current studies have shown that the state of microglia in AD can comprise a wide variety of different phenotypes that play different roles in different stages of the disease and microenvironments. Aside from the classic M1 and M2 phenotypes, studies have characterized conditions such as disease-associated microglia (DAM) and reactive microglia (RAM) that have specific functional and molecular profiles in AD pathology.

M1 microglia are activated when stimulated by proinflammatory factors such as interferon-γ and lipopolysaccharide, and release proinflammatory factors such as TNF-α, IL-6, IL-1β, and inducible nitric oxide synthase. Excessive secretion of these factors aggravates neuroinflammatory reaction and toxic injury of neurons, and promotes the accumulation of Aβ and the hyperphosphorylation of tau protein. In contrast, M2 microglia are activated by anti-inflammatory factors such as interleukin-4 (IL-4) and interleukin-13 (IL-13), and secrete anti-inflammatory and neurotrophic factors such as interleukin-10 (IL-10), transforming growth factor β (TGF-β), BDNF, and glial-derived neurotrophic factor (GDNF).

Additionally, disease-associated microglia (DAM) have distinct initial AD gene expression patterns and are found surrounding Aβ plaques and clear Aβ as well as modulate tau pathology. TREM2 variants were significantly associated with AD risk increase and that its physiological function is to allow for DAM formation and thus increased Aβ clearance. Pathology of tau also significantly increases with deficient TREM2 function or microglial deficiency, pointing toward an essential role of DAM in the prevention of tau spreading. The phenotypes of AD in microglia are beyond the simple M1 and M2 phenotypes but more evolved phenotypes such as DAM. Each state has its own corresponding functions to perform in the different stages of the disease and microenvironment, and in the future, further molecular mechanisms and functional difference among the states would have to be investigated by studies to un-scramble the multi-functional role of microglia in AD.

One of the potential complications following surgery or injury (or indeed many other forms of acute stress) in older individuals is inflammation in the brain, triggered by inflammation in the body. This can lead to issues such as postoperative delerium, or more lasting cognitive decline. Researchers here provide evidence to suggest that the inflammatory signaling produced by senescent cells is an important mediator of this unwanted side-effect. This signaling can trigger senescence in bystander cells, and given sufficient levels of inflammation, this can occur throughout the body. Timely administration of senolytic treatments that selectively destroy senescent cells can in principle prevent this from happening, however.

Aging has been identified as a leading risk factor for many diseases, including neurodegenerative disorders. While cellular senescence has been linked to age-related neurodegenerative conditions, its involvement in peripheral stress-associated brain disorders is just beginning to be explored. In this study, we investigated the impact of senescent cells on peripheral stress-induced neuroinflammation using orthopedic surgery as a model.

Our results demonstrate an increased accumulation of senescent cells and neuroinflammation in the aged mouse hippocampus following surgery. Intermittent treatment of the mice with the senolytic drugs dasatinib and quercetin (D/Q) showed a significant reduction in surgery-induced senescent cell burden. This reduction in senescent cell accumulation was correlated with reduced surgery-induced neuroinflammation, as evidenced by decreased glial cell activity. Consistent with these observations, we also observed reduced levels of proinflammatory senescence-associated secretory phenotype factors in circulation, following fracture surgery, in mice treated with D/Q.

Overall, our findings underscore the pivotal role of cellular senescence in surgery-induced neuroinflammation and highlight the therapeutic potential of eliminating senescent cells as a potential strategy to manage peripheral stress-induced neuroinflammatory conditions.

LinK: https://doi.org/10.1093/pnasnexus/pgaf103

A growing body of work implicates the accumulation of senescent cells in degeneration of function and structure in the discs that separate vertebrae in the spine. This is a prevalent issue, causing pain and loss of function. The ability to restore lost function is limited at best, but clearance of senescent cells via senolytic drugs has shown promise in animal studies of degenerative disc disorders. Here, researchers employ a novel senolytic approach to produce beneficial outcomes in mice.

Low back pain (LBP) is often related to IVD degeneration and is the number one global cause of years lived with disability. The personal costs of reduced quality of life and the economic cost to healthcare systems are enormous. Senescent cells (SnCs) accumulate in degenerating intervertebral discs (IVDs) and are proposed to directly contribute to disease progression and back pain. Senescence-associated secretory phenotype (SASP) factors secreted by SnCs generate a pro-inflammatory environment that accelerates the breakdown of the extracellular matrix (ECM) and worsens IVD degeneration.

The senolytic drugs o-vanillin and RG-7112 remove human senescent IVD cells and reduce SASP factor release from cells and intact IVDs. The senolytic drug RG-7112 is a p53/MDM2 complex inhibitor. o-Vanillin is a natural senolytic and senomorphic substance that has been shown to reduce senescence burden and SASP factor release and to improve tissue homeostasis in human IVDs, indicating that they could potentially reduce pain. Here we treated sparc-/- mice, an animal model of LBP, with oral administration of o-vanillin and RG-7112 as single or combination treatments. Treatment reduced LBP and SASP factor release and removed SnCs from the IVD and spinal cord. Treatment also lowered degeneration scores in the IVDs, improved vertebral bone quality, and reduced the expression of pain markers in the spinal cord.

Together, our data suggest RG-7112 and o-vanillin as potential disease-modifying drugs for LBP and other painful disorders linked to cell senescence.

Link: https://doi.org/10.1126/sciadv.adr1719

Broadly, there are two viewpoints on the approach the treatment of aging as a medical condition. The first approach is most clearly represented by the Strategies for Engineered Negligible Senescence (SENS). The goal is to repair or otherwise address the underlying cell and tissue damage that causes aging. This damage is already catalogued and new additions have been few and far between in recent decades. There is little expectation that therapies will have to be personalized to any great degree. Any one therapy that addresses any one cause of aging will produce benefits in every older person. In this, the damage repair approach is analogous to the initial development and early use of antibiotics. Antibiotics applied in much the same way to every patient produced such a large improvement in outcomes that personalization of use, even were it possible at the time, was a low priority. Personalization of treatments came only later. Thus the first step in the SENS program of damage repair is to produce therapies and test them to see how effectively they produce rejuvenation.

The second approach to the treatment of aging is called geroscience, and is largely focused on manipulating the operation of metabolism so as to slow aging. Today's open access paper provides a good summary of the geroscience program and goals. As a field it is very connected to personalized medicine, systems biology, and other views that prioritize differences between individuals. Geroscience starts from the point of considering that some people age more slowly than others, and then asks how we can do that for everyone, and whether there are ways to go a little further than presently exists in nature. The first step for the geroscience program is a great deal of further research aimed at obtaining a greater understanding of how specific differences in genetics, metabolism, and environment act to produce the observed differences in pace of aging and vulnerability to specific forms of cell and tissue damage and dysfunction.

At the end of the day, the most important difference between SENS-style damage repair and geroscience is that the latter is very limited in its ambitions (and most likely in outcomes) in the matter of human healthy life span. It seeks only to modestly slow aging, and will likely only achieve that goal. In contrast, damage repair approaches aim at outright rejuvenation. These two approaches to aging are not in conflict in principle, are complimentary strategies - but they are in conflict when it comes to the space of ideas, funding, and the will to make progress.

From geroscience to precision geromedicine: Understanding and managing aging

The last decade has witnessed a dramatic change in aging research. Geroscience is an emerging field that seeks to understand the biological mechanisms of aging and how they contribute to age-related diseases. It operates on the principle that aging is the primary risk factor for many age-related diseases, such as diabetes, cardiovascular disease, cancer, and neurodegenerative disorders. By studying the biological processes that drive aging, mostly in rodents and occasionally in non-human primates, geroscientists aim to develop interventions that can extend the quality of life and healthspan, i.e., the period of life spent in good health. In addition, geroscientists analyze specimens from healthy and diseased individuals of various ages to identify diagnostically relevant biomarkers of biological aging and to deconvolute age-associated pathways that can be targeted by gerotherapeutics for prevention or treatment of specific diseases. The acceleration of geroscientific discoveries has been fueled by the growing societal interest in aging, the creation of specific research centers, the expansion of public and private funding programs, and the increasing number of venture funds and biotech companies developing potential anti-aging remedies. The field holds promise for transforming the way we approach age-related diseases, shifting the focus from treating manifest conditions to targeting aging itself as a root cause.

Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors. Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans. Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation. New molecular profiling technologies enable the characterization of gerogenic and gerosuppressive pathways, which serve as biomarkers of aging, hence inaugurating the era of precision geromedicine.

In our vision, geromedicine should pursue three general objectives that distinguish this discipline from other medical specialties that usually target manifest diseases. First and foremost, in (apparently) healthy individuals, geromedicine should apply a systems biology approach analyzing interactions of biological, clinical, psychological, social, and environmental measures to model and predict health trajectories, incidence of disease, and utilization of gerotherapeutics, hence proposing "proactive measures" to decelerate, halt, or reverse such effects. Second, geromedicine should spot "precocious derangements" - the potential precursors of disease - in still-healthy individuals to prevent the development of specific pathologies. Third, geromedicine should seek the biomarker-informed detection of "subclinical lesions" (such as asymptomatic cancers or arterial stenoses) to intercept them by early therapeutic intervention and hence to avoid their transition to clinically manifest diseases and the consequent health deterioration that would affect the entire organisms.

Researchers here report on a novel approach to encourage nerve regeneration, and demonstrate positive results in mice with spinal cord injury. Delivering platelet-derived growth factor BB (PDGF-BB) as a protein therapy to the injured nerve tissue changes the behavior of pericyte cells that normally interfere in any possible regrowth of the axons making up the nerve. In the presence of PDFG-BB, pericytes act to indirectly encourage axon regrowth. As the researchers note, this discovery likely has other applications beyond treating spinal cord injuries.

Spinal cord injuries are severe not only because they prevent transmission of information across the site of the injury, but because all of the vasculature structure and function is also compromised. Previous research suggesting pericytes interfere with spinal cord injury recovery had led some scientists to recommend clearing them from the lesion site to aid repair. But cancer research has indicated pericytes' properties change when they're exposed to a protein called platelet-derived growth factor BB (PDGF-BB), and the cells act to encourage blood vessel formation. This is one way tumors generate their own blood supply.

Earlier neuroscience research also indicated that pericytes are highly "plastic," meaning they are very responsive to changes in the microenvironment - including the presence of PDGF-BB. Researchers saw potential to harness that cell-protein relationship to stabilize the vasculature surrounding a spinal cord injury. In the process, they found the newly sprouted blood vessels established a pathway for regenerated axons to follow.

Turning to experiments in animals with spinal cord injury, researchers waited for seven days after the injury - the equivalent of about nine months in a human adult - before injecting a single dose of PDGF-BB at the injury site. Analysis of tissue four weeks after the injury showed that the PDGF-BB injection produced robust axon regenerative growth compared to the axon response in injured control mice. Electrophysiological and movement assessments of injured animals treated with PDGF-BB detected sensory activity beyond the lesion site and showed the mice regained better control of their hind limbs compared to control mice. The animals also were less sensitive to a non-painful stimulus, suggesting they did not experience the neuropathic pain that is often triggered by a spinal cord injury.

Link: https://news.osu.edu/building-cellular-bridges-for-spinal-cord-repair-after-injury/

This very interesting paper finds evidence of early adult impairment of cognitive function to correlate with Alzheimer's-associated biomarkers such as tau and neurofilament light chain. It is well known that Alzheimer's disease has a decades-long onset. Measurable biomarkers are associated with future pathology well in advance. Nonetheless, to extend that back to as early an age as mid-20s is a novel way of looking at the progression of cognitive decline over a lifetime. One has to wonder to what degree this is a measurement of the effects of poor lifestyle maintenance or exposure to persistent pathogens on the brain in early adult life. Similarly, whether a continuum of the same pathological processes leads unbroken from low levels in early life to high levels in late life, or whether early life and late life exhibit significantly different mechanisms that happen to converge on impaired cognitive function.

Data from the National Longitudinal Study of Adolescent to Adult Health were analyzed. Analytic sample sizes ranged from 4,507 to 11,449 participants in Wave IV and from 529 to 1121 participants in Wave V. The survey-weighted median (IQR) age was 28 (26-29) years in Wave IV and 38 (36-29) years in Wave V. We measured the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score comprised of age, education, sex, systolic blood pressure, body mass index, cholesterol, and physical activity, and also apolipoprotein E ε4 allele (APOE ε4) status. We further measured total Tau and Neurofilament light (NfL), high sensitivity C-reactive protein (hsCRP), Interleukin (IL)-1β, IL-6, IL-8, IL-10, and Tumor necrosis factor alpha (TNF-α). Outcomes included immediate word recall, delayed word recall, and backward digit span.

Several key risk factors for Alzheimer's Disease were associated with standard measures of cognition in 24- to 44-year-olds in the U.S., suggesting that these factors may be related to cognitive function decades before the onset of Alzheimer's Disease. The CAIDE score was consistently linked to all three cognitive function measures (immediate recall, delayed recall, and backward digit span). Notably, a key genetic risk factor, APOE ε4, was not associated with recall nor backward digit span, suggesting that the effects of APOE ε4 may not become apparent until middle to older age. Total Tau was associated with lower immediate word recall but not backward digit span scores. Although higher levels of NfL showed a trend toward lower backward digit span scores, the association was not statistically significant. A limited number of immune markers were significantly associated with cognitive function at ages 24-34 years; however, some of these associations appeared to become more robust in the following decade of life. For instance, IL-6 was not associated with backward digit span in Wave IV but showed a significant association with lower backward digit span in Wave V. Similarly, IL-8 was not associated with cognitive scores in Wave IV but was associated with all three measures of cognition in Wave V.

These findings suggest that cardiovascular, neurodegenerative, and immune markers may be associated with critical measures of cognitive function at much younger ages than previously recognized, with some associations becoming more prominent between the early midlife ages of 33 and 44.

Link: https://doi.org/10.1016/j.lana.2025.101087