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21 April 2026 - 12:38 AM
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
ATF5 as a Point of Tradeoff in Muscle Mass versus Muscle Quality 20 April 2026 - 10:22 AM
In the search for ways to slow the age-related loss of muscle mass that afflicts every older person, researchers here find that ATF5 is a point of control that regulates a trade-off between muscle mass and muscle quality. Mice lacking functional ATF5 retain muscle mass with age, but muscle quality declines to a greater degree instead. This rules it out as a target for therapy. It is always possible that further investigation of the interactions surrounding ATF5 will lead to insight into how to decouple mass versus quality, but that sort of investigation of biochemical pathways tends to take a very long time.
In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging.
To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body knockout (KO) and wild-type (WT) male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial reactive oxygen species production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of mitochondrial protease LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance.
Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.
Link: https://doi.org/10.18632/aging.206365
View the full article at FightAging
Mitrix Bio as an Example of the Trend Towards Alternative Paths to Initial Human Data 20 April 2026 - 10:18 AM
Enormous costs are imposed by regulators in the US and Europe on the process of manufacturing a candidate drug to Good Manufacturing Practice (GMP) standards and then running a first clinical trial. Combine this with three years of a bad market for biotech, in which investors have pulled back from investing in preclinical companies, and one sees a much greater pressure than usual to expand alternative paths to obtaining initial human data in a responsible way. Right to Try initiatives within the US are underway, and ever more groups within the medical tourism industry are attempting to position themselves as service providers for an alternative to a first clinical trial in the US or Europe. Próspera in Honduras is the most visible of a fair number of entities. At the end of the day, much of the cost and requirements imposed by the FDA and other bodies are not necessary for responsible safety. When regulators make the task of conducting manufacture and a safety trial in humans cost $20M, but it can actually be accomplished responsibly for $5M, as is the case for many classes of therapy, something must change - and change is coming.
Mitrix Bio has reported preliminary Phase 1 safety results for what it describes as large infusions of transplanted mitochondria in humans, while simultaneously launching a small network of clinics offering the experimental intervention under Right to Try frameworks. Taken together, the announcements mark a transition from laboratory concept to early clinical deployment - albeit on a limited scale.
The initial safety work was conducted at a clinic in Dallas, Texas, involving two older participants who received escalating doses of transplanted mitochondria, with monitoring of blood chemistry and physical condition throughout. According to the company, no obvious adverse effects were observed during the study period. Alongside this, new Mitochondrial Transplant Institute clinics have opened in Newport Beach, Dallas and Palm Beach, where treatments will be offered on an individualized basis by physicians, targeting a wide range of chronic and degenerative conditions.
Mitrix's approach involves the use of bioreactors to grow mitochondria derived from an individual's own cells, with the aim of enabling larger-scale infusions. In the recent safety study, doses were increased incrementally, allowing investigators to assess tolerability before proceeding further. The absence of immediate adverse effects supports continued investigation, and though efficacy data has not yet been released, the company is aiming for full efficacy data by the end of this year.
Link: https://longevity.technology/news/mitrix-moves-mitochondria-into-the-clinic/
View the full article at FightAging
