Fight Aging!

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Aging and Cancer-Inextricably Linked Across the Lifespan

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

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

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

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

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

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

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

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

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

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

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

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

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

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

How does stochastic nuclear DNA damage contribute to degenerative aging? Most mutation occurs in regions of the genome that are not used, in somatic cells with few divisions remaining before the Hayflick limit and self-destruction. Thus the impact is minimal. One point of view on this topic is that only mutations in stem cells are important. These mutations spread slowly in waves throughout a tissue, replicated in the somatic cell lineages descended from mutated stem cells, a process known as somatic mosaicism. There is some evidence for somatic mosaicism to contribute to a few age-related dysfunctions, but not very much of it.

Another point of view with limited evidence, but very interesting evidence, is that the process of repairing repeated double strand breaks, wherever they occur in the genome, changes the molecular mechanisms responsible for controlling the structure of nuclear DNA in deterministic ways, such as by depleting specific factors. This leads to the characteristic epigenetic changes of aging in every cell, as every cell undergoes this form of stochastic DNA damage.

In today's open access paper, researchers propose another, quite different way in which DNA damage can be linked to epigenetic changes. The authors argue for mutational damage to the genome to directly alter epigenetic regulation of the structure of DNA. The researchers looked at mutations occurring at CpG sites where the genome is methylated to adjust its structure, and found that mutation at a CpG site doesn't just affect the methylation status of that CpG site, but also nearby sites as well, altering the expression of numerous genes in predictable way.

Why Our Biological Clock Ticks: Research Reconciles Major Theories of Aging

There are two prevailing theories about the relationship between aging and DNA. The somatic mutation theory suggests that aging is caused by the accumulation of mutations, permanent changes in our DNA sequence that occur randomly. The epigenetic clock theory suggests that aging occurs due to the accumulation of epigenetic modifications, minor changes to the chemical structure of DNA that do not alter the underlying sequence, but instead change which genes are on or off. Unlike mutations, epigenetic modifications can also be reversed in some cases.

Researchers analyzed data from 9,331 patients catalogued in the Cancer Genome Atlas and the Pan-Cancer Analysis of Whole Genomes. By comparing genetic mutations to epigenetic modifications, they found that mutations were predictably correlated with changes in DNA methylation, one type of epigenetic modification. They found that a single mutation could cause a cascade of epigenetic changes across the genome, not just where the mutation occurred. Using this relationship, the researchers were able to make similar predictions of age using either mutations or epigenetic changes.

Somatic mutation as an explanation for epigenetic aging

DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.

Senescent cells accumulate with age in part because the immune system becomes less able to clear senescent cells in a timely manner. Researchers have much yet to discover regarding the details of this decline, but some of the existing discoveries seem analogous to the ways in which cancer cells can shield themselves from the immune system via altered surface features. Such discoveries pave the way for the development of ways to restore at least some of the lost competence of the aged immune system, encouraging it to better destroy senescent cells. Here, the focus is on natural killer cells, now well known to be involved in clearance of senescent cells and the target of a number of research programs in this context.

Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the natural killer (NK)-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells.

We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the senescence-associated secretory phenotype (SASP) via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.

Link: https://doi.org/10.1126/sciadv.adn2811

In recent years, the level of GATA4 expression has been connected to a variety of age-related issues, such as scarring in heart tissue. More generally GATA4 is associated with cellular senescence, a major issue in aging. Senescent cells accumulate with age to disrupt tissue structure and function via pro-inflammatory signaling. Additionally, senescence in specific cell populations, such as stem cells, impairs the ability of these cells to support and maintain tissues. In this context, researchers here review what is known of the role of GATA4 in the senescence of mesenchymal stem cells specifically.

The Mesenchymal Stem Cell (MSC) is a multipotent progenitor cell with known differentiation potential towards various cell lineages, making it an appealing candidate for regenerative medicine. One major contributing factor to age-related MSC dysfunction is cellular senescence, which is the hallmark of relatively irreversible growth arrest and changes in functional properties. GATA4, a zinc-finger transcription factor, emerges as a critical regulator in MSC biology. Originally identified as a key regulator of heart development and specification, GATA4 has since been connected to several aspects of cellular processes, including stem cell proliferation and differentiation.

Accumulating evidence suggests that the involvement of GATA4-nuclear signalizing in the process of MSC senescence-related traits may contribute to age-induced alterations in MSC behavior. GATA4 emerged as the central player in MSC senescence, interacting with several signaling pathways. Studies have shown that GATA4 expression is reduced with age in MSCs, which is associated with increased expression levels of senescence markers and impaired regenerative potential. At the mechanistic level, GATA4 regulates the expression of genes involved in cell cycle regulation, DNA repair, and oxidative stress response, thereby influencing the senescence phenotype in MSCs.

The findings underscore the critical function of GATA4 in MSC homeostasis and suggest a promising new target to restore stem cell function during aging and disease. A better understanding of the molecular mechanisms that underlie GATA4 mediated modulation of MSC senescence would provide an opportunity to develop new therapies to revitalize old MSCs to increase their regenerative function for therapeutic purposes in regenerative medicine.

Link: https://doi.org/10.1016/j.reth.2024.11.017

With advancing age, muscle mass and muscle strength are both steadily reduced, leading to sarcopenia and dynapenia. Interestingly, a sizable fraction of the observed outcomes of aging on muscle function in wealthier populations are avoidable, a consequence of our modern age of comfort and machineries of transport. We exercise a good deal less than our ancestors did. Humans evolved in a hunter-gatherer environment of daily exertion. Present day hunter-gatherers exhibit a good deal less heart disease and greater maintenance of muscle mass and function than is the case for those of us who drive to work and the grocery store. Use it or lose it, as they say.

Nonetheless, even the athletic succumb to aging eventually. A great deal is known of the various contributions to muscle aging, such as loss of stem cell function, mitochondrial dysfunction, inflammation, detrimental changes in neuromuscular junctions, and so forth. This is a microcosm of aging as a whole, in that: (a) there is little understanding of which of the many contributions are most important, (b) there is little understanding of how these contributions interact with one another, which are primary, which are secondary, and (c) for every mechanism there is essentially an unlimited amount of exploratory research into relevant cellular biochemistry that could be conducted. Mining sometimes finds gold, fundamental research sometimes finds something that can be turned into a therapy.

From molecular to physical function: The aging trajectory

Aging is accompanied by a decline in muscle mass, strength, and physical function, a condition known as sarcopenia. Muscle disuse attributed to decreased physical activity, hospitalization, or illness (e.g. sarcopenia) results in a rapid decline in muscle mass in aging individuals and effectively accelerates sarcopenia. Consuming protein at levels above (at least 50-100% higher) the current recommended intakes of ∼0.8 g protein/kg bodyweight/day, along with participating in both resistance and aerobic exercise, will aid in the preservation of muscle mass.

Physiological muscle adaptations often accompany the observable changes in physical independence an older adult undergoes. Muscle fibre adaptations include a reduction in type 2 fibre size and number, a loss of motor units, reduced sensitivity to calcium, reduced elasticity, and weak cross-bridges. Mitochondrial function and structure are impaired in relation to aging and are worsened with inactivity and disease states but could be overcome by engaging in exercise.

Intramuscular connective tissue adaptations with age are evident in animal models; however, the adaptations in collagenous tissue within human aging are less clear. We know that the satellite muscle cell pool decreases with age, and there is a reduced capacity for muscle repair/regeneration. Finally, a pro-inflammatory state associated with age has detrimental impacts on the muscle. The purpose of this review is to highlight the physiological adaptations driving muscle aging and their potential mitigation with exercise/physical activity and nutrition.

Population aging is a shift in the distribution of ages across the population from younger to older. This is a part of the great demographic transition taking place across most of the world today, accompanying the rise in wealth and overall quality of life. As we do not yet have the means to control aging through medicine, it is the case that as the older fraction of the population grows, so too does the overall incidence of age-related disease and disability. The paper noted here is one of any number of views into the sizable amount of data on this phenomenon. As the authors' scenario 3 illustrates, just to keep up with the aging of the population, just to maintain the present rates of death and disability, would require sizable improvements in the ability of medical services to extend healthy life span.

We used health-adjusted life expectancy (HALE) to measure quality of life and disability-adjusted life years (DALY) to quantify the burden of disease for the population of Guangzhou. Changes in HALE and DALY between 2010-2020 and 2020-2030 were decomposed to isolate the effects of population aging. Three scenarios were analyzed to examine the relative relationship between disease burden and population aging. In Scenarios 1 and 2, the disease burden rates in 2030 were assumed to either remain at 2020 levels or follow historical trends. In Scenario 3, it was assumed that the absolute numbers of years of life lost (YLL) and years lived with disability (YLD) in 2030 would remain unchanged from the 2020 levels.

Between 2010 and 2020, 56.24% [69.73%] of the increase in male [female, values in brackets] HALE was attributable to the mortality effects in the population aged 60 and over, while -3.74% [-9.29%] was attributable to the disability effects. The increase in DALY caused by changes in age structure accounted for 72.01% [46.68%] of the total increase in DALY. From 2020 to 2030, 61.43% [69.05%] of the increase in HALE is projected to result from the mortality effects in the population aged 60 and over, while -3.88% [4.73%] will be attributable to the disability effects.

The increase in DALY due to changes in age structure is expected to account for 102.93% [100.99%] of the total increase in DALY. In Scenario 1, YLL are projected to increase by 45.0% [54.7%], and YLD by 31.8% [33.8%], compared to 2020. In Scenario 2, YLL in 2030 is expected to decrease by -2.9% [-1.3%], while YLD will increase by 12.7% [14.7%] compared to 2020. In Scenario 3, the expected YLL rates and YLD rates in 2030 would need to be reduced by 15.3% [15.4%] and 15.4% [15.6%], respectively, compared to 2020.

Link: https://doi.org/10.1186/s41256-024-00393-8

Using vitamin B3 derivatives as a means to modestly improve metabolism to treat various conditions has a several decade history. The results have been poor; largely this is a history of failed clinical trials. This mostly predates the recent focus on declining NAD+ levels in mitochondria in aging, and the use of vitamin B3 derivatives, such as nicotinamide riboside, to increase NAD+ levels. Exercise produces larger gains than these supplement approaches in NAD+ levels. The clinical trial noted here is fairly characteristic of the type; one sees modest gains in some of the parameters that one might expect to be linked to improved mitochondrial function, but no significant effect on the disease state.

Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 gram/day) on cognition and plasma Alzheimer's disease biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.

The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (z-scores) for cognition and step counts from wearables.

Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau217 concentrations after taking NR, while an 18% increase with PBO. No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores, or step counts. For the within-individual comparison, pTau217 concentrations significantly decreased during the NR phase compared to the PBO, while step counts significantly increased during the NR phase than PBO.

Link: https://doi.org/10.1002/trc2.70023

Senescent cells accumulate with age, and contribute to the dysfunction of aging via their inflammatory secretions. A cell becomes senescent in response to reaching the Hayflick limit on replication, or in response to damage or stress. In the normal course of events, a senescent cell ceases replication, and this is an irreversible change. A few approaches have been demonstrated to reverse this aspect of the senescent state. The question is whether it is a good idea to do so. For example, senescent cells accumulate DNA damage on entry to the senescent state. Some senescent cells are senescent for good reason, such as potentially cancerous DNA damage. It has been thought that allowing these cells to replicate again is just asking for trouble.

Still, some researchers have explored reversal of senescence. In today's open access paper, quite compelling evidence is provided for reversal of senescence to be a good thing: the mice involved in the study live longer, show improved function, and suffer no increase in cancer incidence. This is quite fascinating, and certainly not what one might expect. One way to look at this is to theorize that most senescent cells present in an aged animal are not in fact senescent for any good reason, and that much of their DNA damage is innocuous or can be repaired on exiting the senescent state. Possibly, as seems to be the case for telomerase gene therapy, increased cancer risk due to enabling the activity of problem cells is outweighed by improvements in immune function and surveillance of those problem cells.

Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells

Senescent cells (SnCs) accumulate during aging and secrete the senescence-associated secretory phenotype (SASP), promoting secondary senescence and disrupting normal tissue functions. Consequently, targeting SnCs has emerged as a promising strategy to prolong healthspan and delay the onset of age-related diseases. Therapies targeting SnCs are broadly divided into two major categories: elimination of SnCs (senolytic) and suppression of pathological SASP signaling (senomorphic). These strategies have shown therapeutic benefits in aging and related diseases, including extending lifespan, alleviating inflammation, and improving cognition. However, they also have certain limitations. While the senolytic strategy may effectively eliminate SnCs when scarce, the prevalence of SnCs in tissues increases as individuals age. Eliminating them may result in considerable tissue damage and compromise normal organ function. Moreover, although SASP suppression has rejuvenating effects, it can impede immune surveillance of pathogens and cancer cells. Developing new rejuvenation strategies that target SnCs is crucial to address these challenges.

In this study, we demonstrated that human embryonic stem cell-derived exosomes (hESC-Exos) reversed senescence by restoring the proliferative capacity of SnCs in vitro. In aging mice, hESC-Exos treatment remodeled the proliferative landscape of SnCs, leading to rejuvenation, as evidenced by extended lifespan, improved physical performance, and reduced aging markers. Analysis identified miR-302b enriched in hESC-Exos that specifically targeted the cell cycle inhibitors Cdkn1a and Ccng2. Furthermore, miR-302b treatment reversed the proliferative arrest of SnCs in vivo, resulting in rejuvenation without safety concerns over a 24-month observation period. These findings demonstrate that exosomal miR-302b has the potential to reverse cellular senescence, offering a promising approach to mitigate senescence-related pathologies and aging.

The immune system isn't just a means to defend against pathogens and potentially cancerous cells. It is also intimately involved in tissue function and maintenance, in regeneration from damage, in clearing debris, and communicates at a distance throughout the body via a panoply of signaling molecules. Beyond these functions, which are affected by the age-related decline of the immune system, there is also the point that chronic inflammation changes cell behavior for the worse. A sizable part of the problem of immune aging is the rise of unresolved inflammatory signaling and its effects on tissues.

For decades, the general assumption was that the immune system had no impact on the healthy central nervous system (CNS) and was often regarded as exclusively harmful in the context of brain disorders. This understanding was largely based on the concept of "CNS immune privilege," supported by the presence of the blood-brain barrier (BBB) and the presumed absence of a lymphatic system in the CNS. More recently, a transformed understanding of brain-immune relationships has been established, which opened new avenues in the field of neuroscience, highlighting the fact that neurons require the assistance and tuning provided by the adaptive immune system in the form of novel communication routes between the two systems. According to this view, brain fitness depends on immune fitness, which in turn is modified by our lifestyle.

This intricate dance between the immune and the nervous systems takes part primarily at the brain's borders, where immune cells are concentrated. In aging, the function of these borders and the immune cell composition change, thereby altering the signals transmitted to the brain, negatively impacting brain function. This implies that the cognitive decline observed in aging is not caused solely by the decline in neural function but also by the age-dependent alterations in both the immune niches surrounding the brain and the peripheral immune system. Understanding this lifelong communication route and identifying those immune processes that become defective in aging could aid in developing potential strategies for immune system rejuvenation as a means to slow down or even arrest brain aging.

Link: https://doi.org/10.1016/j.neuron.2024.12.004

A person dies, and there is the irresistible urge to draw a line under their life and summarize. So to the late Mikhail Blagosklonny and his contributions to the modern debate over the causes of aging. Hyperfunction theory doesn't end with the originator, any more than any thread of scientific thought on the matter of aging - Robert Bradbury would no doubt be most interested to see where thought on the role of double stranded breaks in DNA as a mechanism of aging has ended up these days, were he still alive. Still, here we are, a chance to look back at one portion of the ongoing debate over programmed aging versus antagonistic pleiotropy, and the primacy versus secondary nature of molecular damage.

Blagosklonny directly engaged with Aubrey de Grey, a proponent of damage-based theories, in a 2021 exchange. Blagosklonny emphasized that hyperfunction, not damage accumulation, underpins aging, arguing that Hyperfunction Theory explains why damage accumulates - not from aging but as a downstream byproduct of hyperactive signaling: "Hyperfunction of signaling pathways can occur without progressive changes of their activity. For example, when the same activity of growth-promoting pathways remains unchanged in postdevelopment, it is a hyperfunction. By analogy, a car driving 65 mph on highway is not speeding (hyperfunction) but driving 65 mph on the driveway is. In the latter case, the car certainly will be damaged, but not by rusting (molecular damage), but by damage of its macroparts. Similarly, hyperfunction does not cause molecular damage, but causes organ damage. Thus, the brain is damaged by stroke, which can be a result of hypertension, which, in turn, is developed by hyperfunctional cells of multiple tissues. There is no place for molecular damage in this sequence of events..."

In his rebuttal, de Grey argued that while the Hyperfunction Theory offers valuable insights, damage repair remains essential for addressing aging: "While hyperfunction undoubtedly contributes to aging, it cannot fully explain the accumulation of oxidative and genetic damage that impairs cellular function." Blagosklonny further posited that while molecular damage accumulates, it does not necessarily constrain lifespan under typical conditions; however, if interventions extend lifespan significantly, such damage may become more limiting. This dialogue highlights the contrasting paradigms while reinforcing Blagosklonny's central assertion that aging interventions should prioritize targeting hyperfunction at its source.

Building on the Hyperfunction Theory, Blagosklonny proposed that targeting overactive growth pathways could mitigate aging and its associated diseases. This theoretical framework directly informs the exploration of rapamycin, an mTOR inhibitor, as a potential therapeutic agent. The Hyperfunction Theory, together with João Pedro de Magalhães' related developmental model has inspired the emergence of an expanding suite of programmatic theories, encompassing hypofunction, costly programs, constraint theory, and adaptive death.

Link: https://doi.org/10.18632/aging.206189

The thymus is a small organ, and the location in which thymocytes created in the bone marrow mature into T cells of the adaptive immune system. Unfortunately, the thymus atrophies steadily with advancing age. Active tissue is replaced with fat, reducing the supply of new T cells to a tiny fraction of what it was in early adult life. This process is a major factor in the aging of the immune system, leading over time to an adaptive immune system packed full of exhausted, senescent, malfunctioning T cells, the consequence of a lack of replacements.

A range of approaches are under development aimed at producing regrowth of the aged thymus, and consequent restoration of the adaptive immune system. In today's open access paper, researchers here comment on a novel approach to the regrowth of the aged, atrophied thymus. It involves delivery of RANKL, a transmembrane protein that also has a circulating form. RANKL appears necessary for sustained thymic function, and levels are reduced with age. It is likely that selective delivery of RANKL to only cells relevant to thymic function would be necessary in order to produce a viable therapy, however, as the protein is known to be involved in other processes throughout the body.

Rejuvenating the immune system

A recent study elucidates the role of the RANK-RANKL axis in the thymus during aging. The study demonstrates that decreased RANKL levels occur in thymocytes, leading to impaired cellularity and function of thymic epithelial cells (TECs) and endothelial cells (ECs), and subsequently to thymic involution. Their findings were recapitulated in young mice by neutralizing RANKL levels, while exogenous RANKL administration in aged mice restored thymic architecture, TEC and EC abundance, and their functional properties. Similarly, RANKL stimulated cellularity and maturation of epithelial and endothelial cells in human thymic organocultures. Moreover, RANKL treatment in aged mice improved T-cell progenitor homing to the thymus and boosted T-cell production. As an outcome, peripheral T-cell renewal and effective antitumor and vaccine responses were achieved.

In the aging thymus, apart from reduced key thymocyte subsets, diminished RANKL expression in these cells was also evident. The aging process is characterized by accumulation of DNA lesions, due to impaired efficiency of DNA repair networks with age as well as by epigenetic changes. Overall, these changes result in profound chromatin modifications reflected by global heterochromatin loss and redistribution. These events subsequently drive transcriptional changes that are anticipated to affect potent RANKL regulators such as hormones, cytokines, and signaling cascade components. As an example, histone demethylases influence lifespan by modulating components of cardinal longevity routes, such as the IGF-1 axis. IGF-1 induces RANKL and its levels are known to decrease with age, thus providing a possible explanation of low RANKL expression during thymic involution.

Researchers have investigated inhibition of the Hippo pathway as a potential basis for regenerative therapies. Meanwhile some of the factors connected to Hippo, such as YAP and TAZ, have been connected to regulation of cellular senescence. This review outlines more of bigger picture of the relationship between Hippo signaling and cellular senescence, an important contribution to degenerative aging.

The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases.

Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest. It acts as a powerful defense mechanism against normal organ development and aging-related diseases. On the other hand, the accumulation of senescent cells without their proper removal contributes to the development or worsening of cancer and age-related diseases.

A correlation was recently reported between the Hippo pathway and cellular senescence, which preserves tissue homeostasis. This review is the first to describe the close relationship between aging and the Hippo pathway, and provides insights into the mechanisms of aging and the development of age-related diseases. In addition, it describes advanced findings that may lead to the development of tissue regeneration therapies and drugs targeting rejuvenation.

Link: https://doi.org/10.3390/cells14010013

Forms of calorie restriction and fasting tend to reduce the chronic inflammation characteristic of aging, and also produce numerous other beneficial alterations to the operation of metabolism. In the case of inflammatory age-related diseases, such as neurodegenerative conditions, a body of work exists to suggest that some benefit can be obtained via these lifestyle interventions. As pointed out here, the human data on the effects of calorie restriction and fasting on the progression of neurodegenerative conditions is far from rigorous and extensive enough to keep scientists happy, however.

Interest has grown in intermittent fasting (IF) as a potential lifestyle intervention for promoting brain health and slowing cognitive decline. IF has been shown to increase levels of circulating ketones to higher levels than caloric restriction (CR), supporting its potential for neuroprotection. As more research emerges, the question is whether IF can be integrated into existing lifestyle recommendations to further support cognitive function in the face of decline. The objective of this review is to discuss IF as it relates to neuroplasticity, inflammation, and neurocognitive disorders. Rather than examining IF as a preventive strategy, this paper evaluates its potential as a therapeutic approach to mitigate existing symptoms and improve brain function in the context of early to advanced neurocognitive disorders.

Preclinical evidence demonstrates that IF enhances hippocampal neurogenesis and synaptic plasticity through pathways involving BDNF and CREB. IF also reduces neuroinflammation, as shown in animal models of Alzheimer's disease, vascular cognitive impairment, and high-fat diet-induced cognitive impairment. Human studies, though limited, suggest that regular IF may improve cognitive function and reduce markers of oxidative stress and inflammation in individuals with mild cognitive impairment. Further clinical research is necessary to confirm long-term safety and efficacy and to refine IF protocols for broader clinical application.

Link: https://doi.org/10.1016/j.jnha.2025.100480

Benign prostate hyperplasia is a common aspect of aging in men, an enlargement of the prostate over time that occurs for underlying reasons that remain incompletely understood. Given too much enlargement the condition becomes far from benign, as it can interrupt the ability to urinate. It also appears to increase the risk of later prostate cancer. Empirically, various medications and lifestyle changes seem to help in some patients, but reliable prevention and reversal of the condition remains out of reach.

In today's preprint paper, researchers provide evidence linking a subpopulation of T cells that arises with age to the development of benign prostate hyperplasia, implying a link to immune aging. This is particularly interesting in the context that prior infection and inflammation of the prostate (known as prostatitis) has been shown to increase the risk of later benign prostate hyperplasia. There is also the suggestion that this can be tied in to the presence and activity of senescent cells present in the aged prostate, with the T cells encouraging greater bad behavior on the part of senescent cells.

Immune cell single-cell RNA sequencing analyses link an age-associated T cell subset to symptomatic benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is among the most common age-associated diseases in men; however, the contribution of age-related changes in immune cells to BPH is not clear. The current study determined that an age-associated CD8+ T cell subset (Taa) with high Granzyme K (GZMKhi) and low Granzyme B (GZMBlow) gene expression infiltrate aged human prostates and positively correlate with International Prostate Symptom Score (IPSS).

A velocity analysis indicated that CD8+ T cell differentiation is altered in large BPH prostates compared to small age-matched prostates, favoring Taa accumulation. In vitro granzyme K treatment of human BPH patient-derived large prostate fibroblasts increased secretion of pro-inflammatory senescence-associated secretory phenotype (SASP)-associated cytokines. This data suggests that granzyme K-mediated stimulation of prostate stromal fibroblast SASP cytokine and chemokine production promotes prostate immune cell recruitment and activation. Overall, these results connect symptomatic BPH with immune aging.

Senescent cells accumulate with age in tissues throughout the body, and their pro-inflammatory signaling becomes increasingly disruptive to tissue structure and function. Studies suggest that senescent cells contribute meaningfully to near all age-related conditions. Selective clearance of senescent cells has produced sometimes quite impressive regression of age-related disease in animal models. One more example of this sort of research is presented here, in which researchers show that senolytic treatment to reduce the burden of cellular senescence in aged mice reduces the negative impact of periodontal disease, such as bone loss.

Cellular senescence has emerged as one of the central hallmarks of aging and drivers of chronic comorbidities, including periodontal diseases. Senescence can also occur in younger tissues and instigate metabolic alterations and dysfunction, culminating in accelerated aging and pathological consequences. Senotherapeutics, such as the combination of dasatinib and quercetin (DQ), are being increasingly used to improve the clinical outcomes of chronic disorders and promote a healthy life span through the reduction of senescent cell burden and senescence-associated secretory phenotype (SASP). Recent evidence suggests that senescent cells and SASP can contribute to the pathogenesis of periodontal diseases as well.

In this study, we investigated the effect of DQ interventions on periodontal tissue health using preclinical models of aging. In vitro, DQ ameliorated biological signatures of senescence in human gingival keratinocytes upon persistent exposure to periodontal bacteria, Fusobacterium nucleatum, by modulating the levels of key senescence markers such as p16, SA-β-galactosidase, and lamin-B1, and inflammatory mediators associated with SASP including interleukin-8, matrix metalloproteinase (MMP)-1, and MMP-3. In vivo, the oral administration of DQ mitigated senescent cell burden and SASP in gingival tissues and reduced naturally progressing periodontal bone loss in aged mice. Collectively, our findings provide proof-of-concept evidence for translational studies and reveal that targeting gingival senescence and the senescence-associated secretome can be an effective strategy to improve periodontal health, particularly in vulnerable populations.

Link: https://doi.org/10.1177/00220345241299789

Hearing loss has been correlated with the risk of numerous forms of neurodegenerative condition. There are many studies similar to the one noted here, correlating degree of hearing loss with risk of Parkinson's disease. While it seems to be the case that hearing loss can accelerate degeneration in the brain, a consequence of reduced input and brain activity in some areas, it is also the case that both hearing loss and neurodegenerative conditions arise from the same underlying forms of cell and tissue damage that drive aging more generally.

Hearing impairment is implicated as a risk factor for Parkinson's disease (Parkinson's) incidence, with evidence suggesting that clinically diagnosed hearing loss increases Parkinson's risk 1.5-1.6 fold over 2-5 years follow up. However, the evidence is not unanimous with additional studies observing that self-reported hearing capabilities do not significantly influence Parkinson's incidence. Thus, additional cohort analyses that draw on alternative auditory measures are required to further corroborate the link between Parkinson's and hearing impairment.

This was a pre-registered prospective cohort study using data from the UK Biobank. Data pertaining to 159,395 individuals, who underwent speech-in-noise testing via the Digit Triplet Test, DTT, and were free from Parkinson's at the point of assessment, were analysed. A Cox Proportional Hazard model, controlling for age, sex and educational attainment was conducted. During a median follow up of 14.24 years, 810 cases of probable Parkinson's were observed. The risk of incident Parkinson's increased with baseline hearing impairment [hazard ratio: 1.57], indicating 57% increase in risk for every 10dB increase in speech-reception threshold (SRT). However, when hearing impairment was categorised in accordance with UK Biobank SRT norms neither 'Insufficient' nor 'Poor' hearing significantly influenced Parkinson's risk compared to 'Normal' hearing.

In conclusion, the congruence of these findings with prior research further supports the existence of a relationship between hearing impairment and Parkinson's incidence.

Link: https://doi.org/10.1016/j.parkreldis.2024.107219

A quarter of humanity dies from heart attack and stroke, caused when an atherosclerotic plaque ruptures to create fragments that block an important blood vessel. Everyone develops atherosclerotic plaque to some degree with advancing age. Cholesterol is manufactured in the liver and transported in the bloodstream attached to forms of low density lipoprotein (LDL) particles. Excess cholesterol is ingested by macrophages and then attached to high density lipoprotein (HDL) particles for transport back to the liver and reuse. This is a complex system of many moving parts and regulators and sensors, and like all complex systems, it runs awry with the damage of aging or obesity. In particular, excess deposition of cholesterol into blood vessel walls starts to overwhelm the ability of macrophages to clean it up, and a fatty plaque begins to form to narrow and weaken that blood vessel.

That is a very high level description, but dive deeper and there is increasing complexity in the details. Other factors are involved, such as the state of chronic inflammation, making macrophages less able to undertake repair activities. Or the presence of oxidized cholesterols or oxidized LDL particles that are more disruptive than cholesterol and LDL, molecule for molecule. Or other mechanisms that can hamper macrophages, increase inflammatory reactions in blood vessels, or otherwise alter cholesterol transport for the worse, from the effects of hypertension on cells in blood vessel walls to the pro-inflammatory signaling of senescent cells to raised levels of lipoprotein (a).

To date, most approaches to the treatment of atherosclerosis have focused on lowering LDL cholesterol levels in the bloodstream. Unfortunately this only (a) slows plaque growth, (b) very slowly, over years, makes plaques a little less likely to rupture by reducing their lipid content. Lowering LDL cholesterol in the bloodstream cannot reliably or rapidly regress atherosclerotic plaque, and so a quarter of humanity continues to die from the consequences of having atherosclerotic plaque. There are a great many other targets that research and development programs might choose as a basis for therapy, however. The challenge, as ever in the matter of everything to do with aging, is that the only good way to find out whether a given approach works well is to try it. Determining just how important one mechanism is versus all the others can only really be determined by fixing that one problem in isolation and observing the results.

So far, all of the well-funded alternative approaches to lowering LDL cholesterol in the bloodstream have failed to demonstrate the ability to reliably and rapidly regress atherosclerotic plaque. Bitterroot Bio's CD47-based approach only slows plaque growth. The same goes for the Silence Therapeutics approach to lowering circulating lipoprotein (a). And so forth. Of the less well funded approaches that have made it out of the laboratory and into preclinical development in biotech companies, so far as I am aware only Repair Biotechnologies and VasoRx have mouse data showing significant plaque regression.

(To be clear, every boutique cardiovascular physician can roll out a few patients with amazing plaque reduction from whatever their special combination of lifestyle interventions, LDL-lowering therapies, and other treatments happens to be. The problem is that any degree of regression of atherosclerotic plaque isn't the reliable outcome for any of these approaches. The average for plaque regression is close to zero. New technologies, new approaches are needed).

Cyclarity Therapeutics is an interesting case. Like Repair Biotechnologies, this company emerged from the SENS community, though unlike Repair Biotechnologies the scientific program giving rise to the company was developed at the SENS Research Foundation. The company uses carefully designed cyclodextrins to sequester and clear 7-ketocholesterol, a toxic altered form of cholesterol that is suggested to be important in driving atherosclerosis by incapacitating the macrophages attempting to repair atherosclerotic plaque. There is no animal model that exhibits a human-like level of 7-ketocholesterol, however. It would be very costly in time and funding to produce and validate such a model, so the Cyclarity leadership chose to move directly into humans without the usual preclinical animal data to show effects on plaque - and fortunately found investors willing to fund that program. We can hope that clearing 7-ketocholesterol will be a way to reliably regress atherosclerotic plaque! Yet it may prove to be another way to only slow the growth of plaque. The only way to find out is to try it and see.

Cyclarity Therapeutics Secures Approval for First-in-Human Clinical Trial

Cyclarity Therapeutics is pleased to announce regulatory approval to begin its first-in-human clinical trial. The trial will be conducted at CMAX, one of Australia's leading clinical research centers, in partnership with Monash University. This effort will be led by Dr. Stephen Nicholls of the Victorian Heart Institute (VHI), a distinguished leader in cardiovascular medicine. In addition to a traditional single (SAD) and multiple ascending dose (MAD) phase 1 trial, the authorization includes an allowance to enroll 12 patients with Acute Coronary Syndrome (ACS) to assess the safety of UDP-003 in individuals with plaque buildup, as well as to explore anecdotal evidence of efficacy. This represents a critical first step in evaluating the potential impact of our therapy in a population with high unmet need.

Cyclarity Therapeutics: Our Science

Cyclarity aims to deliver simple and affordable therapies for cardiovascular disease and other chronic diseases of aging. Cyclarity's research has combined computational and synthetic chemistry programs to create custom-engineered cyclodextrins (polysaccharides with known industrial and pharmaceutical excipient uses) to capture, and remove from cells, oxidized cholesterol derivatives such as 7-ketocholesterol, which are broadly toxic molecules with no known biological function. Our Lead Product: UDP-003 is a first-in-class drug; a specially engineered cyclodextrin which will target and remove toxic oxidized cholesterol, a key driver of atherosclerosis, neurodegenerative diseases, and other chronic diseases. UDP-003 is designed to restore the cardiovascular self-repair function and reduce arterial plaque.

At the high level, we can say that the immune system becomes less capable and more inflammatory with age. The immune system is very complex, however, and so the details of its age-related decline are also very complex. There are countless different populations of cells with distinct behaviors and gene expression profiles, even within a clearly demarcated cell type, such as T cells or circulating monocytes. These various populations interact with one another and tissues and molecules outside cells to generate the overall character of the immune response. As is the case for all of the aging of biological systems, establishing the specifics of cause and effect is challenging.

Aging profoundly affects the immune system leading to an increased propensity for inflammation. Age-related dysregulation of immune cells is implicated in the development and progression of numerous age-related diseases such as: cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. Monocytes and monocyte-derived macrophages, being important players in the inflammatory response, significantly influence the aging process and the associated increase in inflammatory disease risk. Ischemic stroke is among age-related diseases where inflammation, particularly monocyte-derived macrophages, plays an important deteriorating role but could also strongly promote post-stroke recovery. Also, biological sex influences the incidence, presentation, and outcomes of ischemic stroke, reflecting both biological differences between men and women.

Here, we studied whether human peripheral blood monocyte subtype (classical, intermediate, and non-classical) expression of genes implicated in stroke-related inflammation and post-stroke tissue regeneration depends on age and sex. A flow cytometry analysis of blood samples from 44 healthy volunteers (male and female, aged 28 to 98) showed that in contrast to other immune cells, the proportion of natural killer cells increased in females. The proportion of B-cells decreased in both sexes with age.

Gene expression analysis by qPCR identified several genes differentially correlating with age and sex within different monocyte subtypes. Interestingly, ANXA1 and CD36 showed a consistent increase with aging in all monocytes, specifically in intermediate (CD36) and intermediate and non-classical (ANXA1) subtypes. Other genes (IL-1β, S100A8, TNFα, CD64, CD33, TGFβ1, TLR8, CD91) were differentially changed in monocyte subtypes with increasing age. Most age-dependent gene changes were differentially expressed in female monocytes. Our data shed light on the nuanced interplay of age and sex in shaping the expression of inflammation- and regeneration-related genes within distinct monocyte subtypes.

Link: https://doi.org/10.1371/journal.pone.0300946

The ovaries exhibit significant age-related loss of function somewhat ahead of the rest of the body. Why is this the case? There is no good answer at present as to why the underlying mechanisms of aging produce a faster decline in the ovaries. The ability to compare the biochemistry of aging in the ovaries with the biochemistry of aging in the rest of the body may be an opportunity to learn something about aging more generally, however. So one sees papers such as this one, in which researchers review what is known of the mitochondrial dysfunction associated with aging specifically in the ovaries versus its role in aging elsewhere in the body.

Ovarian aging is a major health concern for women. Ovarian aging is associated with reduced health span and longevity. Mitochondrial dysfunction is one of the hallmarks of ovarian aging. In addition to providing oocytes with optimal energy, the mitochondria provide a co-substrate that drives epigenetic processes. Studies show epigenetic alterations, both nuclear and mitochondrial contribute to ovarian aging. Both, nuclear and mitochondrial genomes cross-talk with each other, resulting in two ways orchestrated anterograde and retrograde response that involves epigenetic changes in nuclear and mitochondrial compartments.

Epigenetic alterations causing changes in metabolism impact ovarian function. Key mitochondrial co-substrate includes acetyl CoA, NAD+, ATP, and α-ketoglutarate. Thus, enhancing mitochondrial function in aging ovaries may preserve ovarian function and can lead to ovarian longevity and reproductive and better health outcomes in women. This article describes the role of mitochondria-led epigenetics involved in ovarian aging and discusses strategies to restore epigenetic reprogramming in oocytes by preserving, protecting, or promoting mitochondrial function.

Link: https://doi.org/10.3389/fendo.2024.1424826

It is probably fair to say that the majority of work conducted to date on the treatment of aging as a medical condition has focused on mimicking and enhancing beneficial cellular responses to stresses such as lack of nutrients, heat, cold, toxins, and so forth. The bounds of the possible are illustrated by the results of regular exercise and the practice of calorie restriction. These interventions trigger all of the stress response mechanisms, so it seems unlikely that researchers will greatly improve on their performance with a therapy that targets only one of those mechanisms, or only one of the many regulators governing a given response mechanism. Both exercise and calorie restriction only slow the progression of aging, and are far removed from anything we might regard as a rejuvenation therapy capable of significant reversal of aging.

Autophagy is the most well studied of the cellular stress responses, the processes by which a cell recycles damaged structures. A number of drug development programs have aimed at increased autophagy as a means to improve aspects of health. An equally interesting set of mechanisms is covered in today's open access review paper, the integrated stress response that operates in mitochondria to produce outcomes that affect the behavior of the whole cell and its signaling to other cells. There are ways to manipulate this stress response to produce beneficial outcomes, some of which have produced life extension in mice approaching that of calorie restriction.

The mitochondrial integrated stress response: A novel approach to anti-aging and pro-longevity

Mitochondria play a pivotal role in cellular energy metabolism, primarily responsible for the production of most cellular adenosine triphosphate (ATP) through a process known as oxidative phosphorylation (OXPHOS). However, this significant burden also causes mitochondria to be under constant stress. Especially under the condition of aging, mitochondrial function deteriorates due to the accumulation of mtDNA mutations, the destabilization of respiratory chain complexes, and alterations in mitochondrial dynamics. Consequently, the mitochondrial quality control system, which is primarily comprised of proteases, can be initiated. Furthermore, mitochondrial stress can also trigger cellular nonautonomous factors that facilitate communication between organelles, thereby regulating gene expression, metabolic reprogramming, and organismal longevity. Collectively, these processes form the mitochondrial integrated stress response (ISRmt).

Current studies indicate that the activation of the ISRmt relies primarily on mitochondrial stressors. The mild or early stage of ISRmt may elicit an adaptive stress response that is conducive to well-being and longevity while postponing the onset of multiple mitochondrial disorders. Evidence from model organisms reveals that mutations that reduce the activity of the mitochondrial respiratory chain yield a mean adult lifespan increase ranging from 20% to 300% in C. elegans. A similar increase in longevity has been achieved by reducing the expression of electron transport chain (ETC) components through the use of RNA interference (RNAi). In mice, a reduction in ETC proteins, particularly complex I subunits, increases lifespan by approximately 30%. The improvements in mitochondrial function and oxidative metabolism are contingent upon the adaptive ISRmt. Therefore, this beneficial adaptive stress response, which is induced by the inhibition of OXPHOS complexes, the depletion of mtDNA, or the uncoupling of mitochondria, has the potential to antagonize age-related diseases and promote longevity in clinical settings.

However, it is of paramount importance to address the off-target effects and toxicity associated with chronic ISRmt activation, especially in clinical trials. In this paper, we put forward three suggestions. Firstly, the induction of ISRmt should be reversible, such as the use of ETC component inhibitors rather than gene mutations. Secondly, the therapeutic strategy targeting the ISRmt should focus on boosting endogenous adaptive factors including FGF21, GDF15, and MTHFD2. Finally, pharmacological modulation of the core elements of ISRmt (eIF2α phosphorylation) warrants greater consideration due to the highly variable metabolic phenotypes. In comparison to pharmacological methods, FGF21, and its analogs have been proven to be generally well tolerated in clinical trials. Metformin, the most widely applied ISRmt inducer, has been approved by the FDA for treating type 2 diabetes, indicating its potential for human application.

The assembly, processing, and activities of RNA molecules in the cell is a vast topic, even if narrowed to just one part of the body. A short paper can really only briefly summarize the primary areas of interest for researchers involved in the study of neurodegenerative conditions, as is the case here. Transcription of genes to produce RNA molecules is the first step in gene expression, and sweeping changes in gene expression take place with age. A cell is a state machine, its state largely determined by which RNAs and proteins are produced, and in what amount, at any given time. The state of cells determines the function of tissues. Even just the RNA portion of this picture is an enormously complex, incompletely understood soup of molecular interactions.

Neurodegenerative diseases are prevalent age-related diseases. As of 2024, approximately 6.9 million Americans are affected by Alzheimer's disease (AD), making it the most common neurodegenerative disease, followed by Parkinson's disease (PD). There are also many less prevalent or rare neurodegenerative diseases such as Huntington's disease (HD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Though the clinical symptoms of these diseases vary, multiple neurodegenerative diseases share similar underlying pathological mechanisms. The presence of pathological inclusions and causative mutations of RNA-binding proteins (RBPs) is increasingly observed among neurodegenerative diseases. In addition, pathological repeat expansion in multiple diseases, such as ALS, FTD, HD and various types of spinocerebellar ataxia, yields repeat-containing RNAs that could cause neurotoxicity via various mechanisms.

In the post-genomic era, a variety of RNA processing pathways and emerging types of coding and noncoding RNAs have been commonly identified in the disease context, with potential contributions to neurodegeneration. Therapeutic strategies targeting RNA to modulate disease-linked genes have achieved significant success. Here, we focus on RNA-related pathogenic mechanisms in neurodegenerative diseases and updates on RNA-targeting therapeutic approaches that hold great promise. We start with the various RNA processing pathways and provide representative examples of how these pathways are dysregulated in neurodegenerative diseases. Next, we discuss the mechanisms that lead to RBP dysfunction, resulting in dysregulation of RNA processing. Finally, we review the current progress in RNA-targeting therapeutics. The different RNA processing pathways are often interconnected, and most RBPs have multifunctional roles across several RNA processing steps, creating significant interplay among them.

Link: https://doi.org/10.1038/s44318-024-00352-6

One of the benefits of physical fitness and the physical activity required to sustain that fitness is a slower aging of the brain. Human data provides only correlational data, but animal studies have demonstrated causation in the improved health and slowed aspects of aging resulting from exercise. Researchers here delve into the biochemistry of aging in brain and body cells, finding a great deal more downregulation of gene expression in the brain than elsewhere in the body with aging, and that physical exercise can reduce the extent of those changes.

It is been noted that the expression levels of numerous genes undergo changes as individuals age, and aging stands as a primary factor contributing to age-related diseases. In this study, we screened for aging genes using RNAseq data of 32 human tissues from the Genotype-Tissue Expression (GTEx) project. RNAseq datasets from the Gene Expression Omnibus (GEO) were used to study whether aging genes drives age-related diseases, or whether anti-aging solutions could reverse aging gene expression.

Aging transcriptome alterations showed that brain aging differ significantly from the rest of the body, furthermore, brain tissues were divided into four group according to their aging transcriptome alterations. Numerous genes were downregulated during brain aging versus body tissue aging, with functions enriched in synaptic function, ubiquitination, mitochondrial translation, and autophagy.

Transcriptome analysis of age-related diseases and retarding aging solutions showed that downregulated aging genes in the hippocampus underwent further downregulation in Alzheimer's disease but this downregylation was effectively reversed by high physical activity. Furthermore, the neuron loss observed during aging was reversed by high physical activity.

Link: https://doi.org/10.3389/fnagi.2024.1450337

One of the many reasons to think that chronic inflammation is an important aspect of degenerative aging is that extremely old individuals, those who have outlived more than 99% of their birth cohort, tend to exhibit levels of inflammation that are similar to those of younger adults. A number of studies of centenarians (100 years and older), semi-supercentenarians (105 years and older) and supercentenarians (110 years and older) have noted unusually low levels of inflammatory markers, typically lower than the inflammation normally seen in later life from 60 to 100 in the general population.

This is not to say that being older than 100 is a walk in the park, as matters presently stand. These individuals approach a 50% yearly mortality rate, are frail, and suffer many of the usual issues of old age. Calling them relatively healthy might be accurate, but it isn't by any means a desirable state of being when compared to healthy adult life at younger ages. Returning to the point on inflammation, today's open access paper is one of a number to demonstrate that extremely old survivors past the age of 100 exhibit lower inflammatory signaling than the average individual in the few decades approaching 100. Near everyone with a greater burden of chronic inflammation than these survivors dies before reaching 100 years of life.

Immune-Inflammatory Response in Lifespan - What Role Does It Play in Extreme Longevity? A Sicilian Semi- and Supercentenarians Study

Among Long-Lived Individuals (LLIs, ≥90 years), centenarians (≥100 years), including semi-supercentenarians (105-109 years) and supercentenarians (≥110 years), are a focus of extensive research. Most of them are resistant to or manage age-related diseases such as cancer, diabetes, cardiovascular diseases, and stroke. Thus, they are categorized as survivors, escapers, or delayers. However, it is important to recognize that the growing number of centenarians is due to advancements in hygiene and sanitation, as well as healthier lifestyles. Consequently, contemporary and future centenarians are likely to be less selectively unique than those from previous decades. Semi- and supercentenarians represent a uniquely selective group. They have endured significant adversities, including two World Wars, the Spanish flu, and the COVID-19 pandemics. Therefore, it is plausible to infer that their immune systems exhibit remarkable traits that can provide insights into the mechanisms influencing the achievement of such extreme longevity.

Age-related dysregulation of immune-inflammatory responses (IMFLAM) has indeed been recognized for several years. In 1980, researchers conceptualized the term immunosenescence, while in 2000, others highlighted that aging is marked by a progressive increase in pro-inflammatory status, known as inflammaging. This persistent systemic inflammation is associated with cellular senescence, immune decline, organ dysfunction, and age-related diseases. Simultaneously, chronic inflammation accelerates immunosenescence, resulting in reduced immune capacity and a weakened ability to clear senescent cells and inflammatory agents, thus perpetuating a detrimental cycle.

This paper analyzes the inflammatory scores - INFLA-score and Systemic Inflammation Response Index (SIRI) - and Aging-Related Immune Phenotype (ARIP) indicators calculated from the dataset of the DESIGN project, including 249 participants aged 19 to 111 years, aiming to understand the IMFLAM role in achieving longevity. Statistical analyses were performed to explore the correlations between these parameters and age. Both INFLA-score and SIRI showed a significant increase with age. However, no statistical differences were found when comparing the values of semi- and supercentenarians to other age groups, which are similar to adults and lower than younger centenarians. Regarding ARIP values, it is noteworthy that when comparing the CD8+ Naïve/Effector scores between groups, no significant differences were observed between the semi- and supercentenarian group and the other groups. These results support the idea that the control of IMFLAM response can promote extreme longevity.

Senescent cells can in principle be distinguished by cell surface markers, and the immune system has evolved to detect and destroy these cells, yet senescent cells accumulate in later life. This is essentially the same situation as for cancerous cells, and thus much the same development process as already exists in the cancer research community could be undertaken to develop immunotherapies, including vaccines, that target senescent cells. The one big difference is that senescent cells sometimes serve useful purposes when present for the short-term, such as helping to coordinate regeneration from injury. This isn't a problem when we consider small molecule drugs that stress senescent cells in order to kill them, as those drugs are only present in the body for a short period of time. A highly efficient vaccine against senescent cells would be a lasting change to the dynamics of clearance, however, and could have some negative effects in addition to the broad benefits it would bring to older individuals.

A number of studies have shown that aging of the body is accompanied by the accumulation of senescent cells in various tissues and organs. This leads to tissue homeostasis and functional disorders typical of old age. Senescent cells typically express some age-related markers (such as p16INK4A, p21CIP1, etc.), have increased senescence-associated β-galactosidase (SA-β-Gal) activity, produce a number of cytokines and pro-inflammatory substances (the Senescence-Associated Secretory Phenotype, SASP), and have various defects in the protein quality control machinery. The physiological features of senescent cells affect their antigen profiles.

It is worth noting that senescent cells play an important role in some physiological processes. Thus, SASP factors are involved in tissue remodeling in early ontogenesis, as well as in repair and regeneration processes at later stages of development. In addition, cell cycle arrest, which is the most important feature of senescence, prevents possible malignancy. Senescent cells are normally present in tissues in limited numbers. However, the accumulation of these cells during the aging process is associated with the dysfunction of various tissues and organs, and the cumulative effect of SASP production contributes to chronic age-related inflammation, which increases the risk of developing age-related diseases.

Despite the promising results of using some drugs aimed at killing senescent cells (senolytics) or reducing the negative effects of SASP (senomorphics), the existing pharmacological approaches still do not possess the high specificity toward senescent cells, do not take into account their diversity, and are associated with the risk of side effects. In this context, a promising alternative is the development of methods for targeted elimination of senescent cells with the help of adaptive immunity mechanisms. Various attempts to create senolytic vaccines that remove senescent cells from specific tissues have already been made.

However, the development of such vaccines is associated with certain problems. Unique Senescent-Specific Antigens (SSAs) absent in normal cells are still unknown, which hinders the development of safe senolytic vaccines due to the risk of damage to the healthy tissues. The high antigenic diversity of senescent cells, both at individual and population levels, significantly complicates the search for target antigens for the creation of universal senolytic vaccines. Obviously, tolerance to senescence-associated antigens is a serious problem. Since senescent cells are the body's own cells, the mechanisms of central and peripheral tolerance can act toward the antigens they express. Thus, overcoming tolerance to senescence-associated antigens is one of the key challenges in the development of senolytic vaccines.

Link: https://doi.org/10.3390/vaccines12121389

The difference between the sexes in the matter of aging can be summarized crudely as being that women live longer but in worse physical condition than male survivors of an equivalent age. How and why this is the case is the subject of a great deal of research, but the research community has yet to reach a good conclusion on the biochemistry involved. Yet this may well be irrelevant to the future of therapies aimed at repairing the cell and tissue damage that causes aging, as that underlying damage is the same for both sexes. To the degree that medical science can produce rejuvenation, the details of how uncontrolled aging progresses differently in different people becomes a matter of curiosity only, not a priority.

Men typically have shorter lifespans than women in most modern societies and face a higher risk of lethal age-related diseases, such as cardiovascular disease. Despite numerous intrinsic and extrinsic factors (e.g., sex chromosome, sex hormone, gene expression, lifestyle, etc.) being linked to sex-biased lifespan and morbidity, the biological foundation for men achieving longevity has yet to be investigated thoroughly. Notably, epidemiological data disclose a paradoxical phenomenon: the number of long-lived men (LLMs) is significantly lower than that of long-lived women (LLWs), yet LLMs generally exhibit better health status, including good physical performance and decreased cancer risk, suggesting a potential male-specific longevity strategy in humans. These findings emphasize the importance of studying LLMs to uncover the biological basis enabling men to achieve healthy aging and longevity.

In this study, we conducted whole-genome bisulfite sequencing (WGBS) to analyze the methylomes of LLMs and LLWs as well as younger men (YMs) and younger women (YWs). Despite the observed accelerated epigenetic aging in LLMs compared to LLWs, through thorough comparisons with LLWs, YMs, and YWs, we identified thousands of differentially methylated genomic units (DMUs) in LLMs, some of which exhibit potential as methylation markers for LLM discrimination. Contrary to the notion of accelerated epigenetic aging, we suggest that these identified DMUs may play roles in promoting longevity or suppressing age-related diseases, including cancer, through the regulation of target gene transcription. Taken together, our study provides evidence suggesting that LLMs possess distinctive methylation characteristics, underscoring their potential relevance to healthy aging and longevity in men.

Link: https://doi.org/10.1016/j.celrep.2024.115158

What can be found in a human blood sample that either correlates with or predicts exceptional healthspan or lifespan? Quite the variety of research efforts touch on this question, from the development of aging clocks to the construction of omics databases for blood and tissue samples taken from centenarians. People age as a result of the same underlying processes of damage and dysfunction, but the pace of aging clearly varies widely. It is generally accepted in the research community that efficient ways to measure the state of biological aging are needed in order to speed the development of therapies to treat aging. Without the ability to rapidly determine the effects of an alleged anti-aging therapy immediately after administration, the only recourse is to wait and see. Thus animal studies are expensive and slow, research can be stuck for years in a dead end that only later is shown to be not so great, and human data is non-existent, as no-one will fund ten year clinical studies for potential drugs.

Today's open access review paper surveys some of the work conducted to date in search of signatures of longevity that can be measured in blood samples and other non-invasive assays. In some cases, signatures can be plausibly connected to processes relevant to longevity, such as suppression of the chronic inflammation of aging. In other cases, no-one really knows why the correlation exists. It also remains a question, on a case by case basis, as to whether ways to adjust the signature will also slow aging to some degree; in most cases, probably not, as the signature is a downstream consequence of underlying processes and causes little further harm in and of itself.

The Biomarkers in Extreme Longevity: Insights Gained from Metabolomics and Proteomics

In this review, we integrate longevity-related biomarkers discovered by metabolomics and proteomics and further categorize them based on different classes. The mechanisms of longevity-related metabolites have been elucidated, especially for specific fatty acids like EPA, DHA, and short-chain fatty acids, which effect lifespan by reducing inflammation and activating the Nrf2 pathway. The mechanisms underlying the health benefits of the changes in certain metabolites are still largely unknown. For example, the mechanism of some isomers of secondary bile acids affects the body's immunity remains to be further studied. Additionally, the metabolic pathways and products of metabolites should also be considered. Some intermediates (such as kynurenic acid) have neuroprotective effects, which were produced from tryptophan. Regarding proteins, APOE, FOXO, and SIRT are essential signaling proteins for cell survival, which can regulate cell proliferation, metabolism, inflammation, and stress responses by influencing multiple signaling pathways, including PI3K/Akt, NF-κB, etc. Moreover, post-translational modifications such as nitrosylation and glycosylation have important effects on the function and communication of proteins. The interaction between various modifications and star proteins creates a complex network that modulates cell survival to extend lifespan. Therefore, integrating candidate longevity-related biomarkers to conduct a "biomarker library of health and longevity" can further grasp the profile of centenarians or extreme longevity in humans and provide a theoretical foundation for anti-aging.

Appropriate analytical methods are crucial for different research objects based on the research question and sample characteristics. In metabolomics, untargeted and targeted metabolomics both have different advantages and disadvantages. It is worth noting that a certain degree of lipid metabolism dysfunction and neural functional damage happens during the aging process. Therefore, targeted metabolomics focusing on specific metabolites such as short-chain fatty acids, bile acids, and neurotransmitters can better reflect the physiological status of the elderly. In proteomics, general proteomics can provide a more comprehensive protein map for the longevity population. With an increase in age, protein homeostasis gradually declines and results in wrong translation modification such as nitrosylation and glycosylation. Consequently, post-translational modifications of proteins are considered crucial indicators affecting the function of proteins. The study of longevity cohorts based on untargeted metabolomics and general proteomics has been extensively reported. We regard that targeted metabolomics and PTM proteomics focusing on specific biomolecules will attract more attention in aging studies to discover more valuable longevity-related biomarkers, whether metabolites or proteins. Moreover, blood and fecal samples are commonly preferred for biomarker discovery due to their relatively easy access. If tissue-specific characteristics are exhibited in the liver or muscle tissues of centenarians, it potentially leads to obvious alterations in circulating blood metabolites. However, there are significant challenges in obtaining tissue samples such as liver and muscle from living individuals. We wish that better technology may have appeared in the future to offer the possibility to analyze the tissue or organ specificity of centenarians.

Researchers here review the evidence for age-related loss of mitochondrial function to contribute to degenerative disc disease. It is certainly a contribution, but as for every aspect of aging it is very challenging to determine how important any given contribution is versus all of the others. So yes, mitochondrial quality control falters with age, and mitochondria become more damaged and dysfunctional as a result. This happens throughout the body. But is it more or less important for disc degeneration specifically than, say, the chronic inflammation of aging? Absent ways to individually fix each aspect of aging, so that results of treatment can be observed and compared directly, it is difficult to mount compelling arguments.

Intervertebral disc degeneration is the most common disease in chronic musculoskeletal diseases and the main cause of low back pain, which seriously endangers social health level and increases people's economic burden. Disc degeneration is characterized by nucleus pulposus (NP) cell apoptosis, extracellular matrix degradation, and disc structure changes. It progresses with age and under the influence of mechanical overload, oxidative stress, and genetics.

Mitochondria are not only the energy factories of cells, but also participate in a variety of cellular functions such as calcium homeostasis, regulation of cell proliferation, and control of apoptosis. The mitochondrial quality control system involves many mechanisms such as mitochondrial gene regulation, mitochondrial protein import, mitophagy, and mitochondrial dynamics. A large number of studies have confirmed that mitochondrial dysfunction is a key factor in the pathological mechanism of aging and intervertebral disc degeneration, and balancing mitochondrial quality control is extremely important for delaying and treating intervertebral disc degeneration.

In this paper, we first demonstrate the molecular mechanism of mitochondrial quality control in detail by describing mitochondrial biogenesis and mitophagy. Then, we describe the ways in which mitochondrial dysfunction leads to disc degeneration, and review in detail the current research on targeting mitochondria for the treatment of disc degeneration, hoping to draw inspiration from the current research to provide innovative perspectives for the treatment of disc degeneration.

Link: https://doi.org/10.1186/s12967-024-05943-9

In mice, senolytic therapies to clear senescent cells seem such a panacea for age-related conditions that it is always interesting to see evidence for an aspect of aging that is not helped by removal of a portion of the burden of lingering senescent cells. Here, researchers show that senolytics do nothing to help aged mice resist influenza infection if they are administered during or shortly before exposure. Based on what is known of the role of cellular senescence in aging, one would expect an aged mouse that has been treated once with senolytics to later be more resilient to stresses of all sorts, but it likely takes some time for the benefits to be realized, longer than was allowed for here.

Aging is a major risk factor for poor outcomes following respiratory infections. In animal models, the most severe outcomes of respiratory infections in older hosts have been associated with an increased burden of senescent cells that accumulate over time with age and create a hyperinflammatory response. Although studies using coronavirus animal models have demonstrated that removal of senescent cells with senolytics, a class of drugs that selectively kills senescent cells, resulted in reduced lung damage and increased survival, little is known about the role that senescent cells play in the outcome of influenza A viral (IAV) infections in aged mice.

Here, we tested if the aged mice survival or weight loss IAV infections could be improved using three different senolytic regimens. We found that neither dasatinib plus quercetin, fisetin, nor ABT-263 improved outcomes. Furthermore, both dasatanib plus quercetin and fisetin treatments further suppressed immune infiltration than aging alone. Additionally, our data show that the short-term senolytic agents do not reduce senescent markers in our aged mouse model. These findings suggest that acute senolytic treatments do not universally reverse aging related immune phenotype against all respiratory viral infections.

Link: https://doi.org/10.1111/acel.14437

Senescent cells are created constantly throughout life, largely as somatic cells reach the Hayflick limit on replication, but also in response to cell damage and stress. In youth, the immune system rapidly removes these cells. With age, immune clearance falters and lingering senescent cells grow in number in tissues throughout the body. These cells secrete a potent mix of pro-inflammatory signals that can be beneficial in the short term, drawing the attention of the immune system to potential problems, but this signaling becomes disruptive to tissue structure and function when sustained over the long term. The greater the number of senescent cells, the worse the consequent chronic inflammation and harmful outcomes. This is a significant contribution to degenerative aging.

While the development of therapies to selectively destroy senescent cells is very much an ongoing concern, with the first few drugs in clinical trials for several years now, finding a convenient measure to assess the burden of cellular senescence has proven to be harder than expected. One can always take a tissue biopsy and count senescent cells via histology, but this is far from convenient. For all that these cells secrete a wide range of well-known inflammatory signals, the amounts in circulation that can be assessed via a blood sample do not correlate well to the burden of senescent cells. There are too many other sources and sinks operating, muddying the waters. Similarly, directly assessing senescence in white blood cells from a blood sample doesn't map well to the global burden of such cells in tissues, as the immune system is subject to stresses that are very different from those associated with cells in tissues.

Still, it seems plausible that there must be some useful measure of the burden of senescence that can be obtained from circulating signal molecules. In today's open access paper, researchers put forward IL-23R as a candidate for that molecule. If validated, this should help to speed the development of more effective senolytic therapies to clear senescent cells from the aged body and brain.

IL-23R is a senescence-linked circulating and tissue biomarker of aging

Characteristic properties of senescent cells include upregulation of cell cycle regulatory proteins, including p16ink4a, the senescence-associated secretory phenotype (SASP), and activation of senescent cell anti-apoptotic pathways (SCAPs). The SASP is cell-type- and context-specific and can confer adverse changes to local tissue environments and systemic organs. Use of the p16-InkAttac transgenic model, which permits systemic clearance of p16-positive cells through a temporally controlled suicide gene, has demonstrated that senescent cell deletion alleviates features of age-related pathology in several organs, including kidney, adipose, skeletal muscle, eye, heart, and brain. A recent comparison of cell-type-specific versus whole-body transgenic targeting of p16-postitive cells demonstrated greater benefits in aged bone composition following systemic clearance, which supports the notion that the adverse influence of senescent cells and the SASP results from both local and distant signaling.

Despite considerable senolytic testing underway in preclinical models and humans, understanding of the comparative effects of senolytic drugs and senescent cell targeting efficiency across tissues is limited. The central goal of this study was to identify age- and senescence-related plasma and tissue biomarkers that are responsive to senotherapeutic intervention. We assessed system-wide profiles of senescence, SASP, and inflammatory biomarkers in aging and their alteration by clinically relevant senolytic compounds versus transgenic p16-InkAttac senescent cell targeting in mice.

We discovered that the abundance of IL-23R, CCL5, and other proteins showing age-dependent increases in circulation were reduced by senotherapeutic agents. CA13 decreased in aged plasma, and senolytics restored this factor toward youthful levels. In secretory tissues, gene expression of Il23r and Ccl5 coincided with expression of senescence markers and aged plasma protein abundance in vivo, and these factors were significantly upregulated and secreted by senescent cells in vitro. Our results suggest that senescent cells in aged kidney, liver, and spleen are viable sources of these aging biomarkers in blood circulation. Among the drugs tested, venetoclax suppressed age-related changes in the greatest number of circulating and tissue biomarkers in aged mice. In human plasma, we discovered that IL-23R abundance increased with age in both women and men.

Epigenetic clocks assess data derived from a bulk set of cells derived from tissues. This will be a mix of cells of different types and subpopulations, and thus some portion of age-related changes might be due to shifts in the relative numbers of these cell types. This has already been explored to some degree in the context of white blood cells in a blood sample, and the better commercial epigenetic age assays are now somewhat improved for that exploration. Here researchers discuss the problem more generally, and demonstrate that separating out cell types can be expected to improve epigenetic clocks and age assessment for any tissue.

The ability to accurately quantify biological age could help monitor and control healthy aging. Epigenetic clocks have emerged as promising tools for estimating biological age, yet they have been developed from heterogeneous bulk tissues, and are thus composites of two aging processes, one reflecting the change of cell-type composition with age and another reflecting the aging of individual cell-types. There is thus a need to dissect and quantify these two components of epigenetic clocks, and to develop epigenetic clocks that can yield biological age estimates at cell-type resolution.

Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clock's accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that these cell-type specific clocks yield improved estimates of chronological age in the corresponding cell and tissue-types. We find that neuron and glia specific clocks display biological age acceleration in Alzheimer's disease with the effect being strongest for glia in the temporal lobe. Moreover, CpGs from these clocks display a small but significant overlap with the causal DamAge clock, mapping to key genes implicated in neurodegeneration. The hepatocyte clock is found accelerated in liver under various pathological conditions. In contrast, non-cell-type specific clocks do not display biological age-acceleration, or only do so marginally.

Link: https://doi.org/10.18632/aging.206184

Cells react to the state of the extracellular matrix that they reside in. Changes to the molecules of the extracellular matrix do take place with age, and as a whole this aspect of aging is comparatively poorly studied and understood. Researchers here characterize one specific molecular alteration of extracellular matrix molecules that is found in aged lung tissue, show that it changes cell behavior for the worse via interaction with the cell surface, and demonstrate that an immunotherapy approach to remove these problem molecules reduces age-related pathology in an animal model of lung disease.

Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable. IsoAsp-Gly-Arg (IsoDGR) modification has previously been observed in structural proteins such as fibronectin, laminin, tenascin C, and several other extracellular matrix (ECM) constituents of human arteries, leading to increased leukocyte infiltration of coronary vessels. These ECM proteins are also essential components of human lungs, which consist of a complex anatomy of fibrous proteins (collagen, elastin), glycoproteins (fibronectin, laminin), glycosaminoglycans (heparin, hyaluronic acid), and proteoglycans (perlecan, versican). These long-lived lung proteins are particularly susceptible to isoDGR accumulation, potentially triggering macrophage infiltration and expression of pro-inflammatory cytokines. Indeed, isoDGR structurally mimics the Arg-Gly-Asp (RGD) integrin binding motif, and may therefore mediate leukocyte recruitment to induce pulmonary inflammaging, but it is unknown whether this motif drives age-linked lung diseases such as fibrosis and emphysema

We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b+ macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo.

Link: https://doi.org/10.1111/acel.14425

Evidence points to increased autophagy as an important factor in many of the interventions that slow aging to extend life in short-lived laboratory species such as flies, worms, and mice. Autophagy is a collection of cellular maintenance processes responsible for clearing out excess and damaged structures in the cell, transporting them to a lysosome for disassembly. In principle, fewer damaged components leads to improved function across the board, and thus a greater resilience to the damage and dysfunction of aging.

Mild stresses placed on cells provoke greater autophagy. These include transient lack of nutrients, heat, cold, and excess oxidative molecules produced by mitochondria during periods of high energy demand, such as during exercise. The biochemistry of autophagy in longer-lived mammalian species such as our own in response to these interventions is very similar, at least where the data exists to make the comparison, such as for exercise and calorie restriction. Nonetheless, life span in longer-lived species changes little in response to greater autophagy: a calorie restricted mouse can live as much as 40% longer, but that certainly isn't true for humans.

Exercise-driven cellular autophagy: A bridge to systematic wellness

Among various interventions, physical exercise is recognized as a structured, intentional form of physical activity that enhances physical fitness, prevents diseases, and aids in recovery. Despite extensive research on its systemic benefits, the molecular mechanisms underlying exercise-induced health improvements remain incompletely understood, particularly regarding its impact on cellular processes across organ systems. One such cellular process is autophagy, a conserved metabolic pathway that maintains cellular homeostasis by degrading and recycling intracellular components. Autophagy is critical for cellular survival, development, and differentiation, as well as for mitigating diseases and maintaining health. Dysregulated autophagy is implicated in various pathological conditions, including neurodegenerative diseases, cancer, and metabolic disorders, highlighting its therapeutic potential.

Autophagy is indispensable for maintaining cellular health and is often impaired in systemic diseases. Interestingly, physical exercise-a macroscopic, non-pharmacological intervention-has been shown to activate autophagy, indicating a potentially critical link between these two processes. While numerous studies have independently explored the benefits of exercise and the mechanisms of autophagy, a comprehensive understanding of how exercise-induced autophagy contributes to systemic health and disease recovery is still lacking. Specifically, the molecular basis by which exercise modulates autophagic flux across different tissues and its implications for treating systemic diseases remains an area of limited clarity.

This review aims to address this knowledge gap by synthesizing current evidence on the role of exercise-induced autophagy in promoting health and mitigating disease. We will focus on the molecular mechanisms by which exercise regulates autophagy, the tissue-specific impacts of this regulation, and the potential therapeutic applications of targeting autophagy activation through exercise.

Most epigenetic clocks are produced by applying machine learning techniques to DNA methylation data derived from immune cells in reference blood samples taken from individuals of various ages. A clock is just an algorithm based on the fraction of genomes in the sample that are methylated at a number of specific Cpg sites. It is not too surprising to find that these clocks produce a different result when used on epigenetic data from tissue samples instead of blood samples, or that different tissues produce different results. After all, not all cell types have the same epigenetic response to aging. Some groups are working towards universal clocks for multiple species and multiple tissues, trying to find commonalities. Meanwhile, the most well known clocks function poorly outside the context in which they were manufactured, blood samples.

DNA methylation (DNAm) data from human samples has been leveraged to develop "epigenetic clock" algorithms that predict age and other aging-related phenotypes. Some DNAm clocks were trained using DNAm obtained from blood cells, while other clocks were trained using data from diverse tissue/cell types. To assess how DNAm clocks perform across non-blood tissue types, we applied DNAm algorithms to DNAm data generated from 9 different human tissue types. For all samples, we generated DNAm clock estimates for 8 epigenetic clocks and characterized these tissue-specific clock estimates in terms of their distributions, correlations with chronological age, correlations of clock estimates between tissue types, and association with participant characteristics.

For each clock, the mean DNAm age estimate varied substantially across tissue types, and the mean values for the different clocks varied substantially within tissue types. For most clocks, the correlation with chronological age varied across tissue types, with blood often showing the strongest correlation. Each clock showed strong correlation across tissues, with some evidence of some residual correlation after adjusting for chronological age. This work demonstrates how differences in epigenetic aging among tissue types leads to clear differences in DNAm clock characteristics across tissue types. Tissue or cell-type specific epigenetic clocks are needed to optimize predictive performance of DNAm clocks in non-blood tissues and cell types.

Link: https://doi.org/10.18632/aging.206182

The aging of the immune system is clearly an important factor in degenerative aging as a whole. The immune system does much more than merely defend the body against pathogens and potentially harmful malfunctioning cells. It is also intimately involved in tissue maintenance, tissue functions, and regeneration from injury. All of this suffers when the immune system becomes more inflammatory and less capable with advancing age. As for all aspects of aging, there is more than enough available biological data relating to immune system function to build clocks that reflect biological age, the burden of damage and dysfunction leading to mortality.

Precisely assessing an individual's immune age is critical for developing targeted aging interventions. Although traditional methods for evaluating biological age, such as the use of cellular senescence markers and physiological indicators, have been widely applied, these methods inherently struggle to capture the full complexity of biological aging. We propose the concept of an 'immunosenescence clock' that evaluates immune system changes on the basis of changes in immune cell abundance and omics data (including transcriptome and proteome data), providing a complementary indicator for understanding age-related physiological transformations.

Rather than claiming to definitively measure biological age, this approach can be divided into a biological age prediction clock and a mortality prediction clock. The main function of the biological age prediction clock is to reflect the physiological state through the transcriptome data of peripheral blood mononuclear cells (PBMCs), whereas the mortality prediction clock emphasizes the ability to identify people at high risk of mortality and disease. We hereby present nearly all of the immunosenescence clocks developed to date, as well as their functional differences. Critically, we explicitly acknowledge that no single diagnostic test can exhaustively capture the intricate changes associated with biological aging. Furthermore, as these biological functions are based on the acceleration or delay of immunosenescence, we also summarize the factors that accelerate immunosenescence and the methods for delaying it.

A deep understanding of the regulatory mechanisms of immunosenescence can help establish more accurate immune-age models, providing support for personalized longevity interventions and improving quality of life in old age.

Link: https://doi.org/10.1016/j.arr.2024.102653

In principle one could develop rejuvenation therapies without a way to measure the overall state of biological age. Each of the underlying causes of aging is measurable today: senescent cell burden, mitochondrial dysfunction, presence of amyloids, and so forth. Therapies can be assessed for efficacy in terms of the degree to which they repair the specific forms of cell and tissue damage that they are intended to repair. That doesn't tell us how much of an effect any given therapy will have on life span, however. It remains the case that while the causes of aging are well discussed, their importance relative to one another remains unknown.

It seems plausible that any approach to rejuvenation therapy will receive comparatively little support in today's environment without some measure of success beyond repair of a form of damage, meaning a measure of the degree to which the future risk of age-related disease and mortality is reduced. Unfortunately, that measure is expensive and slow to achieve via the old-fashioned approach of waiting to see what happens following treatment. Hence the strong focus on the development of aging clocks, technologies that may lead to a consensus method of quickly measuring biological age, and thus the effects of a potential rejuvenation therapy.

Critical review of aging clocks and factors that may influence the pace of aging

Aging research has delineated the aging process by classifying two separate but interconnected mechanisms: intrinsic and extrinsic aging. Intrinsic aging describes changes in biological hallmarks including cellular and molecular changes, genetics, and hormonal changes that have been described to occur naturally over time. Extrinsic aging, however, is regulated by exposure to environmental stressors, dietary habits, oxidative stress, and other factors that accelerate physiologic aging. Traditionally, aging has been quantified by chronological age, which is the exact number of years an individual has lived. However, chronological age does not fully capture the heterogeneity of the aging process, excluding many extrinsic factors that contribute to aging.

Subsequently, the calculation of biological age, which aims to account for interindividual variations in aging rate, has become a topic of interest in aging research. Aging clock models are tools that utilize various modeling approaches to estimate chronological or biological age. Moreover, aging clock models can estimate the rate of aging (ΔAge), otherwise known as the difference between model-predicted biological age and chronological age. Positive differences between model-predicted biological age and chronological age indicate accelerated aging whereas a negative difference indicates decelerated aging. If the calculated ΔAge exceeds the mean absolute error (MAE) of the aging rate estimation, these individuals can be determined to be fast or slow agers.

Aging clocks models may utilize any hallmark changes that occur because of aging, and these may include epigenetic changes, telomere length, genomic stability, altered intercellular communication, chronic inflammation, and gut microbiome dysbiosis, among others. Notably, some of the first aging clock models include the Horvath clock and Hannum clock, which are both epigenetic clocks modeled after changes in DNA methylation patterns and varying cytosine phosphate guanine (CpG) sites across the genome. Several aging clock models have emerged since then, varying from microbiome-based clocks to proteomic clocks. Recent advancements in the development of large databases, omics technologies, and deep learning models have accelerated the creation of aging clock predictions. Thus, this review aims to summarize the currently available aging clock models, with the goal of identifying existing and potential clinical applications.

Frailty is a state of chronic inflammation, immunosenescence, physical weakness, and reduced resilience to stresses. It is the outcome of a high burden of the cell and tissue damage of aging, and all of the downstream consequences of that damage. Frailty is well known to correlate with an increased mortality risk, and the study here is one of many to demonstrate this point. We might look on frailty as a pointer to the most severe issues in aging, a list of those problems that should be addressed with the highest priority, if possible. Certainly both immune dysfunction and loss of muscle mass and strength are well studied, with numerous therapeutic research and development programs underway at various stages.

This study aimed to explore the association of 3-year change in frailty index (FI) with risk of all-cause mortality in an older Chinese population. We analyzed the data of 4,969 participants from the Chinese Longitudinal Healthy Longevity Survey. The primary outcome was all-cause mortality, which was a binary variable and defined as completed data and censored data. Cox proportional-hazard models were used to assess the association of 3-year change in FI with risk of all-cause mortality.

During a median of 4.08 years of follow-up, deaths were observed in 1,388 participants. We observed a 2.27-fold higher risk of all-cause mortality with increase in FI ≥ 0.045 versus change in FI < 0.015 (hazard ratio = 2.27). Similar significant associations were observed in the subgroup analyses by age, sex, and residence at baseline. Additionally, a nonlinear dose-response association of 3-year change in FI with risk of all-cause mortality was observed. In conclusion, excessive increase in FI was positively associated with an increased risk for all-cause mortality. Approaches to reducing FI may be of great significance in improving the health of older Chinese individuals.

Link: https://doi.org/10.1186/s12877-024-05639-1

In the northern hemisphere, mortality increases in the winter. This is in large part because influenza is a winter phenomenon, and old people are vulnerable to infection and downstream consequences of infection. Cold weather provides a number of opportunities beyond infection for additional stresses to be placed on an aged body, however. An important characteristic of the frailty of old age is an inability to resist stresses that younger people would take in their stride, instead tipping over into the downward spiral to mortality. Researchers here survey the seasonality of human mortality, quantifying the overall size of the effect.

Seasonal fluctuations in mortality affect annual life expectancy at birth (e0). Nevertheless, evidence on the impact of seasonal mortality on longevity is very limited and mainly restricted to assessing season-specific mortality levels due to shocks (e.g., heatwaves and influenza epidemics). We investigated the influence of seasonality in mortality on life expectancy levels and temporal trends across 20 European countries during 2000-2019. We used harmonised weekly population-level mortality data from the Human Mortality Database. Seasonal contributions to life expectancy at birth and age 65, by sex, were estimated using the excess mortality approach and decomposition analysis. Time-series analysis was used to evaluate the impact on long-term mortality trends.

Seasonal mortality had a substantial but stable impact on e0 between 2000 and 2019. On average, we found an annual reduction in life expectancy due to seasonal excess mortality of 1.14 years for males and 0.80 years for females. Deaths in the elderly population (65+) were the main driver of this impact: around 70% and 90% of these reductions in life expectancy were attributable to older ages. Excess mortality in winter had the strongest impact on annual life expectancy, especially in Portugal and Bulgaria (around 0.8-year loss on e0). The study revealed significant cross-country variations in contributions of seasonal mortality. The most pronounced effects were observed in winter months and at older ages. These findings underscore the need for timely and targeted public health interventions to mitigate excess seasonal mortality.

Link: https://doi.org/10.1136/jech-2024-223050

Senescent cells are created constantly throughout life, but are rapidly removed by the immune system. Only in later life does the efficiency of immune clearance falter to allow senescent cells to accumulate. Lingering senescent cells cause harm in proportion to their numbers, secreting inflammatory signals that disrupt tissue structure and function. Numerous approaches to the selective clearance of senescent cells exist, and numerous companies are developing senolytic therapies that should improve health in later life, turning back aspects of aging by removing the senescent cells that are actively maintaining a degraded state of tissue function.

Instead of clearing senescent cells via present methods that attack features of senescent cell biochemistry to force apoptosis, is it possible to address the age-related changes that cause slowed immune clearance? On the one hand there are many avenues of research and development that might restore some lost function in the aged immune system, and it remains to be seen as to how they will affect surveillance of senescent cells. On the other hand, it appears that senescent cells in older individuals are different from those in younger individuals in ways that hamper the immune system. In today's open access paper, researchers find that senescent cells expressing GD3 at their cell surface can evade the attention of natural killer cells of the innate immune system. Sabotaging this mechanism would aid in immune clearance of senescent cells in aged individuals.

A ganglioside-based immune checkpoint enables senescent cells to evade immunosurveillance during aging

Advancing age goes hand in hand with the increased susceptibility to develop diseases that lead to functional decline, loss of autonomy, and healthcare system saturation. Mechanistically, the accumulation of senescent cells (SnCs) in tissues emerges as a key driver of aging and age-associated diseases. Thus, according to the geroscience hypothesis, considerable efforts are being made to find senotherapeutic strategies that allow the elimination or modification of SnCs to prevent and simultaneously treat many age-related diseases. Different senolytic compounds target the SnC intrinsic property to resist apoptosis due to Bcl-2 family protein overexpression.

Despite the existence of immune pathways to eliminate them, some SnCs can be tolerated in tissues for decades, and how they can be tolerated by the immune system remains an open question. The mechanisms by which these SnCs evade T cell surveillance can depend on immune checkpoints such as PD-L1. However, how SnC cells can evade from innate immunity, such as natural killer (NK) cell killing, is still elusive. In the present study, we discovered that SnCs can gain an immune privilege when they express at their cell surface a high level of the ganglioside GD3, leading to the escape from natural killer (NK) cell killing. This is the case for a large panel of SnC types, which upregulate the ST8SIA1 gene encoding the enzyme synthesizing GD3. In contrast, oncogene-induced SnCs do not trigger ST8SIA1 expression, enabling their elimination by NK cells.

Moreover, we demonstrate that anti-GD3 immunotherapy in mice prevents the development of bleomycin-induced lung fibrosis and attenuates different types of age-related disorders: lung and liver fibrosis and osteoporosis. These findings reveal GD3 as a senescence immune checkpoint and as a promising target for anti-senescence therapy.

Mitochondria are the power plants of the cell, producing chemical energy store molecules used to power cell activities. Energy hungry tissues such as muscle and brain are particularly sensitive to differences in mitochondrial function. Here, researchers show in a human study population that better mitochondrial function in muscle tissue correlates with slower aging in many areas of the brain. Interestingly, this relationship occurs regardless of physical fitness, though it is true that any given individual can be expected to achieve better mitochondrial function through attaining a greater degree of physical fitness. Physical fitness is beneficial in many ways, but it is the improvement in mitochondrial function resulting from greater physical fitness that drives the relationship with brain aging noted here, not the fitness per se.

This longitudinal study demonstrates a significant relationship between skeletal muscle mitochondrial oxidative capacity and brain structural changes up to over a decade, emphasizing the strong connection between mitochondrial health and brain aging and neurodegeneration. By investigating two different neuroimaging modalities across multiple brain regions, we identified specific brain regions and connecting tracts that were related to mitochondrial oxidative capacity assessed in the skeletal muscle. These longitudinal findings provide mechanistic insights into the connection between muscle bioenergetics and brain aging and lay a foundation for future research on mitochondrial bioenergetics in the brain.

One potential mechanism is that muscle mitochondrial function indicates general mitochondrial health and that muscle mitochondria can be considered a proxy measure of mitochondrial health across multiple tissues, including the brain. Another possibility is that the measure of oxidative capacity captures general muscle health and that positive signaling through soluble molecules and/or microvesicles may act in neurotrophic signaling that promotes brain health. While skeletal muscle oxidative capacity is related to fitness, the longitudinal associations between skeletal muscle oxidative capacity and brain atrophy were independent of concurrent fitness levels. Longitudinal associations with microstructural change persisted after accounting for the fitness measure of 400-meter walk time but were attenuated after adjusting for VO2 max. This attenuation is not surprising as fitness and vascular factors are strongly associated with white matter microstructure.

Because of the observational nature of this study, the detected longitudinal associations may shed light on but do not prove a causal relationship. In addition, we cannot exclude that higher skeletal muscle oxidative capacity reflects in part the lifetime history of exercise and physical activity which may affect several aspects of brain health but may not be fully captured by the assessment of current fitness levels.

Link: https://doi.org/10.1038/s41467-024-55009-z

Numerous research groups are investigating the cellular biochemistry of highly regenerative species such as salamanders and zebrafish. The goal is to find the differences that ensure regrowth of lost tissue rather than the scarring that occurs in mammals. So far, many of these differences appear to involve the continued operation of processes of regulated growth that take place during embryonic development. It is hoped that some of these differences can form a practical basis for regenerative therapies that will allow the safe regrowth of loss limbs and organ tissues. The approach noted here appears promising, as it is just a difference in expression of a gene regulating chromatin structure, rather than a difference in protein structure and function between species. Engineering higher or lower expression of specific native genes is practical, but introducing novel proteins with different sequences into an adult organism is more challenging to achieve safely, as the immune system can react poorly.

In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program.

Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury.

Link: https://doi.org/10.1038/s44161-024-00588-9

Rate of living theories of aging emerged from the observation that metabolism is generally slower in larger, longer-lived species. There are enough exceptions to disprove any specific hypothesis regarding what exactly might limit life span in species with a fast metabolism, however, and for this and other reasons rate of living theories fell to the wayside, somewhere along the way towards the development of a modern understanding of cellular biochemistry. Nonetheless, we are left with the observed that, yes, larger species tend to live longer, and yes, species with slower metabolisms also tend to live longer. Exceptions aside, that does suggest that something is there to be learned.

Here, researchers propose that the count of respiratory cycles over the course of a lifetime is the underlying roughly constant number that links all of the observed correlations of mass and metabolism across the majority of species. One can hypothesize, as was the case for the free radical theory of aging, that the apparent evidence for rate of living theories must say something about evolutionary limits placed on the amount of oxidation and cell damage an organism can sustain. This is, in turn, because oxidative molecules produce DNA damage at some pace, and there may be an evolutionary limit on the amount of mutational damage that can be sustained. At the same time, mutational damage is necessary for evolution to occur, and organisms that sustain more mutational damage will evolve more rapidly, potentially outcompeting those that evolve more slowly. We may be observing the result of optimization into a narrow window of possibilities.

On the causal connection in lifespan correlations and the possible existence of a 'number of life' at molecular level

Understanding the relevant processes that drive ageing and determine the longevity of organisms has been a subject of research for several decades, with many proposed theories of ageing that can be divided by the level of the primary factor: molecular, cellular, system, and evolutionary level. One of the theories at molecular level, is the somatic mutation theory of ageing, in which accumulation of mutations in the somatic DNA over time eventually cause a functional decline. This theory has been recently supported by, that reported a strong inverse relationship of the somatic mutation rate per year with species lifespan, with no other life-history trait showing a comparable association. Reference also found that the lifespan mutation burden varied only by a factor of around 3, despite widely different life histories among the species examined (i.e variation of around 30-fold in lifespan and around 40,000-fold in body mass). This result, established among the species, can be interpreted as support for a approximately constant total number of mutations over the lifetime of mammals and thus, being some kind of 'Number of Life' which effectively predetermines the extension of life.

Another 'Number of Life', to be approximately constant for different classes of living organisms (not only mammals), has been also proposed recently: the total number of 'respiration cycles' in a lifespan, Nr, which generalize the well-known empirical relation between the heart frequency and the lifespan, namely Nh the total number of heartbeats in a lifetime. In this paper, we study the causal connection in lifespan correlations, showing that six phenotypic traits (metabolic rate, mass, female and male sexual maturity, litter size, and heart frequency) acting at the system level, are all related to lifespan thru the existence of an approximately constant number of respiration cycles in a lifespan.

Consistent with a direct proportionality between the somatic mutation rate and the respiration frequency, which might suggest a possible origin of the constant number of cycles per lifetime at molecular level, thru being a manifestation at system level the fixed number of end-of-lifespan mutation burden at molecular level (or vice versa). One possible link between the respiration process and the rate of somatic mutations, might be through the byproducts of the respiration process, such as free radicals and oxidants that are candidates traditionally hypothesized to be responsible of the ageing process, as far as production rates of those byproducts of respiration determines the rate of somatic mutations.

The nucleolus structure of the cell is where ribosomes are built, but it appears to be influential in a range of mechanisms relating to stress response, quality control, and damage repair in cells. All of these are in turn linked to pace of aging. The relationships are by no means fully understood in detail, however. This is an area of ongoing exploration in which researchers are finding ways to adjust nucleolar function to slow aging in model organisms such as yeast and nematode worms.

To cope with hazardous protein toxicity (proteotoxicity), protein quality control mechanisms act in concert to supervise the integrity of nascent and mature proteins and direct terminally damaged proteins for degradation. In the early stages of life, this protein homeostasis (proteostasis) network successfully maintains the integrity of the proteome; however, with ageing, misfolded proteins aggregate and accumulate within and outside cells. These aggregates challenge the proteostasis network and often underlie the development of disorders known as 'proteinopathies', including neurodegenerative conditions.

Accordingly, the maintenance of proteostasis through late stages of life bears the promise to delay the emergence of these devastating diseases. Yet the identification of proteostasis regulators is needed to assess the feasibility of this approach. Here we report that knocking down the activity of the nucleolar FIB-1-NOL-56 complex protects model nematodes from proteotoxicity of the Alzheimer's disease-causing amyloid-β peptide and of abnormally long poly-glutamine stretches. This mechanism promotes proteostasis across tissues by modulating the activity of TGFβ signalling and by enhancing proteasome activity. Our findings point at research avenues towards the development of proteostasis-promoting therapies for neurodegenerative maladies.

Link: https://doi.org/10.1038/s41556-024-01564-y

A variety of epidemiological data argues for a role for persistent viral infection in the development of Alzheimer's disease. This is disputed, however. Some conflicting data shows no signs of a relationship, which suggests that the situation is complicated. Mechanistically, persistent viral infections such as herpesviruses might accelerate the onset of neurodegenerative conditions by provoking greater inflammation, greater numbers of dysfunctional microglia in the brain, and greater amounts of the antimicrobial peptide amyloid-β. Here, however, researchers find evidence for a herpesvirus to promote tau protein aggregation, characteristic of later, more damaging stages of Alzheimer's disease. This adds another interesting wrinkle to the present state of data on mechanisms and epidemiology.

Researchers identified forms of HSV-1-related proteins in Alzheimer's brain samples, with greater amounts of viral proteins co-localized with tangles of phosphorylated tau - one of the hallmarks of Alzheimer's disease pathology - in brain regions especially vulnerable to Alzheimer's across disease stages. Further studies on miniature models of human brains in a Petri dish suggested that HSV-1 infection could modulate levels of brain tau protein and regulate its function, a protective mechanism that seemed to decrease post-infection death of human neurons.

While the precise mechanisms by which HSV-1 influences tau protein and contributes to Alzheimer's disease are still unknown, researchers plan to explore those questions in future research. They aim to test potential therapeutic strategies that target viral proteins or fine-tune the brain's immune response and investigate whether similar mechanisms are involved in other neurodegenerative diseases, such as Parkinson's disease and ALS.

Link: https://www.eurekalert.org/news-releases/1069259

Atherosclerosis is the growth of fatty plaques in blood vessel walls, eventually growing to the point of narrowing vessels to reduce blood flow. Rupture of a plaque can cause a downstream blockage, and this is the cause of heart attack and stroke. As a result, atherosclerosis is the largest cause of human mortality. This remains the case even today because present approaches to the treatment of atherosclerosis do not reliably produce any sizable reduction in plaque size, and are very slow to remove enough plaque lipids to reduce risk of rupture by stabilizing the plaque structure. Available approaches have near entirely focused on reducing inflammation and lowering the transport of cholesterol via LDL particles, but this only modestly slows plaque growth and modestly reduces risk of rupture. New approaches capable of reversing the disease are very much needed.

Like every other dysfunction in the body, atherosclerosis interacts with other aspects of aging and age-related disease processes. In today's open access paper, researchers conduct a tour of some of the better explored relationships between atherosclerosis and other common age-related conditions. In some cases there are shared mechanisms driving both conditions, in other cases there is good reason to think that one condition helps to accelerate the development of the other. Certainly, even without the ability of atherosclerosis-induced reduction of blood flow to make other conditions worse, there is reason enough for greater funding to be devoted to new approaches to treatment.

Association between atherosclerosis and the development of multi-organ pathologies

Atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) has long been known to be associated with the development of various multiorgan pathologies characterised by chronic inflammation, oxidative stress, and dyslipidaemia. However, the significant advances made over the past decade have greatly expanded our understanding of how atherosclerosis-associated pathological changes affect the metabolism of vascular cells in different tissues and organs. It is challenging to distinguish the specific pathways affected by atherosclerosis, as many of the adverse effects associated with atherosclerosis are also attributed to the manifestation of other closely related conditions (such as metabolic syndrome, diabetes mellitus, obesity and others) that share common risk factors with atherosclerosis (primarily hypertension, dyslipidaemia, smoking, advanced age, stress, genetic factors and many others).

A strong association has been established between atherosclerosis and ischemic stroke, with napkin-ring sign plaques, a 'spotty' pattern of plaque calcification, and elevated serum levels of aldosterone, C-reactive protein, and ELAVL1 protein being potent stroke biomarkers. Interestingly, atherosclerosis and Alzheimer's disease have been shown to promote each other through several pathways. Notably, the well-studied C/EBPβ/AEP signalling pathway has been demonstrated to connect atherosclerosis and AD through ApoE-mediated vascular dysfunction. Additionally, the ε4 allele of the ApoE gene has been associated with more severe forms of atherosclerosis and a higher rate of cognitive decline in Alzheimer's disease.

Furthermore, chronic kidney disease (CKD) and atherosclerosis have been shown to exacerbate one another. Kidney dysfunction increases the accumulation of certain uraemic toxins, which impair the antioxidant system, increase reactive oxygen species (ROS) generation and promote oxidative damage, thereby exacerbating vascular dysfunction and the development of atherosclerosis. On the other hand, the rupture of atherosclerotic plaques can release cholesterol crystals into the bloodstream, which can become lodged in arterioles, leading to ischaemia and infarction in various tissues and organs, including the kidneys. Similarly, atherosclerosis and kidney stones have been linked through dyslipidaemia and oxLDL accumulation. Atherosclerosis-like responses to inflammation and perivascular calcification have been shown to promote kidney stone formation. Kidney stones, in turn, up-regulate a wide range of atherosclerosis-promoting genes (such as adhesion molecules, extracellular matrix molecules and pro-inflammatory cytokines), which increase the risk of ASCVD.

The role of atherosclerosis in pancreas dysfunction has been mechanistically explained by atherosclerosis-mediated reductions in blood flow to the pancreas, which causes islet hypoxia and β-cell dysfunction. Finally, dyslipidaemia, hypertension, endothelial dysfunction and a hypercoagulable state have been proposed as the major risk factors linking thyroid dysfunction and ASCVD. In vivo and in vitro experiments have demonstrated that thyroid hormones directly activate the expression and production of pro-inflammatory cytokines and adhesion molecules. In particular, TSH has been shown to aggravate vascular inflammation and promote atherosclerosis development.

The results discussed suggest that regular monitoring and timely treatment of atherosclerosis-related vascular risk factors may be a valuable strategy for treating and preventing Alzheimer's disease, pancreas and thyroid dysfunctions, kidney stones, and CKD. On the other hand, the pathologies of many organs may manifest through ASCVD, complicating diagnosis and treatment and potentially leading to life-threatening conditions. Overall, further studies deciphering the diverse mechanisms by which atherosclerosis is associated with multiple organ pathologies would help generate new therapeutic strategies to mitigate the adverse effects of atherogenesis on other organs.

The amount of data on aging in animal models is only going to grow. Many large initiatives are focused on generating as much of a map of the biochemistry of aging as presently possible, and their output already far outpaces the ability of the broader scientific community to synthesize and understand this data. The new transcriptomic map noted here is an example of the type, and enormous research that will keep researchers busy in the decades ahead. A comprehensive understanding of the detailed progression of aging is perhaps less important to the near future of therapies to treat aging, however, as these will emerge from what is presently known of the contributing causes of aging, not from an understanding of the damage done by those causative mechanisms.

Biological ageing can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Mammalian brains consist of thousands of cell types, which may be differentially susceptible or resilient to ageing. Here we present a comprehensive single-cell RNA sequencing dataset containing roughly 1.2 million high-quality single-cell transcriptomes of brain cells from young adult and aged mice of both sexes, from regions spanning the forebrain, midbrain, and hindbrain. High-resolution clustering of all cells results in 847 cell clusters and reveals at least 14 age-biased clusters that are mostly glial types. At the broader cell subclass and supertype levels, we find age-associated gene expression signatures and provide a list of 2,449 unique differentially expressed genes (age-DE genes) for many neuronal and non-neuronal cell types.

Whereas most age-DE genes are unique to specific cell types, we observe common signatures with ageing across cell types, including a decrease in expression of genes related to neuronal structure and function in many neuron types, major astrocyte types and mature oligodendrocytes, and an increase in expression of genes related to immune function, antigen presentation, inflammation, and cell motility in immune cell types and some vascular cell types. Finally, we observe that some of the cell types that demonstrate the greatest sensitivity to ageing are concentrated around the third ventricle in the hypothalamus, including tanycytes, ependymal cells, and certain neuron types in the arcuate nucleus, dorsomedial nucleus, and paraventricular nucleus that express genes canonically related to energy homeostasis. Many of these types demonstrate both a decrease in neuronal function and an increase in immune response. These findings suggest that the third ventricle in the hypothalamus may be a hub for ageing in the mouse brain.

Overall, this study systematically delineates a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal ageing that will serve as a foundation for the investigation of functional changes in ageing and the interaction of ageing and disease.

Link: https://doi.org/10.1038/s41586-024-08350-8

It is commonplace in the research and medical communities to attempt to distinguish normal aging from pathological aging. This seems problematic, as it is all aging under the hood. A healthy older person is still impacted by the mechanisms of aging, a burden of molecular damage and its consequences, just less impacted than a similarly aged peer suffering evident age-related diseases. The pace of aging, and which forms of damage build upon one another to the point of runaway dysfunction and pathology, varies considerably from individual to individual. Nonetheless, there is still the drive to attempt to distinguish normal aging from pathological aging, particularly when it comes to cognitive function.

Aging is typically associated with declines in episodic memory, executive functions, and sleep quality. Therefore, the sleep-dependent stabilization of episodic memory is suspected to decline during aging. This might reflect in accelerated long-term forgetting, which refers to normal learning and retention over hours, yet an abnormal retention over nights and days. Accelerated long-term forgetting has been observed in dementia, mild cognitive impairment, and in people with memory complaints.

Here, we explored whether accelerated long-term forgetting also manifests in healthy aging. We investigated verbal episodic memory in 236 healthy men and women between 18 and 77 years of age. All participants were mentally intact in terms of executive functions, working memory, episodic memory, verbal intelligence, and mood. We related their forgetting rates over one week following learning to their subjective sleep quality and executive functions. Fifteen words were freely recalled and then recognized among 30 distractor words at 30 minutes and again at one week following learning. Although the healthy older adults compared to the healthy younger adults reported a diminished sleep efficiency and learned fewer words, they exhibited no disproportionate forgetting over days.

Hence, accelerated long-term forgetting is not present in healthy aging but might be a first sign of memory dysfunction due to neuropathology.

Link: https://www.nature.com/articles/s41598-024-82570-w

Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body, involved in tissue maintenance as well as defense against pathogens. Like macrophages, microglia adopt packages of behaviors called polarizations. The two of greatest interest are M1, inflammatory and hunting down pathogens and errant cells, versus M2, anti-inflammatory and engaging in tissue maintenance. An increase in inflammatory microglia, a maladaptive response of the innate immune system to molecular damage characteristic of aging, is thought to contribute to the aging of the brain.

There are a few ways to selectively destroy microglia, one of which is use of pexidartinib, PLX3397. This drug inhibits CSF1R activity, which causes microglia to die. The population of microglia then recovers within a few weeks after use of the drug ceases. The newly created microglia tend to exhibit fewer of the maladaptive traits of the old, cleared population, such as overly inflammatory behavior. This has allowed researchers to test microglial clearance as a basis for therapy in animal models of various neurodegenerative conditions. So far the results seem generally positive, but in today's open access paper, results in a mouse model of Alzheimer's disease are not as hoped for.

Partial microglial depletion and repopulation exert subtle but differential effects on amyloid pathology at different disease stages

Microglia are the resident innate immune cells of the central nervous system (CNS). They play a key role in neurodevelopment and plasticity, as well as in the pathogenesis of a wide array of neurodevelopmental and neurodegenerative disorders. In Alzheimer's disease (AD), genetic risk factors are disproportionately linked to immune receptors expressed by microglia, positioning these cells as important targets for disease-modifying therapies. However, in the chronic neuroinflammatory environment in AD, the role of microglia is complex. In fact, removal of microglia in AD mouse models via inhibition of colony-stimulating factor 1 receptor (CSF1R), which is critical for microglial survival and proliferation, reduced plaque formation when administered early but not during advanced amyloid pathology, which is more translationally relevant. Additionally, while some studies have shown that late loss of microglia improved learning and memory, and lessened neuronal loss, others demonstrated that it also increased plaque-associated neuritic damage.

Rather than removing microglia, renewing them through depletion followed by repopulation presents another exciting strategy. Adult microglia are capable of rapidly replenishing their niche within 1 week after removal of CSF1R inhibitor, restoring their morphology and physiological functions. In several injury models and in aging, repopulated microglia have been shown to be beneficial in promoting brain recovery and reversing age-related neuronal deficits. However, in the context of AD, we previously found no beneficial effects of microglial repopulation on either amyloid pathology nor cognitive function in aged transgenic mice harboring both amyloid and tau pathology. On the other hand, early microglia renewal was suggested to partially rescue cognitive deficits by restoring the microglial homeostatic phenotype.

Here, we sought to delineate the dynamic effects of microglial depletion followed by repopulation on microglia function and amyloid-β plaque burden during different stages of amyloid pathology. We administered the CSF1R inhibitor PLX3397 (hereafter referred to as PLX) in 5xFAD mice and tracked microglia-plaque dynamics with in vivo imaging. We revealed a transient improvement in plaque burden that occurred during either the depletion or repopulation period depending on the animal's age. Interestingly, while the improvement in plaque load did not persist long-term, repopulated microglia during mid-to-late pathology stages appeared to retain or increase their sensitivity to noradrenergic signaling, which is largely thought to be anti-inflammatory.

Given that there are several aging clocks built on machine learning based analyses of retinal images, it shouldn't be too surprising to find that specific aspects of aging in the retinal microvasculature can be correlated the old-fashioned way with an increased risk of mortality. As researchers note here, the small vessels of the body and brain are prone to clearly identifiable forms of structural damage that result from processes associated with aging. This damage is only easily viewed in the retina, however.

The retinal arteriole has similar anatomical and physiological features to cerebral and coronary circulations. Given that retinal vessels can be easily and noninvasively observed, they can be used to monitor microvascular health status in vivo. Retinal microvascular abnormalities (RMA), including retinopathy, generalized or focal arteriolar narrowing (FAN), arteriovenous nicking (AVN), and Hollenhorst plaque (HP), are common in older persons, even in those without diabetes. These findings reflect cumulative vascular damage from hypertension, aging, and other biological processes and are hypothesized to serve as potential markers for cardiovascular diseases (CVD).

This study aimed to examine the relationships between RMA and the risk of all-cause and specific-cause mortality among U.S. adults. 5,775 individuals aged ≥ 40 years were included from the U.S. National Health and Nutrition Examination Survey, 2005-2008. RMA and its subtypes were manually graded from retinal photographs. Associations between RMA and the risk of all-cause and cause-specific mortality were examined with Cox regression analysis.

RMA were present in 1,251 participants (weighted, 17.9%), of whom 710 (weighted, 9.8%) had retinopathy, 635 (weighted, 9.3%) had AVN, 64 (weighted, 1.0%) had FAN, and 21 (weighted, 0.3%) had HP. During a median of 12.2 years of follow-up, 1,488 deaths occurred, including 452 associated with cardiovascular disease (CVD), 341 associated with cancer, and 695 associated with other causes. After adjusting confounding factors, the presence of any RMA and retinopathy at baseline was associated with higher risk of all-cause mortality (hazard ratios 1.26 and 1.36 respectively), CVD mortality (hazard ratios 1.36 and 1.53 respectively) and other-cause mortality (hazard ratios 1.33 and 1.55 respectively). Additionally, FAN was significantly associated with an increased risk of other-cause mortality (hazard ratio 2.06). Although AVN was not associated with mortality in the whole population, it was significantly related to higher risks of all-cause and CVD death in those with obesity (hazard ratios 1.68 and 1.96 respectively).

Link: https://doi.org/10.1186/s12889-024-21117-0

Researchers here propose a way to make existing senolytic small molecules more efficient by attaching them to a compound that binds to lipofusin, a form of molecular waste originating in lysosomes that is hard to break down. The resulting compound senolytic molecule is encapsulated in some form of delivery system for cell uptake, here a micelle, but other forms of nanoparticle would probably also do the job. Lipofuscin accumulation is a feature of senescent cells. It is also found in very long-lived non-dividing cells in old tissues, such as neurons, so some thought should probably be given to limiting their exposure to such a drug.

The emerging field of senolytics is centered on eliminating senescent cells to block their contribution to the progression of age-related diseases, including cancer, and to facilitate healthy aging. Enhancing the selectivity of senolytic treatments toward senescent cells stands to reduce the adverse effects associated with existing senolytic interventions. Taking advantage of lipofuscin accumulation in senescent cells, we describe here the development of a highly efficient senolytic platform consisting of a lipofuscin-binding domain scaffold, which can be conjugated with a senolytic drug via an ester bond.

As a proof of concept, we present the generation of GL392, a senolytic compound that carries a dasatinib senolytic moiety. Encapsulation of the GL392 compound in a micelle nanocarrier (termed mGL392) allows for both in vitro and in vivo (in mice) selective elimination of senescent cells via targeted release of the senolytic agent with minimal systemic toxicity. Our findings suggest that this platform could be used to enhance targeting of senotherapeutics toward senescent cells.

Link: https://doi.org/10.1038/s43587-024-00747-4

The raised blood pressure of age-related hypertension is an interesting problem because (a) it causes a great deal of downstream harm in the form of pressure damage to tissues and associated dysfunctions, (b) the mechanisms controlling blood pressure are actually quite well understood, and so (c) there are many different ways to reduce blood pressure without actually addressing the underlying cell and tissue damage that causes aging. Studies suggest that control of hypertension via present pharmaceutical approaches can sizeably reduce the risk of age-related disease.

Broadly speaking, blood pressure is determined by the combination of heart rate, constriction of blood vessels throughout the body, and regulation of water content of blood by the kidneys. Complex feedback loops of pressure sensing, blood sodium sensing, and downstream signaling juggle these processes to maintain blood pressure at a given level. Pharmaceuticals are used to block or upregulate portions of that signaling in order to induce reduced blood volume via greater uptake of water by the kidneys or lesser degrees of vessel constriction in order to expand the volume of the vascular system. Heart rate is not typically targeted in this context, for all of the obvious reasons.

In today's open access paper, researchers note that the use of calorie restriction as an intervention acts to reduce the increase of blood pressure in aged rats. It functions via the renin-angiotensin system of the kidney, a part of the regulatory systems that control the water content of blood and thus blood volume. Calorie restriction prevents some of the age-related disruption of this regulatory system, and thus removes some fraction of age-related hypertension.

Fasting recovers age-related hypertension in the rats: reset of renal renin-angiotensin system components and klotho

Aging is associated with imbalances in hormonal and metabolic processes that contribute to homeostasis and enable the organism to adapt to changes in its environment. One of the key control systems that changes during the aging process is the renin-angiotensin system (RAS), which is a critical control system that affects the regulation of blood pressure and sodium balance. During aging, RAS through over activation of AngII/Ang II type 1 receptor and overproduction of reactive oxygen species (ROS) and inflammatory responses acts as an accelerator in cell and organ senescence, and causes to hypertension, chronic kidney disease, atherosclerosis, and sarcopenia. On the other hand, the other parts of RAS, AngII/Ang II type 2 receptor and ACE2 (angiotensin converting enzyme 2)/ Ang (1-7)/Mas receptor, modulate the harmful effect of ACE/Ang II/AT1 receptor and play a positive impact in RAS balance and delay senescence. It seems that both local (tissue) and circulating RAS are involved in aging-related disease.

Several studies suggest the anti-aging effects of ACE-inhibitors and angiotensin receptor blockers (ARBs) in rodent models. Beneficial effects of RAS blockers on aging through increased klotho and sirtuin expression and activation of vitamin D signaling parallel the effects of calorie restriction (CR) in delaying aging. Evidence shows that fasting has a beneficial role on human health by improving various metabolic markers. Our recent findings revealed that the restoration of RAS equilibrium in both the aorta and heart may be a part of involving mechanisms of fasting benefits on its cardiovascular rejuvenation.

In this study, age-related changes in kidney RAS components were evaluated. Then, the effect of a 3-month period of two fasting regimes, fasting one day per week (FW) or fasting every other day (EOD) on the components of renal RAS and arterial blood pressure in three age groups of rats was investigated. The results showed that changes in the blood pressure and kidney-RAS system were not significant until middle age. However, senescence was correlated with a significant increase in blood pressure, decrease in the amount of AT2R protein of kidney, a significant rise in the AT1R / AT2R proteins ratio of kidney and plasma Ang II level, and a significant decrease in klotho plasma level in older rats contrast to young rats. On the other hand, EOD fasting reversed the aging effect on blood pressure and RAS, so that under EOD the mentioned parameters in old rats reduced to levels of young animals and also the ACE2 protein was significantly higher than young animals.

As noted here, mitochondria accomplish much more than only manufacturing adenosine triphosphate (ATP) to power the cell. Yes, they are power plants, but also communication hubs, generating molecular signals of many sorts that influence other mitochondria, the surrounding cell, and other cells. When mitochondria become dysfunctional in the ways characteristic of aged tissue, these communications are altered in potentially harmful ways. How this all plays out in detail is by no means fully mapped and understood, and this is typical of much of the overlap between degenerative aging and cell biochemistry.

Mitochondria have roles beyond energy generation. They are essential for pathways within cells and organisms that control immunity, stress reactions, metabolism, and cellular fate. To carry out these duties, mitochondria have formed intricate intercellular and intracellular communication systems. Within cells, communication pathways consist of direct connections between mitochondria and other subcellular structures and indirect transportation of ions, metabolites, and other intracellular messengers through vesicles. Mitochondria can trigger stress reactions or other cellular alterations that release mitochondrial cytokine factors outside of cells. These factors can move between different tissues and react to immunological challenges originating from outside of cells.

Mitochondrial communication refers to the processes by which mitochondria share information and energy capacity with neighboring mitochondria. Additionally, it encompasses the physical interactions and exchange of chemicals and metabolites between mitochondria and other organelles. Nevertheless, the process of mitochondrial communication relies on the synchronized effort of numerous elements, and as a result, it is not infallible. The deregulation of communication between mitochondria and host cells has significant implications and serves as a fundamental element in various pathological diseases, including the aging process.

In this review, we comprehensively discuss the signal transduction mechanisms of intercellular and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of intercellular and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.

Link: https://doi.org/10.1186/s11658-024-00669-4

The trajectory of bone density over time is affected by the balance of activities between osteoblast cells that build bone and osteoclast cells that break down bone. With age, osteoclast activity begins to outweigh osteoblast activity, leading eventually to osteoporosis. There is some evidence for this age-related loss of bone density to be influenced by the composition of the gut microbiome. To the degree in which everything in aging is connected by mechanisms of chronic inflammation, this makes some sense: a more inflammatory gut microbiome could make everything worse, including osteoporosis. Here, however, researchers use germ-free mice to show that dramatic differences in the presence of a gut microbiome make little difference to age-related loss of bone density. This argues for a minimal role for the gut microbiome, inflammation or otherwise.

Emerging evidence suggests a significant role of gut microbiome in bone health. Aging is well recognized as a crucial factor influencing the gut microbiome. In this study, we investigated whether age-dependent microbial change contributes to age-related bone loss in CB6F1 mice. The bone phenotype of 24-month-old germ-free (GF) mice was indistinguishable compared to their littermates colonized by fecal transplant at 1-month-old. Moreover, bone loss from 3 to 24-month-old was comparable between GF and specific pathogen-free (SPF) mice. Thus, GF mice were not protected from age-related bone loss.

16S rRNA gene sequencing of fecal samples from 3-month and 24-month-old SPF males indicated an age-dependent microbial shift with an alteration in energy and nutrient metabolism potential. An integrative analysis of 16S predicted metagenome function and LC-MS fecal metabolome revealed an enrichment of protein and amino acid biosynthesis pathways in aged mice. Microbial S-adenosyl methionine metabolism was increased in the aged mice, which has previously been associated with the host aging process. Collectively, aging caused microbial taxonomic and functional alteration in mice.

To demonstrate the functional importance of young and old microbiome to bone, we colonized GF mice with fecal microbiome from 3-month or 24-month-old SPF donor mice for 1 and 8 months. The effect of microbial colonization on bone phenotypes was independent of the microbiome donors' age. In conclusion, our study indicates age-related bone loss occurs independent of gut microbiome.

Link: https://doi.org/10.1038/s41413-024-00366-0

Mitochondria are the power plants of the cell, vital organelles evolved from symbiotic bacteria that merged with early cellular life to form the first eukaryotes. Every cell contains hundreds of mitochondria, capable of replicating to make up their numbers, as well as fusing together and swapping component parts. Each mitochondrion bears at least one mitochondrial DNA copy, a remnant genome that contains a small number of genes necessary for mitochondrial function. Mitochondrial DNA is more vulnerable to mutational damage and less capable of repair than is the case for DNA in the cell nucleus. It is thought that the accumulation of mitochondrial DNA damage in cells throughout the body contributes to aging via loss of mitochondrial function, but the situation is complicated by selection effects in the mitochondrial population and the operation of mitophagy, a recycling process to clear damaged and dysfunctional mitochondria.

Oocytes are female germline cells, a population that gives rise to egg cells. Oocytes and the cells of their supporting niche have evolved a variety of mechanisms to protect oocyte nuclear DNA from damage; this is fairly well studied. Less well studied is damage that occurs to mitochondrial DNA in oocytes, but it is reasonable to think that oocytes could have evolved the means to minimize mitochondrial DNA damage for all the same reasons that they have evolved ways to better protect nuclear DNA - at least in longer-lived species such as our own. The interesting question is whether any of these evolved mechanisms could usefully be applied to other cells in the body to better maintain their mitochondrial DNA. The first step is to identify these mechanisms, and that is still a work in progress.

Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age

Whereas mitochondrial DNA (mtDNA) mutations have been analyzed in human somatic tissues in detail, the direct examination of mtDNA mutations in human oocytes has been challenging due to methodological limitations. Most previous studies either focused on particular mtDNA sites or used sequencing methods with high error rates. Using a low-error duplex sequencing approach, we have recently shown that mutations across the whole mtDNA increase with age in mouse oocytes. Using the same approach, we have demonstrated that mtDNA mutations increase in macaque oocytes until ∼9 years of age and do not increase afterward. Importantly, we still do not know definitively whether the frequency of de novo mtDNA mutations increases with age in human oocytes.

To address this knowledge gap, we analyzed mtDNA substitution mutations in single oocytes, blood, and saliva from women of ages 20 to 42. We used the highly accurate duplex sequencing method, which we had previously modified to generate high-quality mtDNA sequences directly from single oocytes. We obtained a comprehensive set of mutations to study the impact of age on frequencies of germline and somatic mutations, as well as on their distribution across mtDNA.

We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies (≥1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life.

It is almost always the case that measurement in biology is not as straightforward as the high level summaries make it out to be, and there is almost always some debate over whether the measurements are good enough, robust enough, and actually correct. Mitochondria are the power plants of the cell, conducting energetic reactions to produce the chemical energy store molecule adenosine triphosphate (ATP) needed to power the the cell. It is well established that mitochondrial function declines with age, but until quite recently measuring mitochondrial function required live mitochondria, which opened up all sorts of opportunities for cost, rework, bias, and error in the process of getting those mitochondria out of an animal (or person) and into a device in large enough numbers and good enough condition. Now, however a robust method for assessment in frozen samples exists, and researchers are putting it to good use, to double-check the present consensus on age-related mitochondrial decline.

It is generally accepted that mitochondria become less active in aging animals and that their dysfunction is a key contributor to the aging process. A device called a 'respirometer' can be used to measure mitochondrial activity by detecting how much oxygen these organelles are consuming. However, until recently, this approach could only be applied to freshly isolated mitochondria obtained from mammalian tissues through a long and laborious process, making them difficult to study in large numbers. This limitation has prevented comprehensive analyses of mitochondrial respiration in mammalian tissues.

Using a recently developed protocol for respiratory analysis of frozen tissue samples researchers have now measured a proxy of mitochondrial respiration in over 1,000 samples from a large cohort of young and old mice of both sexes. This included tissues with reportedly high mitochondrial activity, such as certain brain regions, several skeletal muscles, the heart, and the kidneys. The samples also included metabolic tissues like the liver or pancreas, as well as sections of the gastrointestinal tract, the skin, and the eyes.

Due to the process of freezing and thawing, the mitochondria in the samples were not intact and therefore could not be isolated. Researchers measured mitochondrial respiration at three different sites on the electron transport chain in cellular extracts enriched with mitochondrial membranes. The proteins making up this chain are likely to remain relatively stable in mitochondria whose membrane integrity has been lost, which allows measurements that indicate the maximum capacity of the mitochondria to produce ATP to be taken.

Analyzing the differences between old and young animals revealed a net decline in mitochondrial activity in most tissues with age, most notably in samples from the brain and metabolic tissues. These results are consistent with our current understanding of the energetic demands of various tissues and how they decline over time. Intriguingly, in older animals, respiration increased in some tissues with high-energy demand, such as the heart and skeletal muscles, which is potentially at odds with the observation that these organs perform less well with age. Analyzing differences between samples from males and females also revealed that age has a much larger effect on mitochondrial activity across all tissues than sex.

Link: https://doi.org/10.7554/eLife.105191

Transcriptional elongation is the name given to the complex process by which nucleotides are added to the end of an RNA molecule as it is being constructed in the cell nucleus, replicating the blueprint for that molecule encoded in a DNA sequence. The RNA polymerase II complex is the protein machinery that accomplishes this work. In recent years researchers have identified age-related changes in the operation of this machinery that give rise to a greater incidence of errors and other changes in gene expression thought to detrimentally alter cell behavior.

Aging results in a major impairment of RNA and protein biosynthesis that contributes to aging-associated phenotypes. Research over the past two decades has mostly focused on quantitative changes of RNA and protein levels. However, recent work has shown that the quality of molecular processes involved in RNA and protein biosynthesis also declines with age, impacting not only the quantity but critically also the quality of the synthesized molecules. For example, errors during transcription and splicing can result in mRNAs carrying incorrect primary sequences, which can in turn lead to the production of toxic proteins that fuel aging-associated disease. Indeed, recent unbiased screens for factors causal to age-dependent retinal degeneration in flies or for new senescence regulators, identified transcriptional initiation and elongation factors as among the top hits.

It remains largely elusive how individual processes are affected during aging and what their specific contribution to age-related functional decline is. This review discusses a series of recent publications that has shown that transcription elongation is compromised during aging due to increasing DNA damage, stalling of RNA polymerase II, erroneous transcription initiation in gene bodies, and accelerated RNA polymerase II elongation. Importantly, several of these perturbations likely arise from changes in chromatin organization with age. Thus, taken together, this work establishes a network of interlinked processes contributing to age-related decline in the quantity and quality of RNA production.

Link: https://doi.org/10.1016/j.tcb.2024.11.005

Correlations exist between health, life expectancy, lifestyle choices and the web of connections between intelligence, educational achievement, wealth, and status. Higher socioeconomic status and greater intelligence both correlate with a longer life expectancy, but it remains a challenge to move from correlational data to an understanding of the causes and their relative importance. Is it all down to obesity and exercise? Are there genetic factors that link intelligence and the physical robustness needed for greater longevity? Does wealth buy better access to medicine in ways that matter for life expectancy?

It is interesting to ask whether specific choices or life status factors literally accelerate degenerative aging. In the case of being overweight, there is a body of evidence to suggest that, yes, at least some of the known underlying causes of aging are accelerated. The accumulation of senescent cells, for example. For low socioeconomic status it is a little harder to theorize on why there would be a direct mechanistic link to life expectancy and pace of aging. Given present proxy measures for biological age, the accumulated burden of damage and dysfunction, one can show that biological age proceeds faster in people of low socioeconomic status, but that still leaves open the question of why this is the case.

The Pace of Biological Aging Partially Explains the Relationship Between Socioeconomic Status and Chronic Low Back Pain Outcomes

Socioeconomic status (SES) disparities in healthcare have been well documented for decades and have severe implications. Individuals classified as having a lower SES have a shorter life expectancy and are at increased risk for age-related chronic conditions such as chronic pain. Among individuals with chronic low back pain (cLBP), those with a lower SES have greater pain intensity and pain-related disability. This is relevant because low back pain is a leading cause of years lived with disability. Emerging evidence has linked worse pain outcomes to epigenetically induced alterations in pathways involved in neuroinflammation, hormonal dysregulation, impaired immune function, allostatic loads, and poor metabolic control. Interestingly, these major biological pathways overlap with processes that control aging.

We used the Dunedin Pace of Aging Calculated from the Epigenome (DunedinPACE) software to determine the pace of biological aging in adults ages 18 to 85 years with no cLBP (n = 74), low-impact pain (n = 56), and high-impact pain (n = 77). The mean chronological age of the participants was 40.9 years. On average, the pace of biological aging was 5% faster (DunedinPACE = 1.05 ± 0.14) in the sample. Individuals with higher levels of education had a significantly slower pace of biological aging than those with lower education levels (F = 5.546). After adjusting for sex and race, household income level significantly correlated with the pace of biological aging (r = - 0.17), pain intensity (r = - 0.21), pain interference (r = - 0.21), and physical performance (r = 0.20). In mediation analyses adjusting for sex, race, and body mass index (BMI), the pace of biological aging mediates the relationship between household income (but not education) level and cLBP intensity, interference, as well as physical performance.

There is a fair amount of literature on the benefits of brown adipose tissue, involved in thermogenesis, weight loss mechanisms, and most likely a variety of forms of beneficial metabolic signaling. Some interventions known to improve long-term health may act in part by converting a fraction of white adipose tissue to brown adipose tissue. Here, researchers use the blunt but useful approach of transplanting brown fat tissue between mice to observe the outcome, demonstrating that the addition of more brown fat appears beneficial to measures of health.

Brown adipose tissue (BAT), a major subtypes of adipose tissues, is known for thermogenesis and promoting healthful longevity. Our hypothesis is that BAT protects against impaired healthful longevity, i.e., obesity, diabetes, cardiovascular disorders, cancer, Alzheimer's disease, and reduced exercise tolerance. While most prior studies have shown that exercise regulates BAT activation and improves BAT density, relatively few have shown that BAT increases exercise performance. In contrast, our recent studies with the regulator of G protein signaling 14 (RGS14) knockout (KO) model of extended longevity showed that it enhances exercise performance, mediated by its more potent BAT, compared with BAT from wild type mice.

Multiple mechanisms mediated the enhanced exercise capacity in RGS14 KO mice. The most important mechanism is BAT, which mediates SIRT3, MnSOD, MEK/ERK and VEGF pathways. These mechanisms regulate exercise capacity by improved mitochondrial function, protection against oxidative stress, and improved blood flow/angiogenesis. For example, when the BAT from RGS14 KO mice is transplanted to WT mice, their exercise capacity is enhanced at 3 days after BAT transplantation, whereas BAT transplantation from WT to WT mice increased exercise performance, but only at 8 weeks after transplantation. In view of the ability of BAT to mediate healthful longevity and enhance exercise performance, it is likely that a pharmaceutical analog of BAT will become a novel therapeutic modality.

Link: https://doi.org/10.18632/aging.206179

A better understanding of the biochemistry of long-lived, large species may in the near term lead to ways to better prevent cancer: more cells means more cancer risk, so every species larger and more long-lived than humans must have evolved better than human cancer suppression mechanisms. Elephants evolved many copies of tumor suppressor TP53, for example, while some whales appear to make use of other mechanisms to maintain cancer risk at a low enough level to ensure long lives and evolutionary success. That said, as for all of areas of interest arising from studies of the comparative biology of aging, it remains unclear as to the practical costs and feasibility of adapting cellular mechanisms from species A for use in species B. On a case by case basis this may be a prospect for the next twenty years, or it could require a century or more of progress towards reliable engineering of the human genome and cell biochemistry.

The first observations documenting the extraordinary longevity of whales were from the counts of annual ear plug lamina of fin whales (Balaenoptera physalus) and blue whales (Balaenoptera musculus) taken by Japanese whalers. Although most individuals had fewer than 20 lamina, a few specimens had more than 100 annual growth layers. From these data, the oldest blue and fin whales were documented to be at least 110 and 114 years, respectively. At the time, these were the oldest documented nonhuman mammals. Corroborating these ages is more recent evidence of great longevity in bowhead whales (Balaena mysticetus). Archaeological artifacts recovered from the blubber of bowheads taken in the modern Indigenous subsistence hunt include several stone or metal and ivory harpoon points last used in the 1880s. In 2007, a whale was taken in the traditional hunt and found to have an explosive Yankee Whaler harpoon tip embedded in its blubber last manufactured in 1885. These artifacts suggested that bowhead whales lived at least 130 years.

After the recovery of these artifacts, researchers used aspartic acid racemization (AAR) of the eye lens and then a new aging method to estimate the ages of whales taken in the subsistence hunt. In one instance, an individual's AAR-estimated age of 133 years corresponded closely to the 120-year-old whaling artifact recovered from its blubber, validating extraordinary AAR-estimated ages. AAR estimated ages of several individuals exceeded 150 years, and one individual, otherwise healthy, was estimated to be 211 years old. This was older than the documented ages of fin and blue whales by a century and would have likely been considered a laboratory error in the absence of the corroborating archaeological evidence.

From the standpoint of physiological scaling, these superannuated ages should not be unexpected. Whales are the largest living animals, and body size is highly correlated with longevity. There are three confounding issues in current whale age estimation, and all likely result in considerable downward bias on expected life span at the species level. First, although most toothed whales and some baleen whales have tissues with countable annular growth layers, many do not or, if they do, the archives are incomplete or difficult to count in very old individuals because of tissue remodeling, tooth wear, and/or thinning of the oldest annual layers. Second, it is unclear whether we could detect superannuated individuals in most whale populations today. Industrial whaling, which for most species ended only 60 years ago, would have required any individuals now aged over 100 years to have survived at least 40 years of intense whaling, and any individual over 150 would have had to survive 90 years of that same intense hunt. Last and closely related to the previous point, most methods of aging whales require lethal sampling.

Most whale populations have recovered or are recovering from industrial whaling, and although the populations are healthy, they have been growing for the past 60 years and are thus composed almost exclusively of individuals born after 1965. To detect very old individuals today using laminated tissues, AAR, or new molecular clock aging methods would still require extremely large sample sizes before detecting a single superannuated individual. Consequently, we believe that it is reasonable to hypothesize that now estimated baleen whale life spans are biased low.

Link: https://doi.org/10.1126/sciadv.adq3086

Microglia are innate immune cells resident in the brain, analogous in function and behavior to macrophages found elsewhere in the body. They are responsible for clearing debris, aiding in regeneration, destroying pathogens and problem cells, and additionally appear to be involved in maintaining and changing the networks of connections between neurons. An aging brain is characterized by increasing numbers of inflammatory, reactive microglia, representative of the shift to constant inflammatory signaling that takes place throughout the body with advancing age. It is a maladaptive reaction to growing levels of molecular damage, from protein aggregates to mislocalized mitochondrial DNA to the signaling of senescent cells.

Inflammatory microglia are implicated in the development and progression of neurodegenerative conditions. Clearance of microglia, allowing a fresh population to emerge from progenitor cells, appears to improve matters in animal studies of neurodegenerative conditions. Beyond pointing to inflammatory signaling, what exactly are problem microglia doing to provoke neurodegeneration, however? In today's research materials, scientists report the identification of one subset of harmful microglia that are characterized by an active integrated stress response (ISR), leading to secretion of toxic lipids that harm surrounding neurons. In this context, it is worth noting that past animal studies of therapies targeting the ISR have produced interesting results in the context of neurodegeneration.

New Research Identifies Key Cellular Mechanism Driving Alzheimer's Disease

Microglia, often dubbed the brain's first responders, are now recognized as a significant causal cell type in Alzheimer's pathology. However, these cells play a double-edged role: some protect brain health, while others worsen neurodegeneration. Understanding the functional differences between these microglial populations has been a research focus. Researchers have now discovered that activation of a stress pathway known as the integrated stress response (ISR) prompts microglia to produce and release toxic lipids. These lipids damage neurons and oligodendrocyte progenitor cells - two cell types essential for brain function and most impacted in Alzheimer's disease. Blocking this stress response or the lipid synthesis pathway reversed symptoms of Alzheimer's disease in preclinical models.

A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion

The brain's primary immune cells, microglia, are a leading causal cell type in Alzheimer's disease (AD). Yet, the mechanisms by which microglia can drive neurodegeneration remain unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a microglia subset with neurodegenerative outcomes. Autonomous activation of ISR in microglia is sufficient to induce early features of the ultrastructurally distinct "dark microglia" linked to pathological synapse loss. In AD models, microglial ISR activation exacerbates neurodegenerative pathologies and synapse loss while its inhibition ameliorates them. Mechanistically, we present evidence that ISR activation promotes the secretion of toxic lipids by microglia, impairing neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR or lipid synthesis mitigates synapse loss in AD models. Our results demonstrate that microglial ISR activation represents a neurodegenerative phenotype, which may be sustained, at least in part, by the secretion of toxic lipids.

The clinical community practicing first generation stem cell therapies is slowly shifting away from cell transplants towards harvesting extracellular vesicles from cell in culture and transplanting the vesicles instead. In most cases near all transplanted stem cells die, and that the majority of the effects of such therapies in age-related disease - largely reliable suppression of chronic inflammation rather than improved regeneration of tissues - are mediated by the signaling produced by those cells in the short time that they survive in the recipient. Much of cell signaling is carried within vesicles, and to date the evidence suggests that vesicle therapies produce similar results to stem cell therapies, while being an easier proposition from the logistics perspective.

Age is the most important risk factor for degenerative diseases such as osteoarthritis (OA). It is associated with the accumulation of senescent cells in joint tissues that contribute to the pathogenesis of OA, in particular through the release of senescence-associated secretory phenotype (SASP) factors. Mesenchymal stromal cells (MSCs) and their derived extracellular vesicles (EVs) are promising treatments for OA. However, the senoprotective effects of MSC-derived EVs in OA have been poorly investigated.

Here, we used EVs from human adipose tissue-derived MSCs (ASC-EVs) in two models of inflammaging (IL1β)- and DNA damage (etoposide)-induced senescence in OA chondrocytes. We showed that the addition of ASC-EVs was effective in reducing senescence parameters, including the number of SA-β-Gal-positive cells, the accumulation of γH2AX foci in nuclei and the secretion of SASP factors. In addition, ASC-EVs demonstrated therapeutic efficacy when injected into a murine model of OA. Several markers of senescence, inflammation, and oxidative stress were decreased shortly after injection likely explaining the therapeutic efficacy. In conclusion, ASC-EVs exert a senoprotective function both in vitro, in two models of induced senescence in OA chondrocytes and, in vivo, in the murine model of collagenase-induced OA.

Link: https://doi.org/10.18632/aging.206158

A cell is just a state machine; control its gene expression, control over the production of proteins, implies control of its behavior and activity. Given sufficient knowledge and ability to make specific changes in gene expression, there is no such thing as an irreversible cell state - except in the case that nuclear DNA damage has removed the ability to express correct proteins, one would think. So while reversing cellular senescence is one thing, it is interesting to find that at least some cancerous cell types can be reverted to essentially normal cells. Is this a safe and useful approach to cancer therapy, or will it just create a sizable population of cells that retain the mutational damage that will predispose them to becoming cancerous again?

Researchers have developed a groundbreaking technology that can treat colon cancer by converting cancer cells into a state resembling normal colon cells without killing them, thus avoiding side effects. The research team focused on the observation that during the oncogenesis process, normal cells regress along their differentiation trajectory. Building on this insight, they developed a technology to create a digital twin of the gene network associated with the differentiation trajectory of normal cells.

Through simulation analysis, the team systematically identified master molecular switches that induce normal cell differentiation. Three genes, HDAC2, FOXA2, and MYB, were discovered as key control factors that induce differentiation of normal colon cells. When these three genes were knocked down the cancer cells reverted to a normal-like state, a result confirmed through molecular and cellular experiments as well as animal studies. This research demonstrates that cancer cell reversion can be systematically achieved by analyzing and utilizing the digital twin of the cancer cell gene network, rather than relying on serendipitous discoveries. The findings hold significant promise for developing reversible cancer therapies that can be applied to various types of cancer.

Link: https://news.kaist.ac.kr/newsen/html/news/?mode=V&mng_no=42710