LongeCityNews Last Updated: 25 April 2026 - 01:51 PM

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.

A new study has found that partial reprogramming mitigates the damage of myocardial infarction in mice by helping heart muscle cells to complete division [1].

When heart cells get stuck

When a heart attack (myocardial infarction, MI) kills a patch of heart muscle, the adult mammalian heart cannot replace it, since the lost contractile muscle cells (cardiomyocytes, CMs) do not meaningfully regenerate. Instead, the heart heals with scar tissue, which, over time, leads to heart failure [2].

Why do adult cardiomyocytes lose this regenerative capacity? One piece of the puzzle is that mature CMs acquire a rigid, highly organized internal scaffold of contractile machinery called the sarcomere: the repeating protein units that generate force when the heart beats. This is great for pumping blood but terrible for cell division, because dividing requires the cell to dismantle its internal structure.

Another piece is that adult CMs often carry more than the normal two sets of chromosomes (polyploid) or have more than one nucleus per cell (multinucleated). This happens because they can enter the cell cycle and replicate DNA but then fail to complete the final step: cytokinesis, the physical splitting of one cell into two daughter cells [3].

The authors of a new study published in the Journal of Molecular and Cellular Cardiology liken this to turning on the tap without unblocking the drain: CMs are pushed into DNA replication, but if they cannot actually divide, no new heart cells are produced. To try and “unblock” the process, the researchers induced partial reprogramming of CMs using three of the four classic “Yamanaka factors”: OCT4, SOX2, and KLF4 (OSK). The idea was that this would help the cells dismantle their sarcomeres and complete a full division.

Unblocking the drain

OSK overexpression in neonatal and adult mouse CMs reduced the expression of cardiac troponin T, a sarcomere protein that marks mature CM identity, and disrupted the striped, organized sarcomere architecture. The gene expression profile shifted from that of an adult heart cell back toward an embryonic heart cell, suggesting dedifferentiation without loss of cellular identity.

The full four-factor cocktail, OSKM (M stands for c-Myc), had the same effect, but, unlike OSK, it also produced clonal clusters of rapidly dividing cells that lost their CM markers. The authors interpret this as dysregulated proliferation approaching a pre-tumorigenic state, as opposed to the controlled dedifferentiation seen with OSK.

Interestingly, c-Myc is a well-known oncogene; it was already recognized as cancer-causing before Yamanaka’s team included it in the original cocktail, where it acts by dampening the cellular brakes that normally prevent runaway division. It is required for full reprogramming and the production of induced pluripotent stem cells (iPSCs), but not for partial reprogramming.

Since dedifferentiation is thought to be a prerequisite for heart regeneration – as seen in zebrafish and neonatal mice – does OSK also drive cell cycle re-entry? OSKM and c-Myc alone both strongly drove cells into the cycle, confirming c-Myc’s classic proliferation-boosting effect, but OSK did not. So, the central question of the paper became: If OSK does not make cells divide more often, how can it help the heart regenerate?

As the researchers found out, while OSK did not increase the number of cells “attempting” division, far more of the cells that did try completed the split successfully, as if OSK solved the “blocked drain” problem. Supporting this hypothesis, OSK-treated cultures had more single-nucleus cells and fewer two-nucleus cells, a result that is consistent with successful division.

Rescue in vivo

To see if this would work in living animals, the researchers delivered OSK to newborn mouse hearts using a virus (AAV) targeted to heart cells. Two weeks later, the hearts showed the same pattern seen in vitro: dedifferentiated cells, disassembled sarcomeres, and more completed cytokinesis events.

However, when OSK expression was allowed to continue for four weeks, the hearts developed a combination of thin walls, enlarged chambers, and weakened pumping (dilated cardiomyopathy), suggesting that prolonged dedifferentiation becomes harmful. Interestingly, in adult mice, the same duration of OSK caused no obvious damage: it seems that adult hearts tolerate OSK better than developing ones. This might also mean that treatment timing and duration will be important for clinical translation.

For the final and crucial test, the researchers induced heart attacks and injected OSK at the same time. Over the following month, OSK-treated mice, compared to controls, showed better blood pumping (higher ejection fractions) at 14 and 28 days, less scarring (fibrosis), and more dividing heart cells, especially near the injury site. They also had smaller individual heart cells, suggesting less compensatory enlargement; in other words, new cells were sharing the load.

Harvard geroscientist David Sinclair, who was not involved in this new study but whose team has used OSK to successfully restore vision in animal models, discussed the results in an X post: “Why is this such a big deal? Because adult heart cells do not meaningfully divide, which is why the heart heals with scar tissue rather than regeneration. This fundamental limitation has defined cardiology for decades. In 2020, OSK restored function in damaged neurons. Now the same principle is being explored in the heart, building on results already seen in eye, brain, liver, and skin.”

Dr. Sinclair added that the findings were consistent with his Information Theory of Aging, which postulates that cells have a “backup copy” of their youthful epigenetic makeup that can be restored by cellular reprogramming. “Cells retain the instructions for repair; aging is a loss of access to them. Restore that information, and regeneration follows.”

Literature

[1] Yan, Y., Huang, Y., Cao, C., Li, D., Che, Y., Wang, Q., … & Wang, L. (2026). OSK-mediated partial reprogramming induces cardiomyocyte dedifferentiation, overcomes cytokinesis barriers, and promotes post-MI endogenous cardiac regeneration. Journal of Molecular and Cellular Cardiology.

[2] Frangogiannis, N. G. (2015). Pathophysiology of myocardial infarction. Comprehensive physiology, 5(4), 1841-1875.

[3] Derks, W., & Bergmann, O. (2020). Polyploidy in cardiomyocytes: roadblock to heart regeneration?. Circulation research, 126(4), 552-565.

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