on October 14, 2026
Longevity is born from the meeting of genes and environment
For a long time, longevity was considered primarily an inherited trait. Today, research shows a much more complex picture: the genetic makeup contributes to an individual's ability to age, but the expression of genetic variability occurs within a given environment and responds to metabolic, nutritional, and behavioral conditions.
The study of centenarians represents, precisely for this reason, a kind of natural laboratory. These people have lived through an exceptionally long lifespan while maintaining, in many cases, good organ function. Their genetic makeup can therefore help identify biological systems capable of protecting against the accumulation of age-related damage.
The analyzed research material highlights some particularly interesting protagonists: MYTHO, involved in cellular autophagy systems and muscle quality; Klotho, a protein associated with the regulation of aging, muscle function, and cognitive abilities; the LAV-BPIFB4 variant, associated with longevity and lower systemic inflammation; and finally the systems that maintain the efficiency of the mitochondrial network.
The central point that emerges is, however, even more important: genetics does not act in isolation. Physical activity, diet, environment, and metabolic state can profoundly change how the biological systems associated with longevity function.
MYTHO: the cellular cleaning system as a possible regulator of longevity
Among the most interesting discoveries reported in the material emerges MYTHO, identified as a gene that is highly conserved throughout evolution and associated with the regulation of the autophagic system.
The protein is present in several tissues, with a particular expression in muscle and brain. Experiments conducted in worms have shown that its inhibition, whether partial or complete, results in a marked reduction in survival accompanied by a deterioration in quality of life, measured by the ability to move.
The data is particularly significant because it links longevity not only to lifespan, but also to its functional quality.
In mammalian cells, the inhibition of MYTHO has been associated with an increase in senescence markers, including P21, a reduction in autophagy, and the accumulation of damaged cellular components. These phenomena are accompanied by bioenergetic alterations, an increase in reactive oxygen species, and oxidative stress.
Autophagy is, in fact, one of the main systems through which the cell eliminates components that are no longer functional. Damaged proteins and altered organelles can be recognized, sequestered, and degraded through a complex network of intracellular processes.
When this system loses efficiency, cellular damage can progressively accumulate.
Movement and metabolism can influence MYTHO
One of the most interesting aspects is the relationship between MYTHO and lifestyle.
The material highlights how sedentary behavior can reduce its activity, accompanied by a deterioration in bioenergetics and mitochondrial function, as well as pro-inflammatory phenomena and greater cellular damage. Conversely, regular physical activity and calorie restriction are associated with its activation.
These data suggest an important perspective: some genes associated with longevity may not simply be “turned on” or “turned off” independently, but may represent biological sensors of the environment and metabolic state.
Research is also evaluating the possibility of pharmacologically modulating, or using RNA molecules to modulate, the systems regulated by MYTHO. However, this perspective remains experimental and does not currently equate to an anti-aging therapy available to humans.
Klotho: a protein linked to muscles, metabolism, and brain
A second protagonist of longevity research is Klotho, identified at the end of the 1990s.
Experimental studies have shown that increasing Klotho expression in animal models can be associated with a longer lifespan and an improvement in several metabolic and physiological parameters. Conversely, its loss results in alterations including reduced muscle mass, skin changes, adipose tissue accumulation, reproductive alterations, and cardiovascular complications.
Klotho is produced mainly in the kidneys and can be present in the circulation in a soluble form, called alpha-Klotho. The protein is also expressed in other tissues, including the brain and liver.
In humans, circulating levels of Klotho tend to decrease with age. This data has fueled the hypothesis that the reduction of Klotho may contribute to some aspects of biological aging.
One of the proposed mechanisms involves FOXO3, a transcription factor involved in the cellular response to stress. Preserving FOXO3 activity can promote the expression of genes involved in protection against stress, autophagy, metabolism, and the regulation of the cell cycle.
Klotho and cognitive function
Interest in Klotho does not only concern muscle.
A study published in Nature Aging in 2023 evaluated the effect of administering Klotho to aged rhesus macaques. A single low-dose administration improved performance in spatial memory and working memory tasks; the effect was also observed in the following weeks. The study involved 18 aged macaques and does not constitute, naturally, a clinical trial in humans.
The result is nevertheless relevant because it represents an intermediate step between rodent research and a possible future human application. The same researchers emphasize that further studies are needed to determine whether the system can be translated into a therapy intended for humans.
The starting material also recalls the hypothesis that Klotho may modulate platelet factors, including PF4, contributing to the observed effects on cognitive function.
It is therefore important not to confuse promising preclinical evidence with proven therapeutic efficacy.
LAV-BPIFB4: when genetics seem to favor resilience
Another line of research concerns BPIFB4, a gene within which a variant associated with longevity has been identified, called LAV-BPIFB4 (Longevity Associated Variant).
The variant was identified by studying very old people and was subsequently observed in other independent long-lived populations. When present in two copies, the variant determines different functional characteristics compared to the more common form of the protein.
The described association concerns greater healthy longevity, lower levels of systemic inflammation, and a lower risk of certain cardiovascular complications.
The possible biological meaning of LAV-BPIFB4 fits into the framework of inflammaging, that is, the state of low-grade chronic inflammation that tends to accompany aging.
As the years pass, the persistent increase in pro-inflammatory mediators can contribute to the progression of cardiovascular, metabolic, and neurodegenerative alterations, also affecting the intestinal ecosystem.
Experimental studies have suggested protective properties of the variant in models of atherosclerosis, vascular aging, neurodegenerative diseases, intestinal alterations, and complications associated with diabetes or heart attack. However, these are primarily cellular and animal evidence, not yet the demonstration of an effective anti-aging treatment in humans.
Centenarians show that the gene must be read in its environment
One of the most interesting messages from genetic research on centenarians is precisely the downsizing of the idea of absolute genetic determinism.
The study of centenarians' genomes has allowed the identification of numerous variants potentially associated with longevity. However, their interpretation changes radically when the environment in which these people lived is considered.
One example concerns FTO, a gene known for its association with obesity risk. In the centenarians studied, the frequency of certain risk-associated alleles was similar to that observed in obese people. This does not mean that the gene is unimportant, but highlights that its effect depends on the environmental and behavioral context in which it manifests.
The centenarians analyzed had, in fact, spent much of their lives in a very different environment from the current one, with less exposure to conditions now defined as obesogenic.
This observation leads to a fundamental principle of the biology of aging:
a gene does not express its potential in a biologically neutral space, but within an environment.
Diet, movement, metabolism, environmental exposure, and social conditions can therefore modify the way genetic variants translate into health or disease phenotypes.
COA1, STK17A and the protection of cellular integrity
The genomic analysis of centenarians has also identified signals of interest in a region of chromosome 7 between COA1 and STK17A.
COA1 is linked to mitochondrial function and therefore to cellular bioenergetics, while STK17A is involved in DNA repair processes. These are two biological systems particularly relevant in aging because the progressive loss of energy efficiency and the accumulation of genomic damage represent fundamental characteristics of aging.
Another finding concerns clonal hematopoiesis, that is, the accumulation of genetic alterations in blood cells. In the centenarians analyzed, this phenomenon was lower than in controls, suggesting a greater ability to preserve genomic integrity throughout life.
The interest in this result increases considering that clonal hematopoiesis has been associated with an increased cardiovascular risk. The study of these processes therefore allows us to connect longevity genetics, the maintenance of cellular integrity, and cardiovascular health.
Mitochondria: the powerhouses of healthy aging
Longevity cannot be studied separately from bioenergetics.
Muscle represents one of the tissues in which the effect of physical activity on mitochondrial function appears particularly evident. In the analyzed material, studies conducted on young people subjected to immobilization showed a rapid reduction in proteins important for the structure and organization of the mitochondrial network, including OPA1, MFN1 and MFN2. The same systems were also compromised in frail and sarcopenic elderly people, while they tended to be better preserved in elderly people with good muscle mass and functionality.
The data suggests that muscle is not simply an executive tissue of movement, but a true metabolic organ sensitive to physical activity.
When the mitochondrial network is well organized, mitochondria can interact forming a dynamic and functional structure. With inactivity, this network tends to fragment, with a consequent reduction in energy production and an increase in oxidative stress.
OPA1 and the link between muscle, inflammation and systemic aging
The relevance of the mitochondrial network becomes even more evident in experiments conducted in animal models in which OPA1 was specifically inhibited in skeletal muscle.
After a few months, characteristics compatible with an accelerated aging phenotype appeared: reduction in muscle mass and strength, bone alterations, and an increase in systemic inflammation.
In the blood, mediators such as IL-6, IL-1β and TNF-α increased in particular, with levels reported as many times higher than controls.
This result suggests a biologically important concept: muscle mitochondrial health can have consequences that go far beyond the muscle itself.
Muscle tissue can, in fact, influence the organism through metabolic and inflammatory mediators. Chronic muscle dysfunction could therefore contribute to a systemic condition characterized by greater inflammation and lower regenerative capacity.
Subsequent experiments have also suggested that the modulation of IL-6 at the muscle level can attenuate some of these systemic phenomena, with an improvement in aging markers in several tissues.
Physical activity as a modulator of longevity systems
Considering MYTHO, Klotho, mitochondria, and inflammation together, a coherent picture emerges.
Physical activity does not act only by increasing energy expenditure. It represents a biological stimulus capable of modifying the expression and function of numerous cellular systems.
In the analyzed material, exercise is associated with better preservation of the mitochondrial network, greater activity of systems linked to longevity, and higher levels of Klotho.
Sedentary lifestyle, on the contrary, is associated with the loss of bioenergetic efficiency, mitochondrial fragmentation, increased oxidative stress, and the progressive loss of muscle functionality.
This relationship is particularly important in old age because the loss of muscle mass and function, that is, sarcopenia, can trigger a vicious cycle: less movement means less muscle stimulus; less stimulus means worse mitochondrial function; mitochondrial dysfunction promotes oxidative stress and inflammation; these processes can in turn accelerate the loss of function.
From longevity genetics to preventive medicine
Research on centenarians is therefore not simply looking for “the gene of immortality”.
The most interesting goal is to understand which biological systems allow some people to maintain the integrity of the organism for longer.
MYTHO recalls the importance of autophagy and the removal of damaged cellular components. Klotho links kidney function, metabolism, muscle, and brain. LAV-BPIFB4 opens a perspective on the relationship between genetics, inflammation, and cardiovascular protection. COA1 and STK17A instead recall the need to maintain efficient mitochondria and DNA repair systems.
These mechanisms converge on some great biological processes of aging:
autophagy, proteostasis, energy metabolism, mitochondrial function, genomic integrity, inflammation control, and maintenance of muscle mass.
Genetics can therefore confer a favorable predisposition, but the final result depends on the continuous dialogue between genetic heritage and environment.
This is precisely the most relevant message emerging from the study of centenarians: longevity is not only a question of how long we live, but of how long we manage to preserve the efficiency of the systems that keep the organism young and resilient.
The future of longevity research
The therapeutic prospects related to MYTHO, Klotho, and LAV-BPIFB4 are fascinating, but must be interpreted with rigor.
For MYTHO, research is still predominantly preclinical. For Klotho, there are interesting results in animal models, including non-human primates, but these do not equate to a demonstration of clinical efficacy in humans. The study on macaques, for example, showed cognitive improvement after a single low-dose administration, but the same results indicate the need for further research before any therapeutic application in humans.
Similarly, for LAV-BPIFB4, the transition from the genetic variant associated with longevity to a protein-based therapy requires controlled clinical trials to establish its efficacy, safety, dosage, and possible long-term effects.
The most concrete field today remains that of lifestyles capable of supporting the physiological systems of longevity.
Regular physical activity, maintenance of muscle mass and function, adequate nutrition, prevention of metabolic and cardiovascular risk factors, and reduction of sedentary behavior represent interventions that are much less futuristic, but biologically consistent with the mechanisms highlighted by research.
The genetics of centenarians therefore teach a lesson that goes beyond the concept of the “longevity gene”: genes can predispose, but the environment and lifestyle contribute to determining how that predisposition is expressed.
Bibliography
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