Fight Aging!

A few species such as salamanders and zebrafish can regenerate lost limbs and even large sections of internal organs, provided they survive the injury. In comparison, mammals exhibit far less of a capacity for such proficient regeneration as adults, but the actual limits of regeneration vary widely across mammalian species. Spiny mice can regenerate full thickness skin, cartilage, and muscle as well as lost kidney tissue. The MRL mouse lineage can fully regenerate ear tissue, a capacity that was discovered because many researchers use ear notches to label their mice. Ordinary laboratory mice can regenerate the tips of their digits, and so can developing humans. Most such regenerative capacity for most mammals is lost somewhere between birth and adulthood, however.

The research community is attempting to develop a sufficient understanding of the biochemistry of proficient regeneration in salamanders and zebrafish to be able to provoke such regeneration in mammals. A few genes have so far surfaced as points of investigation, alongside significant differences in the behavior of macrophages and senescent cells in the context of injury and regrowth. In today's open access paper, researchers report on their investigations of the SP transcription factor family, leading to a focus on FGF8, one of the genes for which expression is modulated by SP transcription factors. Suitably guided upregulation of FGF8 expression, which required an enhancer from zebrafish, enhanced the ability of mice to regenerate lost digit tips. This is a modest starting point, and clearly not the whole picture, but years of research are now finally leading to the ability to at least modestly enhance regeneration in mammals.

For regrowing human limbs, this salamander gene could hold the key

Investigating a common gene in three very different species - salamanders, mice, and zebrafish - scientists have discovered the potential for a novel gene therapy aimed at eventually regrowing limbs in humans. In salamanders, SP8 does the work in regenerating limbs. Using CRISPR gene-editing technology, researchers removed SP8 from the axolotl genome. Without SP8, the axolotl could not properly regenerate the limb bones; a similar result occurred with the mouse digits missing SP6 and SP8.

With that information in hand, researchers used a tissue regeneration enhancer found in zebrafish to develop a viral gene therapy. That therapy delivered a secreted molecule called FGF8, a gene that is usually turned on by SP8, to encourage digit bone regrowth and partially restore the regenerative effects of the missing SP genes in mice. Human limbs don't have that kind of regenerative power - but might someday, with a therapy that emulates the abilities of SP genes.

Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors

Instructing regeneration of complex structures in mammals remains an unsolved problem. Gene therapy offers a compelling approach to foster endogenous regeneration by delivering therapeutic gene products to specific cells postinjury. We identified a conserved regeneration-linked epidermal transcriptional program in mouse digit regeneration centered on the SP6 and SP8 transcription factors, involving inflammatory responses from osteoclasts. Spatiotemporally focused expression of FGF8, a known target of SP factors, using a zebrafish-derived tissue regeneration enhancer element via adeno-associated viral vectors, could partially rescue digit tip regeneration in SP knockout mice and accelerate digit regeneration in wild-type mice. Our results demonstrate a contextual gene therapy approach to address limb loss based on genes like SP transcription factors conserved across multiple contexts of appendage regeneration.

Exercise influences the composition of the gut microbiome, which in turn influences capacity for exercise. Thus we see correlations in older people between the composition of the gut microbiome and observed level of physical activity and fitness, but breaking that down into specific contributing mechanisms and their relative importance is a challenge. The fastest path to answers is to alter the gut microbiome composition in defined ways and see how it affects capacity for physical activity. Approaches to alteration are in their infancy; the only approaches robustly demonstrated to produce lasting change are flagellin immunization and fecal microbiota transplantation, but while beneficial in the sense of reversing age-related changes in the composition of the gut microbiome, these approaches do not produce a well defined outcome. The future of this field will likely involve cultivation of defined mixes of hundreds or thousands of species in a synthetic microbiome, a major step up in complexity from the present manufacturing processes for probiotics.

Gut microbiota (GM) plays a crucial role in maintaining health through metabolic, endocrine, and immune functions. With ageing, shifts in GM composition, characterised by increased pathogenic and decreased health-promoting bacteria, contribute to dysbiosis, which is linked to several age-related diseases. Given the global trend of increasing sedentary behaviour (SB) and declining physical activity (PA) among older adults, this study aims to explore the relationships between GM and two critical indicators of healthy ageing, movement behaviours, and physical function.

This cross-sectional study assesses the GM composition, PA levels and physical function of 101 healthy, community-dwelling older adults aged 65-85 years. Participants undertook anthropometric measures and functional tests, wore an accelerometer for 7 days and provided a faecal sample which was analysed using 16s rRNA sequencing. All the results were adjusted for key covariates such as diet, age and activity levels.

Key findings include positive associations of Prevotella copri with moderate-to-vigorous PA, physical function, and negative associations with SB, while Roseburia species were linked to better mobility and strength measures. Conversely, potentially pathogenic taxa like Bilophila wadsworthia and Eggerthella were negatively associated with PA and handgrip strength, underscoring their possible detrimental roles in muscle function and healthy ageing. This cross-sectional study highlights the associations between GM, PA, physical function and healthy ageing in older adults. These findings emphasise the potential for leveraging GM and PA interactions to develop nonpharmacological strategies for promoting healthy ageing, warranting further research through interventional and longitudinal studies.

Link: https://doi.org/10.1155/jare/8981398

Senescent cells accumulate with age, generating disruptive inflammatory signaling that is disruptive to tissue structure and function. Numerous research groups and companies are developing therapies capable of either selectively destroying senescent cells or dampening their signaling. Animal studies and initial human trials suggest that the earliest senolytic treatments used to clear senescent cells, derived from cancer therapies, are safe and effective enough for widespread use. The drugs and compounds used cost relatively little, which is a meaningful argument for greater exploration of their utility. Unfortunately they are not a point of focus outside academia and a small number of anti-aging physicians. Few studies have directly compared first generation senolytic treatments, so the data noted here is interesting for supporting the dasatinib and quercetin combination over navitoclax.

Genetic background is a major determinant of disc degeneration, a leading cause of chronic back pain and disability. Herein, we demonstrate that premature disc cell senescence contributes to early-onset degeneration in SM/J mice and test two systemic senotherapeutic strategies to mitigate it: Navitoclax (Nav.) and a cocktail of Dasatinib and Quercetin (DQ).

While Nav. treatment did not improve severe degeneration in SM/J mice or senescence status, DQ-treated mice showed lower grades of degeneration and a decreased abundance of senescence markers, including p19ARF, p21, and the senescence-associated secretory phenotype (SASP). DQ improved disc cell viability and phenotype retention and retarded fibrosis of the nucleus pulposus tissue. Transcriptomic analysis revealed tissue-specific effects of the treatment, with cell cycle regulation and JNK signaling being commonly affected across different tissue types. A comparison of SM/J data with DQ-mediated aging-dependent amelioration of disc degeneration in C57BL/6 N mice identified Junb and Zfp36l1 signaling as shared DQ targets in the mouse disc.

Notably, the in vitro inhibition studies of the JUN pathway in human degenerated NP cells mimicked the benefits of DQ, namely, a reduction in senescence and SASP. This study reinforces the efficacy of senolytic treatment in ameliorating local senescence and intervertebral disc fibrosis.

Link: https://doi.org/10.1038/s41413-026-00526-4