Longevity Secrets: From Genes to an Active Lifestyle

Italy’s count of centenarians has risen: as of January 2024, estimated at over 22,552 according to Istat, with 677 semi-supercentenarians (over 105 years) and 21 supercentenarians (over 110), more than doubling since 2009’s tally of 10. Science, including Italian researchers, has been active for years to confirm these longevity figures, where genes matter but are also shaped by physical activity and healthy lifestyles as well as other factors, such as environmental context and education level. Four of the longevity-gene research projects conducted in Italy were presented at the Milan Longevity Summit (March 21-29, 2025).

The Genetics of Centenarians

For years, at the Immunology Laboratory of Alma Mater Studiorum, University of Bologna, founded by Professor Emeritus Claudio Franceschi, centenarians have been studied as an absolute biological reference for healthy aging. Through molecular characterization of these exceptional individuals and other groups representing specific biological-aging traits, the laboratory pursues biomarkers capable of expressing the quality and speed of aging. Specifically, centenarians are particularly useful for studying genetic traits associated with longevity.

“To extract the maximum genetic information we chose an approach we defined as extreme-phenotype comparison” – explains Paolo Garagnani, associate professor at the University of Bologna – “that is, instead of the canonical case-control study, we pushed the comparison to the extreme by opposing longevity phenotypes to phenotypes of age-related adult disease. With this approach we obtained very interesting results on type 2 diabetes, highlighting how disease-predisposing variants in the gene TCF7L2 decrease progressively from groups of patients with macrovascular complications to reach a minimum in centenarians. This approach, though powerful, has limitations. When, in fact, we tackled the genetics of longevity by testing variants in the FTO gene, we observed that centenarians have a risk-allele frequency overall comparable to the obese group. This observation illuminated the need to place genetic study within the historical, environmental context of the individuals studied. Our centenarians spent the majority of their lives in an environment free of obesogenic stress and, consequently, did not experience any selective pressure for genetic variants that protect against obesity. Genetics does not express itself in space alone, but in environmental contexts that influence the effects of individual genetic variability.”

Since 2012 the research group has analyzed the genomes of 84 centenarians and 40 controls, identifying a total of 17 million variants. By comparing the centenarians’ genomes with those of the control group, they identified a very strong signal on chromosome 7, within a linkage block mapping between the COA1 (Cytochrome C Oxidase Assembly Factor 1) gene and STK17A (Serine/Threonine Kinase 17A). COA1 is linked to mitochondrial function, hence (bio)energetics, while STK17A is involved in DNA repair.

Both functions are critically important in the aging process, and this amplifies the weight of the result. Regarding genetic maintenance of integrity, the study also found that centenarians show a much lower accumulation of mutations in circulating cells (clonal hematopoiesis) than controls, supporting the idea that centenarians have a greater capacity to preserve their genomic integrity². Considering that the accumulation of mutations in circulating cells is associated with an increased risk of cardiovascular disease, the longevity finding becomes even more compelling. Finally, results were presented in the areas of sensory decline and the genetics of heart disease.

Bioenergetics and Transcriptional Regulation

Physical activity, together with diet and a healthy lifestyle, is a foundational pillar for longevity with better health. This is demonstrated by certain studies led by Marco Sandri, a Professor at the University of Padua, who measured the effects of sedentary behavior on muscle tissue samples from healthy 20-year-olds who were bedridden, collected on day 1, 5, and 9 to define how proteins and genes change over time in muscles affected by inactivity.

«We specifically studied RNA and proteins, the latter at the single-cell level — the professor states — and it emerged that all the genes that were strongly down-regulated were associated with a substantial suppression of the bioenergetic level, and that three proteins, OPA1, MFN1 and MFN2, which determine the size and shape of the energy centers—the mitochondria—significantly decrease in bedridden young individuals and were strongly inhibited in unhealthy, sarcopenic, frail elders. Conversely, older adults with preserved muscle mass and function had these proteins at levels similar to, or even higher than, those of the young. This would suggest that they are highly sensitive to the level of physical activity and may play an important role in muscle function.”

The energy centers in a healthy muscle are interconnected to form a network with specific characteristics: a capacity that is lost during unhealthy aging. Therefore, the mitochondrial network begins to fragment with inactivity, leading to reduced energy production and increased oxidative stress. To evaluate the possible relationship between mitochondrial network fragmentation in muscle and aging of body cells, the Sandri team created an adult animal model in which the OPA1 gene, which keeps the mitochondrial network connected, was inhibited specifically in skeletal muscle.

After three months the mice showed signs of premature aging: white fur, a hunch, smaller and weaker muscles, bone problems with osteoporosis, and systemic inflammation with certain cytokines in the blood, including IL-6, IL-1β, and TNF-α, 10 to 100 times higher. “These data suggest that mitochondrial network fragmentation in muscle,” Sandri clarifies, is sufficient to affect bone, promote systemic inflammation, and block tissue regeneration, inducing organ senescence, i.e., accelerated aging.”

However, subsequent experiments appear to show that blocking IL-6, but only in the muscle, yields systemic recovery, with aging markers returning to normal ranges in several tissues such as the liver, skin, and intestine, and a reduction in the inflammatory response in the blood, also improving life expectancy. “Regular physical activity therefore substantially contributes,” the professor emphasizes, to keeping the energy centers, the mitochondria, healthy by reducing inflammation and consequently cellular aging.”

The MYTHO Gene

Focusing then on unknown genes that might be modulated by a key pathway for longevity, conserved across many species and linked to the cellular cleanup system for removing damaged organelles and proteins, Sandri’s group discovered a new longevity gene, dubbed MYTHO (Youthfulness Optimizer and Autophagic Clearing System), a protein highly conserved from worms to humans, expressed in all tissues but predominantly in muscles and brain. Laboratory experiments demonstrated that in worms in which MYTHO was inhibited, partially or completely, not only did survival plummet but life quality, measured by the animals’ ability to move, deteriorated dramatically.

“In mammalian cells — Marco Sandri explains — MYTHO inhibition caused activation of premature-aging markers like P21, inhibition of the degradative system known as autophagy and the waste-disposal centers, promoting the accumulation of toxic markers, bioenergetic problems with increased ROS production and thus oxidative stress. The combination of these cellular events leads to premature mortality in the animal, especially in males, by about 15 months, equivalent to 50 years of human life. Lifestyles can influence MYTHO; for instance, physical inactivity leads to its inhibition, reducing bioenergetics and mitochondrial dysfunction, promoting inflammation and DNA damage, among other effects. However, the gene responds to regular lifestyles, caloric restriction, and physical activity, and can also be activated by drugs that modulate the insulin signaling pathway. The search for RNA-based molecules or drugs that could reactivate its function, to improve quality of life, slow aging, and extend survival, is the next step.”

The Klotho Gene

Discovered in 1997, early studies in mice showed that inducing overexpression could increase the animal’s life by about 30% and improve metabolic and physiological conditions; conversely, blocking Klotho in knockout mice led to muscle loss, thinner skin, adipose tissue buildup, reduced fertility, and cardiovascular problems. 

«Klotho is produced predominantly in the kidneys and circulates systemically — says Fabio Sallustio, Associate Professor at the University of Bari — it is expressed at the cell membrane but is then cleaved by proteases and enzymes to generate a soluble form, or alpha-klotho, where alpha denotes the soluble (serum) portion. It is also produced in the brain and by liver cells. With aging, even in humans, serum Klotho levels decline, while hormone catabolism increases and aging-related conditions such as sarcopenia and kidney disease arise, producing aging phenotypes including weakness and muscle shrinkage. However, some studies show that supplementing Klotho from outside can increase muscle size and robustness, promote muscle regeneration and mitochondrial function, and reduce fibrosis and oxidative stress. Exercise, for example, increases Klotho levels, though the exact mechanism is not yet fully understood. Klotho, in particular — continues Sallustio — prevents the protein FOXO3 (Forkhead Box O3) from being phosphorylated and thus degraded, allowing it to continue binding DNA and activating transcription of several anti-stress and anti-aging genes, including those related to autophagy, metabolism, and the cell cycle. Our recent studies have shown that in the kidney, the major producers of alpha-Klotho are renal stem cells.”