LongeCityNews Last Updated: 09 February 2026 - 08:37 PM

Transposable elements, or transposons, are DNA sequences capable of directing the protein machinery surrounding nuclear DNA to haphazardly insert copies of the transposon elsewhere in the genome, potentially breaking other necessary sequences. Transposons are thought to be the remnants of ancient viral infections, but given that transposon activities are most likely an important mechanism of evolution, driving functional changes that can then be selected, that may not be universally true.

Transposons are suppressed in youth, the structure of DNA managed by epigenetic mechanisms to package away transposon sequences into heterochromatin structures and thus hide them from transcription machinery in the cell nucleus. With advancing age the epigenetic control of DNA structure changes in a variety of ways, altering the expression of many genes to contribute to loss of function, but also unleashing transposons to an ever greater degree.

Beyond mutational damage, transposon activity generates molecules that the cell has evolved to recognize as foreign and react to with inflammatory signaling. The activity resembles a viral infection, in essence. It may be that the greatest harm done by transposon activation is not in fact the mutational damage to DNA, but rather the contribution to a state of systemic sterile inflammation that is characteristic of aging, disruptive to tissue structure and function.

The interplay of epigenetic remodelling and transposon-mediated genomic instability in ageing and longevity

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications, and the reactivation of transposable elements (TEs).

TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation, and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

In Aging Cell, researchers have described why older natural killer (NK) cells lose their ability to eliminate harmful cells and a potential treatment for this decline.

Judgment and ability

At the cellular level, there is no due process. Natural killer (NK) cells judge other cells’ guilt or innocence by their surface proteins. They ruthlessly exterminate any foreign cells they find, which is what causes organ rejection; when they mistakenly attack the body’s own functional cells, autoimmune disorders are the result.

Even when uninfected and native to the body, cells can be guilty of two severe crimes: cancer and senescence. Encouraging NK cells to attack cancer despite its protections is a core part of modern oncology, and senescent cells are able to evade immune clearance as well [1].

However, errors in judgment are not the only potential issues with NK cells. This paper focuses on the armament of these cells, investigating the age-related reduction of their ability to do their jobs at all.

Older cells are much weaker

In their first experiment, the researchers derived NK cells from old groups of approximately 70-year-old humans and 700-day-old mice alongside young groups of approximately 21-year-old humans and 100-day-old mice. The human cells were tested against four groups of human dermal fibroblasts: three that had been driven senescent through toxicity, replication, or radiation, and a fourth that was derived from 75-year-old people; the mouse cells were tested against similar murine counterparts.

The results were entirely unsurprising. In every case, particularly against the naturally aged cells, the younger NK cells were far more effective in killing senescent fibroblasts than their older counterparts.

The differences were obvious even under a microscope. Young human NK cells were able to rapidly and tightly bind to senescent cells, killing them quickly, and then rapidly move on to the next senescent cell. Older NK cells failed at both; they were unable to form tight bonds, and they were lethargic in moving on to the next target.

Testing against various cancer cell lines yielded similar results. Older NK cells were less effective against multiple varieties of lymphoma and leukemia. Like their interactions with the senescent cells, this was found to be due to a lack of conjugation; the older NK cells were simply less able to bind with and properly destroy the cancer cells. An investigation into targeting mechanisms found that recognition of defective cells was not the reason why the older NK cells were less able to attack.

Instead, the older cells were found to have issues with their fundamental cytotoxic machinery. Normally, an NK cell will bind to a target cell and then attack it with a combination of perforin, which penetrates the cell, and granzyme B, which kills it. The attack itself requires granules of these weapons to be released in degranulation, and older NK cells were found to have both less binding ability and less degranulation than younger cells.

These reductions in ability were confirmed with a gene expression analysis. As expected, the older cells had downregulations in metabolism, activation, and core processes responsible for membrane transport and degranulation; the older cells were simply less able to bring their weapons to bear.

A potential solution

The researchers noted a key protein that was upregulated in their analysis: Cdc42, which has been noted to affect microtubular organization and increases with age. Previous work has found that Cdc42 has been implicated in the aging of hematopoietic stem cells (HSCs) [3], and proper microtubular organization is critical in correctly polarizing NKs and allowing cytotoxic granules to get to where they need to be.

A closer look at these cells’ microtubules suggested that this is likely to be the key issue. Older NK cells were significantly less organized than younger cells; in younger cells, Cdc42 sits on one side of the cell while tubulin sits on the other, but older cells did not have this polarity. Exposing older NK cells to CASIN, an inhibitor of Cdc42, was found to be successful in helping the older cells restore this balance.

Older NK cells exposed to CASIN received benefits in both conjugation and degranulation; in conjugation, the CASIN-exposed older cells even appeared to be slightly stronger than the younger ones. There were also benefits for mitochondria as well; older cells exposed to CASIN had even more of the energy transfer molecule ATP than their younger counterparts did, potentially further bolstering their overall ability.

However, CASIN did not give perfect results. While being substantially better than the unexposed older cells, the CASIN-treated older cells were not nearly as able to kill as many leukemic or senescent cells as younger cells were. Compared to untreated older and younger mice, CASIN-treated older mice were roughly halfway between those groups in their ability to remove senescent cells in the bone marrow and the spleen. CASIN was found to only affect the ability of NK cells and did not affect their proliferation.

These results, while substantially beneficial, were still only done in mice, and the potential side effects of using CASIN or another Cdc42 inhibitor in human beings have not been eludicated. The researchers suggest that further work should be done in exploring this approach as a treatment for age-related diseases that involve cancer or senescence.

Literature

[1] Pereira, B. I., Devine, O. P., Vukmanovic-Stejic, M., Chambers, E. S., Subramanian, P., Patel, N., … & Akbar, A. N. (2019). Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nature communications, 10(1), 2387.

[2] Topham, N. J., & Hewitt, E. W. (2009). Natural killer cell cytotoxicity: how do they pull the trigger? Immunology, 128(1), 7-15.

[3] Florian, M. C., Dörr, K., Niebel, A., Daria, D., Schrezenmeier, H., Rojewski, M., … & Geiger, H. (2012). Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell stem cell, 10(5), 520-530.

Most of the approaches demonstrated to alter metabolism in ways that modestly slow aging and extend life involve an increased efficiency of autophagy. This includes mild stresses resulting from exercise, calorie restriction, heat, cold, and low levels of toxin exposure. The processes of autophagy act to recycle damaged or otherwise unwanted cellular components into amino acids that can be used for further protein synthesis, improving cell function. Thus there is interest in the scientific community in finding drugs that can induce increased autophagy. The best known, most readily available, and most advanced in the clinic are varieties of mTOR inhibitor, rapamycin being the canonical example. But many other classes of small molecule may prove to be interesting enough to develop into drugs.

Macroautophagy, henceforth referred to as autophagy, is a cellular process that, in part, can act to break down damaged, dysfunctional, or otherwise unwanted components. Autophagy is crucial for maintaining proteostasis and is a necessary system for cellular survival under stressful conditions. Autophagic efficiency declines during aging, leading to the buildup of damaged proteins and organelles, as well as other nonviable cellular debris.

The amino acid response (AAR) pathway is a highly conserved mechanism that reacts to low levels of amino acids with the increased translation of Gcn4 (in yeast), ATF-4 (in worms), and ATF4 (in mammals). We have previously shown that activation of this pathway through the chemical inhibition of tRNA synthetases (tRS) can activate autophagy and extend lifespan in both worms (C. elegans) and yeast (S. cerevisiae).

In this study, we identify four additional tRNA synthetase inhibitors, REP8839, REP3123, LysRS-In-2, and halofuginone, that extend both healthspan and lifespan in C. elegans. These compounds also trigger a significant upregulation of autophagy, specifically at their lifespan-extending doses. These phenotypes partially depend on the conserved transcription factor ATF-4. Our findings further establish tRNA synthetase inhibition as a conserved mechanism for promoting increased lifespan and now healthspan, with potential implications for therapeutic interventions targeting age-related decline in humans.

Link: https://doi.org/10.3390/biom16010073

Cell therapies seem the least likely of approaches to make it into the clinic as a treatment to selectively destroy the senescent cells that linger to cause harm in aged tissues. While it is a very plausible goal to take a CAR T cell therapy and target it to senescent cells, or use adoptive transfer of other immune cell types known to attack senescent cells, as these are just variations on strategies already well demonstrated to work in other contexts, the cost and logistical effort is enormous in comparison to other approaches to the selective destruction of senescence cells. It is far more likely that therapies to adjust the operation of native immune cells, such as the approach under development by Deciduous Therapeutics, or forms of senolytic vaccine, will emerge from this line of thinking.

One of the most significant risk factors for diseases is aging. Interestingly, some organisms, such as naked mole-rats and most turtles, do not exhibit typical aging-like symptoms or increased mortality as they become older. These aspects indicate that aging is not necessarily an essential event for animal life and are avoidable. Overcoming aging would free humans from age-associated diseases (AADs) and prolong lifespans.

Recent studies have demonstrated that one of the causes of age-related organ dysfunction is excessive chronic inflammation caused by the accumulation of senescent cells (SNCs) and their senescence-associated secretory phenotypes (SASPs). Therefore, the development of drugs and medication to remove SNCs is ongoing.

Natural killer (NK) cells are integral components of the innate immune system that are critical for clearing SNCs. Beyond this direct function, NK cells also orchestrate innate and adaptive immunity responses to survey and eradicate these compromised cells. Consequently, preserving NK cell function throughout the aging process is paramount for mitigating AADs and promoting robust health in later life.

Simultaneously, NK cell-based senotherapy presents compelling avenues for addressing the multifaceted challenges associated with SNC accumulation and aging. Recent investigations into adoptive NK cell-based senotherapy have demonstrated considerable promise in rejuvenating immunosenescence, facilitating SNC elimination. The accumulating evidence provides a promising proof-of-concept for adoptive NK cell-based senotherapy, indicating its potential as a development in longevity therapeutics.

Link: https://doi.org/10.3389/fimmu.2025.1737572