LongeCityNews Last Updated: 19 January 2026 - 09:27 PM

The balance of microbial populations making up the gut microbiome changes for the worse with aging. Populations that provoke inflammation increase in size at the expense of populations that manufacture beneficial metabolites. We have some idea of the size of the resulting contribution to degenerative aging as a result of fecal microbiota transplantation studies, from young donor to old recipient, carried out in killifish and mice. Old recipients provided with a young gut microbiome composition exhibit improved health and extended life.

Sustained programs of exercise are known to improve the composition of the gut microbiome, reducing the magnitude of some of the changes known to occur with age. This may be the result of improved immune function, and thus a greater ability of the immune system to remove unwanted, inflammatory microbes. It is thought that some fraction of the well-known reduced risk of age-related disease and mortality resulting from exercise may be due to an improved gut microbiome. The question, as usual, is how large a fraction.

In today's open access paper, researchers report on a study of exercise conducted in aged mice with the aim of obtaining potentially illuminating data on the relationship between exercise, health, and gut microbiome composition. The most interesting result is not the health benefits, which are expected, but rather that exercise becomes progressively less effective in altering the gut microbiome as the animals become older.

Age-dependent effects of exercise on gut microbiota-mitochondria axis and cognitive function in aging mice

Aging is accompanied by progressive impairments in mitochondrial bioenergetics, apoptosis regulation, and gut microbiota homeostasis, all of which contribute to cognitive decline. In this study, we investigated whether the effects of treadmill exercise on the gut microbiota-mitochondrion-neuronal plasticity axis differed between young (15 months) and old (28 months) mice. Male C57BL/6 mice were randomly assigned to the following groups: early sedentary, early exercise, late sedentary, or late exercise groups and completed an 8-week treadmill training protocol.

Cognitive function was assessed using the passive avoidance test and the Morris water maze test. Hippocampal mitochondrial respiration, Ca2+ retention capacity, and Bax/Bcl-2 expression were quantified, and the gut microbiota composition was analyzed using 16S ribosomal RNA sequencing.

Mice that did not exercise in old age exhibited memory impairment, decreased mitochondrial oxidative respiration, reduced Ca2+ retention, increased Bax expression, decreased Bcl-2 levels, and decreased abundance of Lactobacillus, Bifidobacterium, and Akkermansia. Exercise significantly improved behavioral performance, mitochondrial function, and apoptosis balance, while also increasing beneficial gut microbiota.

Notably, these effects were significantly greater in late-aged compared to early-aged mice. These results demonstrate that the efficacy of exercise in modulating the microbiota-mitochondrion-brain axis varies with age. Early-aged appears to represent a more responsive biological period during which exercise is more effective in improving mitochondrial integrity, microbiota composition, and cognitive resilience. These results suggest that initiating exercise early in the aging process may maximize neuroprotective effects and delay age-related functional decline.

In Aging Cell, four Japanese researchers have recently described the aging of the hematopoietic system, which is responsible for the creation of blood.

A system that affects all the others

Aging and age-related diseases are often discussed in terms of hallmarks, such as senescence and genomic instability. However, the bodies of complex organisms, such as humans, have systems that are all affected differently by these hallmarks, and many of them have downstream consequences for the rest of the body.

These researchers note that hematopoietic aging appears to be driven by metabolic issues, epigenetic alterations, genomic instability, and inflammaging, although they contend that inflammaging may have more roots in environmental factors than intrinsic ones [1].

Being responsible for the creation of blood, this particular aging leads to severe consequences. One major aspect of this system’s aging is clonal hematopoiesis, which generates a steady population of mutant cells that have evolved more towards parasitism than fulfilling the body’s needs; this is directly linked to multiple age-related diseases, such as atherosclerosis [2], and as can be expected, aging of the blood system is linked to the aging of many other organs.

This review, therefore, aims to summarize the current state of knowledge about hematopoietic aging an what might be done about it.

Fundamental causes

DNA aging caused by oxidative stress has been found to be a key part of hematopoietic aging; fortunately, this appears to be potentially mitigated through antioxidants [3]. Mitochondrial dysfunction, another hallmark of aging, spurs this oxidative stress [4], and this is exacerbated by a reduction in the cellular maintenance process known as autophagy, which destroys defective mitochondria and other unwanted organelles [5].

This DNA damage is key to the beginnings of clonal hematopoiesis. Three epigenetic regulator genes, DNMT3A, TET2, and ASXL1, have been identified as conferring advantages to these mutants over more functional cells. Broader changes such as mosaic mutations can also occur, and in men, the Y chromosomes of these cells may be entirely absent with advanced age, making them more susceptible to age-related diseases [6].

The mutant cells are better adapted to survive in an inflammatory environment than regular cells are. They have less mitochondrial maintenance, but their mitochondria are more active, and they have abandoned function in favor of proliferation. While they are still technically stem cells, they behave somewhat more like cancer. Metformin has been reported to mitigate the advantages that these clones have, preventing them from excessively proliferating [7]. Other cells upregulate mitochondrial activity while still maintaining their function, and those cells have been suggested as being useful for therapies [8].

When the marrow promotes aging

Among the characteristics of aged bone marrow, the reviewers found that three stand out in particular: a reduction in the number of blood vessels [9], an increase in fat [10], and the depletion of osteoblasts [11], which are responsible for building bone. Not all bones suffer the same amount of this dysregulation; the femur ages rapidly, but the skull is less vulnerable, and its bone marrow remains robust throughout life [12].

Physical stresses have been reported to be a key part of these negative effects. As the extracellular matrix stiffens, the bone marrow stem cell niche is degraded [13]. Likewise, an increase in fat might be both a cause and consequence of altered hematopoiesis [14]. The contributions of inflammation in the microenvironment are unsurprising, with even short bursts of inflammation leading to long-lasting consequences [15]. This inflammation can come from multiple sources, including the gut flora [16]; while gut-related therapies have been found to work in mice [17], it is uncertain if they can work in people.

Potential therapies

Other than the potential interventions already discussed, the reviewers suggest other strategies for abating this problem. Cellular senescence is one obvious target, as senescent cells leak factors that promote systemic inflammation; however, while senolytics and senomorphics that target these cells have been found to have broad benefits, the researchers note that their effects in this particular context are unclear.

Youthful plasma transfusion appears to be effective in some contexts, such as for bone marrow stromal cells [18], although it may or may not directly affect hematopoietic decline. The reviewers suggest that therapies directly targeted at the hematopoietic niche, such as directly targeting clones, may be more effective. Future work will need to be done to determine the approaches that can halt or reverse clonal hematopoiesis and related problems.

Literature

[1] Franck, M., Tanner, K. T., Tennyson, R. L., Daunizeau, C., Ferrucci, L., Bandinelli, S., … & Cohen, A. A. (2025). Nonuniversality of inflammaging across human populations. Nature aging, 1-10.

[2] Jaiswal, S., Natarajan, P., Silver, A. J., Gibson, C. J., Bick, A. G., Shvartz, E., … & Ebert, B. L. (2017). Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New England Journal of Medicine, 377(2), 111-121.

[3] Yahata, T., Takanashi, T., Muguruma, Y., Ibrahim, A. A., Matsuzawa, H., Uno, T., … & Ando, K. (2011). Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood, The Journal of the American Society of Hematology, 118(11), 2941-2950.

[4] Bratic, A., & Larsson, N. G. (2013). The role of mitochondria in aging. The Journal of clinical investigation, 123(3), 951-957.

[5] Warr, M. R., Binnewies, M., Flach, J., Reynaud, D., Garg, T., Malhotra, R., … & Passegué, E. (2013). FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature, 494(7437), 323-327.

[6] Bruhn-Olszewska, B., Markljung, E., Rychlicka-Buniowska, E., Sarkisyan, D., Filipowicz, N., & Dumanski, J. P. (2025). The effects of loss of Y chromosome on male health. Nature Reviews Genetics, 26(5), 320-335.

[7] Hosseini, M., Voisin, V., Chegini, A., Varesi, A., Cathelin, S., Ayyathan, D. M., … & Chan, S. M. (2025). Metformin reduces the competitive advantage of Dnmt3a R878H HSPCs. Nature, 1-10.

[8] Totani, H., Matsumura, T., Yokomori, R., Umemoto, T., Takihara, Y., Yang, C., … & Suda, T. (2025). Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow. Nature Aging, 1-17.

[9] Stucker, S., Chen, J., Watt, F. E., & Kusumbe, A. P. (2020). Bone angiogenesis and vascular niche remodeling in stress, aging, and diseases. Frontiers in cell and developmental biology, 8, 602269.

[10] Ambrosi, T. H., Scialdone, A., Graja, A., Gohlke, S., Jank, A. M., Bocian, C., … & Schulz, T. J. (2017). Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell stem cell, 20(6), 771-784.

[11] Morrison, S. J., & Scadden, D. T. (2014). The bone marrow niche for haematopoietic stem cells. Nature, 505(7483), 327-334.

[12] Koh, B. I., Mohanakrishnan, V., Jeong, H. W., Park, H., Kruse, K., Choi, Y. J., … & Adams, R. H. (2024). Adult skull bone marrow is an expanding and resilient haematopoietic reservoir. Nature, 636(8041), 172-181.

[13] Zhang, X., Cao, D., Xu, L., Xu, Y., Gao, Z., Pan, Y., … & Yue, R. (2023). Harnessing matrix stiffness to engineer a bone marrow niche for hematopoietic stem cell rejuvenation. Cell stem cell, 30(4), 378-395.

[14] Tuljapurkar, S. R., McGuire, T. R., Brusnahan, S. K., Jackson, J. D., Garvin, K. L., Kessinger, M. A., … & Sharp, J. G. (2011). Changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging. Journal of anatomy, 219(5), 574-581.

[15] Bogeska, R., Mikecin, A. M., Kaschutnig, P., Fawaz, M., Büchler-Schäff, M., Le, D., … & Milsom, M. D. (2022). Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell stem cell, 29(8), 1273-1284.

[16] Agarwal, P., Sampson, A., Hueneman, K., Choi, K., Jakobsen, N. A., Uible, E., … & Starczynowski, D. T. (2025). Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1. Nature, 1-11.

[17] Zeng, X., Li, X., Li, X., Wei, C., Shi, C., Hu, K., … & Qian, P. (2023). Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation. Blood, 141(14), 1691-1707.

[18] Baht, G. S., Silkstone, D., Vi, L., Nadesan, P., Amani, Y., Whetstone, H., … & Alman, B. A. (2015). Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nature communications, 6(1), 7131.

The protein α-synuclein can misfold into a pathological form and then spread from cell to cell in the central nervous system. This occurs in everyone to some degree with age, but only some people experience a burden of α-synclein pathology large enough to lead to Parkinson's disease or other synucleinopathies. It is likely that everyone exhibits some loss of function due to α-synuclein, but as ever, it is hard to pin down exactly how much of each aspect of aging is due to any one specific mechanism. The only efficient way to obtain useful data is to fix that one specific problem and observe the outcome, which is what researchers did here in aged rats. A gene therapy produced intracellular antibodies that reduce α-synuclein levels, albeit perhaps not in the expected way, and the result is improved function in treated animals.

Abnormal accumulation of alpha-synuclein (αSyn) in axons and presynaptic terminals plays a critical role in αSyn-mediated dopaminergic neurodegeneration. A strong correlation between aging and elevated αSyn levels in the substantia nigra has been identified in both humans and non-human primates. This study aimed to investigate whether AAV-mediated NAC32 intrabody expression in the substantia nigra could ameliorate αSyn-associated dopaminergic dysfunction and improve age-related motor deficits in aged rats.

We first investigated the mechanism by which NAC32 reduces αSyn levels. Comparisons of αSyn burden, tyrosine hydroxylase (TH) expression, and locomotor activity were made between young and aged rats. In aged rats, we evaluated behavioral performance, dopaminergic markers, and synaptic markers following AAV1-NAC32 gene delivery into the substantia nigra. Our results showed that the NAC32-mediated αSyn reduction was not prevented by inhibition of proteasomal, lysosomal, or autophagic pathways and was associated with reduced αSyn mRNA levels.

Aged rats exhibited decreased locomotor activity, elevated αSyn levels, and reduced TH expression in the substantia nigra. NAC32 intrabody expression in the substantia nigra significantly reduced αSyn accumulation, restored TH expression, increased synaptic markers and striatal dopamine levels, and improved locomotor performance in aged rats. These effects occurred without detectable elevation of pro-inflammatory cytokine levels in bulk striatal tissue. Our findings suggest that AAV-mediated NAC32 intrabody expression in the substantia nigra may serve as a therapeutic strategy to mitigate αSyn-induced dopaminergic dysfunction and motor impairments associated with aging.

Link: https://doi.org/10.1038/s41598-025-34908-1

Researchers here review the evidence for chronic inflammation to contribute to the vascular dysfunction of hypertension, in which blood pressure increases to harmful levels. The particular focus is on the feedback loop in which inflammatory immune dysfunction contributes to dysfunction in the regulation of hematopoiesis, the manufacture of new immune cells by hematopoietic cells resident in bone marrow, which in turn causes greater inflammatory immune dysfunction. Sustained inflammatory signaling is harmful to tissue structure and function throughout the body, including the vasculature and systems that regulate blood pressure.

Hypertension is a highly prevalent chronic disease all around the world, and the pathogenic mechanism is complicated. The early and rapid decline of the function of human vascular system due to the aging of human body are characteristics of hypertension, which is accompanied by progressive pathological remodeling and arterial stiffening.

The pathogenetic action of oxidation and inflammation is the vital function in the process of endothelial dysfunction and arterial injury. Bone marrow is considered as the birthplace of the immune cell, and the role of bone marrow in hematopoiesis and immune response for the onset of hypertension has been confirmed. In turn, inflammatory and oxidative stress also affect the bone marrow and damage bone marrow function, causing a series of complications in hypertension, resulting in a vicious cycle. Recently, increasing evidence has suggested that bone marrow aging plays an important role in the onset and development of hypertension, and that the function of bone marrow in the pathogenesis of hypertension has been seriously overlooked. Bone marrow microvascular ageing is also involved in the progression of bone marrow ageing.

Thus, this review mainly focuses on bone marrow function in aging and hypertension progression, addresses the current studies on the roles of vascular aging, the bone marrow and the immune system in hypertension, and discusses their interaction and function in the pathogenesis of hypertension. Furthermore, some novel molecular pathological mechanisms are surveyed. This can add a new impetus to the mechanism research of hypertension onset.

Link: https://doi.org/10.1038/s41420-025-02851-9