LongeCityNews Last Updated: 19 March 2026 - 01:30 PM

An increasing number of cells in aged tissues enter a senescent state, ceasing replication and generating pro-inflammatory signals that are disruptive to tissue structure and function. In the case of innate immune cells, however, there is some question as to whether they are in fact senescent or just adopting features of senescence, and that leads to debate over whether these cells are in fact harmful. Neutrophils, also known as polymorphonuclear leukocytes, are an important cell type in the innate immune system. Here, researchers show that neutrophils in aged individuals exhibit features of cellular senescence, but stop short of calling them senescent cells. They also show that this behavior is harmful, as it impedes the immune response to infection.

Aging drives increased susceptibility to respiratory infections by Streptococcus pneumoniae (pneumococci). Polymorphonuclear leukocytes (PMNs) are among the first responders in the lung following pneumococcal infection and are required for bacterial clearance. However, PMN antimicrobial function declines with age. To identify mechanisms underlying this decline, we performed RNA sequencing on PMNs in the lungs of young and old mice following pulmonary infection with S. pneumoniae. We observed significant transcriptomic differences across host age.

Transcriptional analysis followed by functional validation revealed that in infected mice, PMNs from aged hosts failed to upregulate several effector activities including glycolysis and subsequent mitochondrial reactive oxygen species (ROS) production, which are necessary for bacterial killing by PMNs. Conversely, PMNs in aged mice displayed a higher senescence-associated secretory phenotype (SASP) score and upregulated pathways involved in cellular senescence. Follow-up functional characterization found that in uninfected hosts, PMNs in aged mice expressed higher levels of SASP factors IL-10, TNFα, and ROS, had a lower incidence of apoptosis, and had a higher proportion of cells positive for senescence-associated β-galactosidase, features of a senescent-like phenotype.

Importantly, blocking TNFα, one of the SASP factors, altered the senescent-like phenotype and boosted the antibacterial activity of PMNs from aged hosts and increased host resistance to S. pneumoniae pulmonary infection. In conclusion, host aging is associated with altered PMN phenotype, including a shift toward senescent-like energy-deficient cells, which contribute to impaired host defense and represent potential targets for improved interventions against infection in older adults.

Link: https://doi.org/10.1111/acel.70435

The standard view of the evolution of aging is that aging exists because natural selection operates more strongly on features of young animals than on features of old animals. A faster time to reproductive success will be selected over a slower time to reproductive success. This leads to the evolution of biological systems that are front-loaded for early efficiency, but that decay to become dysfunctional over time. Aging is near universal but not actually universal, however. For example, varieties of hydra are in fact immortal, exhibiting no loss of function over time. How to explain the existence of the few immortal species in the presently dominant view of the evolution of aging? Here, researchers build a model of the evolution of aging in which a runaway feedback loop leading to immortality is a possible outcome.

In recent years, senescence is increasingly understood as a process of damage accumulation that accelerates with age throughout an organism's lifespan. That understanding has rarely been introduced to senescence evolution theory. In classic models, including Mutation accumulation and Antagonistic pleiotropy, the intensity of selection over genes is determined by the timing of their effect on mortality. They conclude senescence evolution occurs because of weak selection on late-acting genes. Despite the success of these classic explanations, several phenomena have not been fully addressed. One is the existence of species exhibiting negligible senescence - mortality rate that remains constant with age.

Here we explore, consistent with recent evidence, an alternative model: where genes affect mortality throughout an organism's lifespan, and the shape of this effect determines selection. We expanded Hamilton's classic model of senescence evolution using these notions. Our model takes into account evolutionary dynamics between external mortality risk, potential mortality risk from internal damage, reproduction start age, and reproduction rate. The analysis of the model suggests biological limitations on reducing the potential mortality risk from internal damage can lead to a positive feedback loop in senescence evolution where genes that slow senescence can increase selection for further senescence retardation. Our model sheds light on several phenomena, not fully explained by classic theory, including Peto's paradox, Strehler-Mildvan correlation, and negligible senescence.

Link: https://doi.org/10.1002/ece3.72988

Most programs aiming to produce therapies that treat aging involve some form of manipulation of cellular metabolism, usually via small molecules initially derived from screens that showed effects on function or survival in lower animals. Effect sizes are usually modest, and decrease relative to species life span as species life span increases; large increases in function and life span in a nematode worm translate to modest gains in a mouse. Where we have the ability to compare mice and humans, in the matter of growth hormone metabolism and calorie restriction, we know that sizable gains in mice do not translate to sizable gains in humans.

Researchers, particularly Brian Kennedy's team, have shown that most combinations of this sort of intervention fail to be useful. Any two marginally positive age-slowing changes to metabolism are far more likely to interfere with one another than they are to combine for a greater effect. Yet aging is a combination of forms of cell and tissue damage, and thus multiple treatments will be needed to address aging. To combine therapies is a desirable end goal, but it must be pursued rationally, using combinations made up of therapies that specifically address different forms of age-related damage. In principle, such combinations should be far less likely to interfere in one another's operation, and the outcome for health and longevity more likely to be additive and greater than any one therapy alone.

This view of combined therapies as the end goal was always implicit in the Strategies for Engineered Negligible Senescence (SENS) view of aging and how to go about the construction of rejuvenation therapies. One must repair the damage, and thus one must combine different repair strategies that address different forms of damage. This is the central point that the Longevity Escape Velocity (LEV) Foundation is attempting to demonstrate in their large, long-running mouse studies. The goal is to pick sensible combinations of therapies based on a damage repair philosophy, and show that these combinations can be additive. Nothing is ever straightforward, and there are clearly things to be learned along the way, but so far the LEV Foundation seems to be proving their point, a useful counterbalance to the work of Brian Kennedy.

Robust Mouse Rejuvenation: Breaking the Ceiling of Longevity Research

For decades, the field of biogerontology has largely focused on a single strategy: manipulating metabolism to slow down the rate at which we age. While approaches like caloric restriction have produced fascinating results in short-lived organisms like worms and flies, they have shown clear limits in mammals. At LEV Foundation, we are pursuing a distinct alternative: maintenance through damage repair. All age-related damage can be classified into a manageable number of categories. Since there are different types of damage, a single therapeutic intervention is insufficient. To achieve meaningful rejuvenation, we must move from isolation to synergy.

This necessity is the foundation of the Robust Mouse Rejuvenation (RMR) programme. We define RMR as a specific engineering benchmark: a multi-component intervention that increases both mean and maximum lifespan in mice by at least 12 months. This must be achieved in a mouse strain with a well-documented mean lifespan of at least 30 months, with treatment initiating only at the advanced age of 18 months. To hit this target, the RMR programme consists of large-scale studies designed to determine how leading-edge interventions behave when deployed together.

The RMR1 study served as a first test, operating at an unprecedented scale with 1000 middle-aged mice divided into 10 subgroups per sex. This granular design allowed us to map the complex web of interactions. We selected four interventions that had individually shown promise in extending mouse lifespan: rapamycin, senolytics, telomerase gene therapy, and hematopoietic stem cell transplantation. By administering these simultaneously, we sought to establish whether their combined impact could finally break through the lifespan ceiling that no single intervention has ever managed to overcome.

The overarching conclusion following the completion of RMR1 is a qualified win for synergy. RMR1 successfully demonstrated that combining damage-repair interventions with metabolic modulation (rapamycin) yields additive benefits. Specifically, we observed a distinct rectangularisation of the survival curve. This means that we significantly increased mean lifespan by ensuring more mice survived into late life. However, we must be clear about the limits of this result. We did not observe a radical extension of maximum lifespan (the age of the oldest survivors). While the all-four combination group outperformed both the naive and mock controls, the "robust" goal of shifting the entire mortality window remains the target for future iterations.

RMR1 demonstrated that a single dose of damage repair has a limited window of efficacy. The damage re-accumulates. Future protocols must likely incorporate repeated dosing for interventions like senolytics and gene therapy. However, the male data revealed that combinatorial treatments extend this window significantly when supported by metabolic stability. We have used these critical lessons to design RMR2. The new study replaces the single-dose approach with cyclic treatments using mesenchymal stem cells and an expanded panel of eight interventions. With the blueprint for this next phase complete, funding is the only remaining bottleneck.

A new study reported an association between having more problematic people in close networks and increased biological aging [1].

A look into the dark side

Social connection has been discussed as a factor essential for well-being, reduced epigenetic aging, and inflammatory signaling [2, 3]. However, the dark side of social connections, relationships that are toxic and stressful, and their impact on health and aging, is less studied. Studies to date have mostly focused on the association between conflict and toxic relations in marital relationships and accelerated epigenetic aging [4], with less attention given to relationships outside of marriage.

This study, recently published in Proceedings of the National Academy of Sciences, aims to fill this gap. It focused on investigating “hasslers,” which the authors describe as “people in one’s close social networks who create problems or make life more difficult.” Social connections with such people are a potential source of stress, a well-known factor that is linked to accelerated aging, inflammation, and chronic conditions [5, 6].

Some are more affected than others

The researchers investigated 2,345 people aged 18 to 103 years old. They used “ego networks”, which map social connections around an individual. Study participants had an average network size of 5.07, with approximately 8% of their network classified as hasslers. The networks of 28.8% of study participants included at least one hassler, while about 10% had two or more hasslers.

The number of hasslers didn’t appear to be random. Groups with a higher probability of hasslers included women, the unemployed, daily smokers, people with more adverse childhood experiences, and people who felt that others depended on them. The opposite pattern was seen among people who viewed themselves as important to others and people with better self-reported health.

More hasslers, faster aging

In their next step, the researchers used epigenetic clocks to test whether hasslers in one’s network affect the rate of aging. Epigenetic clocks use markers such as DNA methylation to assess biological age and to judge whether a person ages faster or slower than their chronological age would suggest.

This study’s analysis suggested that “individuals reporting more hasslers exhibit meaningful differences in both the rate and acceleration of biological aging.” The associations remained, albeit sometimes attenuated, even after adjusting for multiple factors, including occupation, adverse childhood experiences, smoking, comorbidity, demographic characteristics, and network size, suggesting an enduring negative effect of social stress on the rate of biological aging.

According to the DunedinPACE epigenetics clock, which measures the rate of aging, each additional hassler in the network was associated with a 1.5% faster pace of aging, or, in other words, aging approximately 1.015 biological years annually instead of only 1 year. While this difference is relatively small, it accumulates over time, and after 10 years, it reflects another 1.8 months of biological aging.

Another epigenetic clock, GrimAge, which was developed to assess the likelihood of death by any cause, offers a different comparison that agrees with the previous conclusion. According to this clock, when compared to the individuals of the same chronological age, people with one additional hassler in their networks were approximately 9.5 months biologically older at the time of measurement.

Such an effect is roughly comparable to 13% or 17% of the effect that smoking that has on accelerated aging, depending on the epigenetic clock used. Further modeling assessment also suggested “that greater exposure corresponds to larger increases in epigenetic aging.”

Not all hasslers are created equal

The prevalence of different groups of hasslers differed. While almost 9% of partners were classified as hasslers, kinship relationships ranged from approximately 5.5% of grandchildren and grandparents reported as hasslers to almost 10% of parents and children. Non-kin relationships showed even higher variability but also some of the categories with the lowest prevalence of hasslers, such as friends, churchmates, or healthcare providers (around 3-5%), suggesting that self-selected ties lead to a lower presence of hasslers, while those that involve interdependence, obligation, and shared space show higher prevalence.

Also, their impact on aging varied by relationship type. For both epigenetic clocks, kin hasslers showed significant associations with accelerated biological aging, and these associations were more pronounced than other relationships. Nonkin hasslers showed a significant association with GrimAge but not with DunedinPACE.

Surprisingly, spouses showed no significant associations in any of the clocks tested. This differs from previous work on this topic, which suggests that marital strain is a driver of aging [4, 7, 8].

An analysis of network patterns suggested an explanation for these results. Since kin hasslers have a stronger position in the network and those relationships are more difficult to leave, conflicts with them are long-lasting and difficult to avoid. The pressure from non-kin hasslers is smaller, since they are more peripheral in the network and those relationships are easier to disengage with and might be less impactful on the individual; nevertheless, they still exert a negative effect, albeit to a lesser extent. By this logic, spousal hasslers should have the strongest effect on accelerated aging. However, this was not observed. The researchers believe it is because the relationship with spouses might involve a mix of negative and positive interactions that lessen the effect.

Beyond aging

The presence of hasslers extends beyond accelerated aging and negatively impacts health across multiple domains, with mental health, including depression and anxiety severity, being affected the most. Physical health is modestly but significantly affected as well. The researchers reported that additional hasslers are associated with poorer general health and physical health, as well as a higher BMI and waist-to-hip ratio.

The authors summarize that “this study provides evidence that negative social relationships operate as potent, chronic stressors capable of shaping epigenetic and physiological risk profiles across adulthood.” However, the authors also caution that, while this study observes an association, it cannot establish causality between the presence of hasslers in the social network and accelerated aging, and more research is necessary to establish if hassling co-occurs with other forms of negative behavior, such as hostility, coercion, chronic criticism, or gaslighting, and their impact on health and aging.

Literature

[1] Lee, B., Ciciurkaite, G., Peng, S., Mitchell, C., & Perry, B. L. (2026). Negative social ties as emerging risk factors for accelerated aging, inflammation, and multimorbidity. Proceedings of the National Academy of Sciences of the United States of America, 123(8), e2515331123.

[2] Holt-Lunstad J. (2024). Social connection as a critical factor for mental and physical health: evidence, trends, challenges, and future implications. World psychiatry : official journal of the World Psychiatric Association (WPA), 23(3), 312–332.

[3] Ong, A. D., Mann, F. D., & Kubzansky, L. D. (2025). Cumulative social advantage is associated with slower epigenetic aging and lower systemic inflammation. Brain, behavior, & immunity – health, 48, 101096.

[4] Wang, W., Dearman, A., Bao, Y., & Kumari, M. (2023). Partnership status and positive DNA methylation age acceleration across the adult lifespan in the UK. SSM – population health, 24, 101551.

[5] Miller, G. E., Chen, E., & Parker, K. J. (2011). Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychological bulletin, 137(6), 959–997.

[6] McEwen, B. S., & Stellar, E. (1993). Stress and the individual. Mechanisms leading to disease. Archives of internal medicine, 153(18), 2093–2101.

[7] Kiecolt-Glaser, J. K., Wilson, S. J., & Madison, A. (2019). Marriage and Gut (Microbiome) Feelings: Tracing Novel Dyadic Pathways to Accelerated Aging. Psychosomatic medicine, 81(8), 704–710.

[8] Kim, J. K., Arpawong, T. E., Klopack, E. T., & Crimmins, E. M. (2024). Parental Divorce in Childhood and the Accelerated Epigenetic Aging for Earlier and Later Cohorts: Role of Mediators of Chronic Depressive Symptoms, Education, Smoking, Obesity, and Own Marital Disruption. Journal of population ageing, 17(2), 297–313.