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21 April 2026 - 12:42 PM
The Gut Microbe in INDY Related Longevity in Flies 21 April 2026 - 10:22 AM
The aging and longevity of flies is very dependent on intestinal function. The noted longevity-associated gene INDY acts on intestinal function, for example. Here, researchers report on their investigation of the role of the gut microbiome in INDY-related longevity in flies. As might be expected given the present state of knowledge of the role of the gut microbe in long-term health and aging, there are signs of a contribution. These results are only a first step, however; the gut microbiome is a complex array of different microbial species, and there is a great deal more that might be catalogued in terms of its relationship to genetic associations with longevity in this species.
Reduction in the Indy (I'm not dead yet) gene, a plasma membrane citrate transporter, in Drosophila and its homolog in worms extends lifespan by promoting metabolic homeostasis. Indy reduction delays the onset of aging-associated pathology in the fly midgut, including preservation of intestinal barrier integrity and intestinal stem cell homeostasis. Gut microbiota has broad impacts on host metabolism, health, and aging. Age-related dysbiosis impairs intestinal barrier function and drives mortality. However, the underlying mechanisms that link increased microbial load to frailty and negative effects on health remain mostly unclear.
Here we show that Indy heterozygote flies have significantly lower bacterial load and increased diversity during aging compared to controls. However, the presence of the microbiome was not required for Indy lifespan extension, though removal of microbes did enhance the effects of Indy reduction on longevity, suggesting potential interactions between the microbiome and Indy. Indy down-regulation was linked to reduced expression of the JAK/STAT signaling ligands Upd3 and Upd2 in the midgut of young flies, which likely contributes to preserved intestinal stem cell homeostasis. Altogether, our results suggest that Indy reduction impacts microbiome load and composition, which preserves gut homeostasis and extends lifespan through impacts on JAK/STAT signaling pathway.
Link: https://doi.org/10.64898/2026.03.25.714291
View the full article at FightAging
PEPITEM as a Potential Therapy for Autoimmune Arthritis 21 April 2026 - 10:05 AM
PEPITEM is a circulating peptide involved in resolution of inflammation and reduction of chronic inflammation. Levels of PEPITEM decline with age, which is one of the reasons why inflammatory athritis becomes worse with age, in that this inhibitory mechanism declines in effectiveness. Studies in animal models have shown that injection of synthetic PEPITEM can improve symptoms; an example of this sort of work is noted here.
Inflammatory arthritis is a group of diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), where the immune system attacks the joints, causing severe joint damage, pain, and disability. Under normal conditions, adiponectin in the bloodstream stimulates white blood cells to produce PEPITEM, which in turn reduces white blood cell migration in the tissues, preventing an unregulated inflammatory response. However, in inflammatory arthritis, white blood cells fail to respond to adiponectin, and secrete less PEPITEM in the joint. The natural 'break' that prevents white cell migration into the joint cavity is lost, and the inflammatory response becomes unregulated.
The initial study of peripheral blood mononuclear cells (PBMCs, white blood cells) harvested from treatment-naïve human donors with suspected inflammatory arthritis showed a reduced capacity to respond to adiponectin, which could be restored by the addition of PEPITEM. Further examination of whole blood indicated a lower bioavailability of PEPITEM in patients with early RA, leading the researchers to hypothesise that supplementation with PEPITEM could restore immune regulation and reduce the inflammatory changes seen in early-stage disease.
Their work in mouse models of inflammatory arthritis and gouty arthritis showed that injection of synthetic PEPITEM could prevent the onset of inflammatory arthritis, with significant reductions in disease incidence. In addition, joint swelling was reduced by PEPITEM when compared with infliximab - the current standard of care. Tissue studies confirmed that these changes were mirrored in synovial tissue (tissue inside the joints), with significantly less joint inflammation, cartilage damage, and bone erosion observed in PEPITEM treated mice, and significantly fewer white blood cells infiltrating the joints. Molecular studies showed significant down regulation of inflammatory mediators (NF-kB and COX2 protein) within the synovial tissue in PEPITEM-treated mice compared to controls, and a significant increase in the foxp3 transcript, which is crucial for the development of a type of white blood cell that suppresses the immune response, to prevent excessive inflammation and autoimmune disease.
View the full article at FightAging
Considering How to Define Animal Models of Intrinsic Capacity in Aging 20 April 2026 - 06:04 PM
The World Health Organization (WHO) launched intrinsic capacity into the space of ideas relating to the study of aging a decade ago; it is defined as "the composite of all the physical and mental capacities that an individual can draw on." At a more detailed level, intrinsic capacity is envisaged as the sum of motor capacity, sensory capacity, general vitality, psychological wellness, and cognition capacity. What the WHO authors did not specify is how to measure any of this, specifically and in detail.
Putting a fuzzy definition in front of the scientific community is like dangling catnip in front of a bunch of cats, and so now there exist a fair number of proposed approaches for measuring intrinsic capacity that are accompanied by published epidemiological data, but there is little to no consensus as to which of these approaches is the one to move ahead with, and no great ability to compare the data produced via one scientist's intrinsic capacity to data produced via another scientist's intrinsic capacity.
This hasn't stopped a continued flow of new publications in which researchers compare someone's definition of intrinsic capacity to other health data, such as epigenetic age. This may all settle into a consensus at some point, but postponing anything to await that outcome seems unwise. Free-form debates of this nature can last decades. Today's open access paper is another that seeks to build upon the concept of intrinsic capacity and efforts to define it precisely, this time in the direction of animal models of aging. Given that no-one can agree on how intrinsic capacity should be measured in human patients, why not expand that discussion to the animal models that inform the development of new therapies with the potential to slow or reverse aspects of aging?
Could animal models be used to longitudinally track intrinsic capacity during aging?
The World Health Organization (WHO) recently highlighted the importance of promoting healthy aging worldwide, a process characterized by the maximization of functional ability, enabling well-being in older adulthood. This concept inspired the development of the Integrated Care for Older People (ICOPE) program and the Intrinsic Capacity (IC) construct, with the latter serving as core element of ICOPE for clinical use. IC represents the composite of all mental and physical internal attributes of an individual. It is often operationalized through five key domains: cognition, locomotion, vitality, sensory function, and psychological capacity.
Research on IC during aging in humans is growing, being marked by high IC variability. Longitudinal monitoring must be prioritized to capture aging trajectories and identify modifiable risk factors. However, the need for a long-time window spanning decades of human life poses a significant challenge to investigating IC decline over time. In contrast, animal models offer a strategic alternative due to their shorter lifespans compared to humans. For example, the typical lifespan of a mouse is 2-3 years, whereas specific fish models (e.g., killifish) may live only 4-6 months. Thus, leveraging these models for longitudinal IC tracking offers a viable pathway that may expedite the elucidation of IC dynamics and mechanisms during aging.
Preserved functional ability can be objectively assessed through behavioral paradigms in animal studies. By using these measurements in observational or experimental settings, animal models can recapitulate the longitudinal trajectories of IC during aging. To facilitate crosstalk with humans and accurately capture age-related changes in IC, assessment tools should meet specific criteria: they should target the corresponding IC domains in humans, show a decline over time with aging, and exhibit sufficient amplitude to distinguish meaningful functional loss. Here, we discuss how longitudinal IC investigations in mice and fish may advance human research and care during aging. Particular attention will be given to assessing, in experimental models, all IC domains longitudinally, interactions across IC domains, and the definition of a set of potentially informative IC assessments in both mice and fish.
View the full article at FightAging
How Inflammaging Is Linked to Epigenetic Aging 20 April 2026 - 04:14 PM
A paper in Cell Genomics has described how age-related systemic inflammation (inflammaging) is related to epigenetic aging as measured by four established clocks.
Tying together two well-known aspects of aging
These researchers note that inflammatory problems have been repeatedly linked to aging, both in inflammaging and in the immune system’s failure to properly respond to threats (immunosenescence). Very often in older people, chronic inflammation is linked to internal factors that have no link to pathology; however, these researchers cite one study that noted the downstream benefits of eliminating hepatitis C, finding that it had beneficial effects on epigenetic aging [1].
The authors of this study decided to investigate this relationship further, looking into the relationship between inflammaging and epigenetic aging as measured by four established clocks: Horvath and Hannum, which are based on chronological age; PhenoAge, a clock that is more closely tied to healthspan; and GrimAge, another healthspan-based clock that is a strong predictor of all-cause mortality. The researchers also included the versions of these clocks that measure the rate of increase (epigenetic aging acceleration, EAA).
A morbid link
For their first analysis, the researchers used data from the BCG-PRIME cohort, whose participants had at least one comorbidity known to worsen length or quality of life. Frailty was one of these comorbidities, and unsurprisingly, frailty was linked to every clock except the EAA_Hannum and EAA_Horvath clocks. Frailty appeared to be even more strongly linked to GrimAge than to chronological age.
Similar results were found in a multimorbidity analysis. Unsurprisingly, the number of various morbidities was strongly linked to GrimAge, although there were significant results among the other clocks. These results were maintained even after adjusting for smoking, which is known to cause both epigenetic damage and COPD, one of the morbidities that was also strongly linked to GrimAge.
The researchers then went to the heart of their study. They performed an analysis that compared these four clocks and their EAA versions to 64 inflammatory biomarkers that were considered to be measurable enough by a quality control analysis. While the EAA versions of Hannum and Horvath failed to have any significant connections, both of their regular versions showed associations with many of these proteins.
GrimAge and PhenoAge had stronger connections. Many CCLs, members of an inflammatory cytokine family of proteins, were associated with these clocks and their EAA variants. Hepatocyte growth factor (HGF) was another hit, as was another well-known inflammatory factor, tumor necrosis factor (TNF), which was more strongly associated with these clocks than with chronological age.
CXCL9 causes faster epigenetic aging
The strongest relationship was between GrimAge and CXCL9, a chemokine with well-established links to inflammation, and a link to age acceleration was found as well. Using a Mendelian randomization analysis, this link was found to be causal: people with more circulating CXCL9 were found to be epigenetically older, and epigenetically aging more quickly, than people with less. This causal link was also established for PhenoAge. Even after multiple statistical correction methods, this association persisted, and both TNF and CXCL10 were found to be casually associated with faster aging according to EAA_GrimAge.
Similarly, these inflammatory factors were found to be linked with multimorbidity, leading the authors to conclude that inflammaging indeed is a driver of age-related diseases.
The researchers then broke their results down by sex. Men and women had very few differences, none of which reached statistical significance. The effects of CXCL9, in particular, appeared to be completely unaffected by sex.
Their next experiment involved testing cells derived from the 500FG and BCG-PRIME cohorts against well-known pathogens. Unsurprisingly, cells that were epigenetically older according to the various clocks did not perform as well against these attacks; despite having more overall inflammation, they failed to properly respond to genuine threats with IFN-γ and IL-22.
This study was only an association study that investigated causal links through statistical methods. While the researchers noted that the strongest hits were related to the interferon pathway (IFN) and that this pathway has been previously linked to stem cell aging [2], this research did not involve any investigation into the mechanisms of action. Future work will need to determine why CXCL9 and related proteins increase with age and if anything can be done to halt this increase.
Literature
[1] Oltmanns, C., Liu, Z., Mischke, J., Tauwaldt, J., Mekonnen, Y. A., Urbanek-Quaing, M., … & Cornberg, M. (2023). Reverse inflammaging: long-term effects of HCV cure on biological age. Journal of hepatology, 78(1), 90-98.
[2] Demerdash, Y., Kain, B., Essers, M. A., & King, K. Y. (2021). Yin and Yang: The dual effects of interferons on hematopoiesis. Experimental hematology, 96, 1-12.
View the article at lifespan.io
