Research news: Longevity limits, healthspan over lifespan, genetics vs. diet, body roundness and mortality risks

In the world of longevity and healthspan, it is easy to get carried away in the excitement and believe we could all live to be 100 years or more, or even that immortality is possible, so it’s refreshing to see a reality check published in Nature Aging journal telling us that radical life extension is unlikely in the twenty-first century. Their data suggests that up to 15% of females and 5% of males will live longer than 100 years. The main reasons they cite are that there is a biological limit to how long the human organism can live and that the life extension benefits of current public health and medicine approaches are beginning to flatten, suggesting they have reached their limit. Research like this reminds us of the importance of focussing on more healthy years as opposed to just more years of life.

Intermittent fasting or calorie-restricted eating are popular strategies for improving health and longevity. A 2024 study published in Nature investigated the effects of different types of dietary restriction on health outcomes and lifespan in mice and found that genetics had a greater influence on lifespan than dietary restriction, however, dietary restriction did have variable effects on extending healthspan. This research highlights the importance of approaching health in a personalised way that uses data to inform what is right for each individual.

Following on this same theme of health and healthspan, a large study published last year in Jama Network followed 32,995 people from 1999-2018 to investigate the effects of ‘body roundness’ on all-cause mortality. They have proposed a new Body Roundness Index as a means of assessing visceral fat accumulation and adiposity. The results showed there was a U-shaped association between body roundness and all-cause mortality with the lowest and highest body roundness scores being associated with higher risk of death. Most people are aware that obesity is associated with poor health outcomes, but many overlook the fact that low-body weight is also associated with poorer health. We know that this is often because of lower healthy muscle mass, and the influence of adipose tissue on metabolic markers such as glucose regulation.?

Mark Payne , Functional Medicine Practitioner (Melbourne Functional Medicine)

DVE-1 and longevity regulation beyond mitochondrial stress

DVE-1 supports longevity in C. elegans through multiple pathways beyond its known role in mitochondrial stress response. It regulates lifespan independently of the mitochondrial unfolded protein response, influencing dietary restriction, germline signalling, and sensory perception. Its reduced nuclear presence in long-lived mutants suggests a broader cytosolic function in ageing.

The limits of human longevity in the twenty-first century

Radical human life extension is deemed unlikely this century. Since 1990, improvements in life expectancy have slowed, and reaching age 100 remains rare without breakthroughs in slowing biological ageing. Maximum lifespan is constrained by biological limits and diminishing returns on public health advancements

Genetic variability and the effects of dietary restriction on lifespan

Caloric restriction (20%-40%) and intermittent fasting enhanced lifespan in genetically diverse mice, with stronger effects tied to stricter calorie reduction. Lifespan varied with genetics and stress resilience, revealing healthspan and longevity are not always aligned. Extreme restrictions caused adverse effects, questioning optimal dietary strategies for ageing.

Urolithin A and its role in optimising ageing health

Urolithin A, derived from gut metabolism, enhances mitochondrial function, reduces inflammation, and improves muscle strength and endurance. It offers potential benefits for healthy ageing but does not affect body composition or overall physical function. Further research is needed to explore its impact on various systems and its long-term benefits.

Body roundness index as a tool for promoting healthy ageing

The Body Roundness Index (BRI) has a U-shaped relationship with all-cause mortality, with both very low and high BRI linked to higher death risk. BRI, which reflects visceral fat more accurately than BMI, may serve as a valuable, non-invasive tool for assessing health risks, aiding longevity-focused strategies.

Epigenetic resilience in axolotls unlocks longevity insights

Axolotls exhibit stable DNA methylation beyond early life, suggesting epigenetic resilience linked to negligible senescence. While methylation predicts age during early years, it ceases thereafter, and regeneration events rejuvenate tissues, shedding light on their remarkable longevity and regeneration abilities. This offers molecular insights into ageing stability and tissue renewal.

Rapamycin relies on spermidine to boost lifespan and healthspan

Endogenous spermidine is crucial for rapamycin's benefits, enhancing autophagy and extending lifespan. Blocking spermidine synthesis hinders these effects, highlighting its role in cellular health. Combining rapamycin with spermidine may optimise longevity interventions while mitigating side effects.

Mitochondrial DNA insertions in the brain linked to ageing

Mitochondrial DNA fragments integrate into the nuclear genome (Numts), particularly in brain tissue, increasing with age and correlating with earlier mortality. In cultured fibroblasts, new insertions appear every 13 days, accelerating under stress and mitochondrial dysfunction, suggesting potential implications for ageing and longevity.

N6-Methyladenine in mitochondrial DNA and its role in ageing

Mitochondrial DNA progressively accumulates N6-methyladenine (6mA) with age, potentially serving as an ageing biomarker. In long-lived mutants, this methylation rate slows, linking mitochondrial epigenetics to longevity. The findings highlight mitochondrial DNA’s role in ageing and introduce a precise, cost-effective method for measuring 6mA levels.

KIBRA and PKMζ: Protecting memory as we age

Memory persistence relies on the interaction between KIBRA and PKMζ, maintaining synaptic strength despite molecular turnover. This partnership supports long-term memory by anchoring PKMζ to active synapses, essential for late-phase potentiation. Disrupting this interaction erases established memories, highlighting its role in sustaining memory longevity.

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