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23 April 2026 - 10:16 AM
Metabolic Acidosis May Be an Important Contributing Cause of Age-Related Frailty 22 April 2026 - 06:06 PM
Aging is a collection of many varied forms of cell and tissue damage and forms of dysfunction in biological systems that all interact with one another as they progress. A cause can contribute to a consequence that in turn accelerates the cause. Except that in any narrow view there are likely another fifteen contributing causes and various consequences muddying the waters, making it challenging to assign relative importance to any one change or mechanism or interaction. Aging is a big ball of yarn, and there are only so many researchers and so much time. For any given mechanism or interaction, our understanding remains incomplete. Research into aging tends to focus on where the lamp presently shines, on the more well understood and well researched areas of cellular biochemistry and systemic dysfunction, but there is still a great deal that goes on elsewhere.
Today's open access paper is focused on a topic that doesn't come up all that often in the context of research into causes of aging. The authors are interested in the links between age-related changes in metabolism and the onset of frailty, a condition characterized by chronic inflammation, loss of muscle mass and strength, and loss of immune resilience. In the eyes of these researchers, evidence from clinical practice suggests that more attention should be given to metabolic acidosis in older people. This is a failure of metabolism to buffer against acidification of tissue environments. The chain of cause and consequence leading this outcome in aging is far from fully explored, as is the case for near all aspects of aging, but one can trace lines that lead from excessive acidosis to the various contributions to frailty.
Acid-Base Dysregulation Links Aging Metabolism to Frailty
For homeothermic humans, energetic efficiency is built on an optimal internal temperature and optimal pH, both of which are critical for maximizing enzymatic activity. Enzyme function underlies most biochemical reactions, including mitochondrial ATP production, the maintenance of membrane stability, membrane potential, and physiological performance. Overall, pH homeostasis at the intracellular and extracellular levels is preserved through complementary buffer systems and by regulation of cellular metabolism and activity, which are subject to both endocrine and behavioral control. Buffer systems such as the bicarbonate system provide the first line of defense against rapid pH fluctuations. Lungs respond within minutes by changes in ventilation, while the kidneys provide long-term regulation through excreting protons (H+) and generating new bicarbonate.
Accumulating epidemiologic evidence indicates that even "mild" deviations in serum bicarbonates have clinically meaningful implications for aging people. Observational studies have linked serum bicarbonate below 25 mEq/L - a threshold often considered clinically normal - to impaired physical performance, including slower gait speed, reduced muscle strength, and altered gait mechanics. Longitudinal data for initially well-functioning older adults (ages 70-79) further established low serum bicarbonate as an independent predictor of incident, persistent lower-extremity functional limitation. Notably, low bicarbonate level remains a significant risk factor for mortality even in individuals with preserved glomerular filtration rate (GFR > 60 mL/min/1.73 m2). The associations persist even with bicarbonate levels in the low-normal clinical range.
While lower bicarbonate levels are correlated with declining GFR, they also occur frequently in older adults with preserved renal function. In these cases, low bicarbonate plausibly reflects a mild or subclinical metabolic acidosis. The mechanistic association between acidosis and physical decline is thought to involve derangements in skeletal muscle metabolism that promote sarcopenia - the progressive loss of skeletal muscle mass, quality, and strength. These acidosis-induced derangements include catabolic signaling, insulin resistance, increased inflammatory cytokines, mitochondrial dysfunction, and oxidative stress, features that are also reported in the aging-related frailty phenotype. In comparison to aging, this catabolic process occurs more rapidly in chronic kidney disease (CKD) because of not only the greater severity of acidosis but also the accumulation of uremic toxins. Based on in vitro evidence, these toxins inhibit myogenic differentiation and damage mitochondria, further accelerating sarcopenia in CKD.
On this basis, it was proposed that acidosis-induced metabolic derangement in skeletal muscle also represents a key driver in aging-related frailty. However, it is critical to distinguish established mechanism from clinical hypothesis: while the cellular pathways are well-characterized in animal and CKD models, we lack longitudinal human data. Without tracking pH against frailty onset, it remains unclear if acidosis is a driver of frailty, a marker of its presence, or a consequence of muscle wasting (via loss of intracellular buffers).
View the full article at FightAging
The Immune System Ages Differently in Men and Women 22 April 2026 - 04:07 PM
An investigation into the aging immune system identified age-related changes, including sex-dependent differences, in immune cell subpopulations and gene expression. In general, females showed greater age-related changes than males, including greater changes in autoimmune gene expression [1].
Cell-by-cell analysis
Aging results in changes to the function and composition of immune cells, collectively referred to as immunosenescence. This decline in immune function manifests as increased susceptibility to infections, cancer, autoimmune diseases, and vascular diseases [2] as well as a persistent low-level inflammatory state known as inflammaging.
Many of these changes are sex-specific; unfortunately, sex-specific aspects of biology are often understudied. As Marta Melé, leader of the Transcriptomics and Functional Genomics group at Barcelona Supercomputing Center (BSC) and director of the study, said, “Many studies still do not take sex into account in their analyses, or directly only use data from men, so they leave key questions unanswered. Our research was born precisely from this need and combines a scientific outlook with a sex perspective, inclusive data, and great computational power.”
The authors of the study focused specifically on aging-related sex-specific changes in immune cell subpopulations. To address that, they analyzed gene expression levels in single cells, rather than the typical bulk analysis, in over 1 million peripheral blood mononuclear cells (PBMCs) from 416 male and 566 female donors aged 19 to 97 years.
“Until now, most studies analyzed the immune system based on the average of many cells at once, which makes it difficult to capture the progressive effects of aging. With cell-by-cell analysis and a much larger sample, we were able to detect (…) patterns and compare them robustly between biological sexes,” explained Maria Sopena-Rios, researcher at BSC and first co-author of the study.
Sex-dependent immune aging
Initial analysis of the immune cells identified populations that showed similar age-dependent changes in both sexes, but the researchers also observed sex-specific differences. Further analysis indicated that women exhibited more pronounced aging-related changes in immune cells, suggesting greater immune system remodeling, including both increases and decreases in various cell populations. Since the changes appear in immune cell subpopulations with different functions, this suggests differences in how male and female immune systems function as they age.
The researchers identified three sex-specific, age-enriched groups: CD8+ TEM and CD14+ monocytes in females, and naive B cells in males. CD8+ TEM was enriched for cytotoxic markers, cell-killing, and natural killer activation signatures. Those activities are important for destroying pathogen-infected and tumorous cells [3]. CD14+ monocytes showed an increase in inflammatory markers, potentially contributing to inflammaging, but they are also involved in viral defense.
The observation that naive B cells are enriched with age in men, specifically the accumulation of their subset CD5+ B cells (more pronounced in some donors), has clinical importance since it has been previously reported that “these expansions may represent the early stages of monoclonal B cell lymphocytosis, a precursor to chronic lymphocytic leukemia, which is more prevalent in older males.” [4]
This analysis of cell types was accompanied by an analysis of gene expression, which indicated that 25% of age-associated changes were shared between sexes but a significant number were sex-specific. Women had more such unique age-associated differentially expressed genes across most cell types (2,306 in women and 1,122 in men), suggesting that women have stronger gene expression responses to this type of aging. Analysis of the various pathways in which those genes were involved indicated that around half were shared between the sexes, and the remainder were female-specific.
Grouping individuals into early (<50 years old), mid (40-60 years old), and late (≥50 years old) age groups revealed that most of the gene expression changes occurred in the late group, especially “around age 70 in female participants and slightly later in male participants.”
Differences in disease susceptibility
Immunosenescence does not affect both sexes in the same way. While the previous results suggest that males are more susceptible to leukemia, females face different immune system-related problems.
Women generally have stronger immune responses, resulting in greater resistance to infections [5,6]. However, they pay a high price for this effectiveness: a significantly increased prevalence of autoimmune diseases compared to men [7]. Multiple pieces of evidence from this study, including age-related changes in cell subpopulations and gene expression, support the previous findings and help explain some of the observations at the molecular level.
An analysis of age-related differentially expressed genes showed enrichment for autoimmune-related functions in an immune cell subtype associated with autoimmune disease pathogenesis. Further investigation showed that autoimmune-related gene expression increases significantly with age in both men and women; however, in women older than 50, these genes show significantly higher levels than in men. All of these observations suggest a potential enhancement of autoimmune susceptibility in women. They also agree with previous observations that certain autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, and psoriasis, generally worsen with age [8-12].
Beyond the immune system
The authors of this study suggest that the identified changes can be used as biomarkers of immunosenescence and disease risk. However, the immune system is not an isolated system; it also affects other organs. As Aida Ripoll-Cladellas, researcher at BSC and first co-author of the study, puts it, “The immune system plays a fundamental role throughout the organism; therefore, the differences we observed have a very important generalized impact on the entire body. Better understanding the aging of the immune system can help us understand processes that go beyond the blood and affect multiple tissues.”
Literature
[1] Sopena-Rios, M., Ripoll-Cladellas, A., Omidi, F., Ballouz, S., Alquicira-Hernandez, J., Oelen, R., Hewitt, A. W., Franke, L., van der Wijst, M. G. P., Powell, J. E., & Melé, M. (2026). Single-cell analysis of the human immune system reveals sex-specific dynamics of immunosenescence. Nature aging, 10.1038/s43587-026-01099-x. Advance online publication.
[2] Aw, D., Silva, A. B., & Palmer, D. B. (2007). Immunosenescence: emerging challenges for an ageing population. Immunology, 120(4), 435–446.
[3] Vojdani, A., Koksoy, S., Vojdani, E., Engelman, M., Benzvi, C., & Lerner, A. (2024). Natural Killer Cells and Cytotoxic T Cells: Complementary Partners against Microorganisms and Cancer. Microorganisms, 12(1), 230.
[4] Molica S. (2006). Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leukemia & lymphoma, 47(8), 1477–1480.
[5] Furman, D., Hejblum, B. P., Simon, N., Jojic, V., Dekker, C. L., Thiébaut, R., Tibshirani, R. J., & Davis, M. M. (2014). Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proceedings of the National Academy of Sciences of the United States of America, 111(2), 869–874.
[6] Fischinger, S., Boudreau, C. M., Butler, A. L., Streeck, H., & Alter, G. (2019). Sex differences in vaccine-induced humoral immunity. Seminars in immunopathology, 41(2), 239–249.
[7] Jacobson, D. L., Gange, S. J., Rose, N. R., & Graham, N. M. (1997). Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clinical immunology and immunopathology, 84(3), 223–243.
[8] Park, E., & Ciofani, M. (2025). Th17 cell pathogenicity in autoimmune disease. Experimental & molecular medicine, 57(9), 1913–1927.
[9] Baecher-Allan, C., Kaskow, B. J., & Weiner, H. L. (2018). Multiple Sclerosis: Mechanisms and Immunotherapy. Neuron, 97(4), 742–768.
[10] Kebir, H., Ifergan, I., Alvarez, J. I., Bernard, M., Poirier, J., Arbour, N., Duquette, P., & Prat, A. (2009). Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Annals of neurology, 66(3), 390–402.
[11] Chen, L., Wu, B., Mo, L., Chen, H., Zhao, Y., Tan, T., Chen, L., Li, Y., Yao, P., & Tang, Y. (2024). Associations between biological ageing and the risk of, genetic susceptibility to, and life expectancy associated with rheumatoid arthritis: a secondary analysis of two observational studies. The lancet. Healthy longevity, 5(1), e45–e55.
[12] Puche-Larrubia, M. Á., Ladehesa-Pineda, L., López-Montilla, M. D., Barbarroja, N., Escudero-Contreras, A., Vazquez-Mellado, J., Collantes-Estévez, E., & López-Medina, C. (2023). Differences between early vs. late-onset of psoriatic arthritis: Data from the RESPONDIA and REGISPONSER registries. Joint bone spine, 90(4), 105563.
View the article at lifespan.io
Age-Related Degeneration of the Pineal Gland 22 April 2026 - 10:22 AM
Some decades ago, the pineal gland was overly mythologized by those interested in intervening in the aging processes, a lot of pseudoscience verging into mysticism. Nonetheless, the pineal gland is important component of the endocrine system, and its functions decline with age. Like the thymus and lymph nodes, the pineal gland becomes structurally disrupted with advancing age, and that is the primary focus of the paper noted here. The researchers seek to categorize this disruption and its relationship with the astrocyte population resident in the pineal gland.
The pineal gland (PG) is an endocrine organ in the brain, primarily composed of pinealocytes (about 95% of the cells); the rest are mainly astrocytes and microglia embedded in a network of blood vessels and nerve fibers. Pinealocytes produce melatonin, which plays an important role in the human body. Numerous studies state changes in the human PG as a result of aging and some neurodegenerative and mental pathologies. A relatively understudied issue is the alteration of the lobular structural organization of the human PG and its potential impact on glandular function.
By analyzing the lobular structure and astrocytic network of the human PG, we have identified two apparently distinct pathways of normal aging. In the first one, an increase in the number of astrocytes within the pineal parenchyma is observed, suggesting a partial compensatory role for astrocytes in maintaining pinealocyte function. In the second pathway, disruption of the lobular architecture appears to result in astrocytic atrophy and a decline in the functional integrity of all pineal components. These observations may explain our findings that the combination of a disrupted lobular structure and a light astrocytic network is the most common pattern, whereas the dense astrocytic network variant is found exclusively in structurally intact lobules of older individuals. Notably, the lobular organization of the pineal gland itself is highly variable and, apart from a slight tendency towards structural disruption with age, does not show a strong age-related pattern.Another indicator of pineal degeneration is the presence of glial cysts, which are commonly observed in the pineal gland across the examined age range. Although typically asymptomatic, these cysts can significantly reduce the volume of the functional parenchyma. Notably, they are most commonly associated with the above-mentioned combination of a disrupted lobular structure and a light astrocytic network. Based on our findings, we propose that pathological conditions may contribute to structural degeneration of the pineal gland and a subsequent decline in melatonin production; however, normal aging appears to be the primary driver of this process.
Link: https://doi.org/10.3390/ijms27073093
View the full article at FightAging
Connecting Gompertz Law Parameters with Specific Outcomes in the Treatment of Aging 22 April 2026 - 10:06 AM
The Gompertz law is a relatively simple equation that describes the exponentially increasing mortality rates observed in an aging population. One fits the equation to existing epidemiological data by adjusting the value of two parameters, α and β. Researchers here use the results of age-slowing interventions in large populations of nematode worms to assign physical, biological meanings to the changes in α and β produced by the treatment of aging. As the researchers describe here, β is related to length of time spent in poor health in later life, while α is related to length of time spent in good health in earlier life.
In populations of many animal species, including humans, mortality rates increase exponentially with advancing age. The scale and rate of increase can be set by two parameters, α and β, respectively, of the Gompertz equation. Interventions that extend lifespan can reduce either or both parameters. A long-standing supposition resulting from use of the equation in human epidemiology is that β corresponds to biological ageing rate, and α to ageing-independent causes of mortality.
Here, we investigate the biological basis of α and β using the nematode Caenorhabditis elegans, through the combined study in populations and individuals of effects of life-extending interventions on mortality and age-changes in health. We demonstrate that reductions in β arise not from slowed biological ageing, but rather from expansion of decrepitude (gerospan) in longer-lived population members. In contrast, reductions in α better reflect healthspan expansion, an indicator of slowed biological ageing. Thus, our investigation presents a new, empirical understanding of the Gompertz parameters that inverts their traditional interpretations.
Link: https://doi.org/10.1038/s41467-026-71780-7
View the full article at FightAging
