on September 22, 2026
Beyond Genetic Determinism
For a long time, aging was interpreted primarily through the paradigm of genetic determinism: the DNA sequence appeared to represent a kind of biological program capable of rigidly defining traits, pathological predispositions, and lifespan.
Contemporary research has made this model much more complex.
The DNA sequence constitutes a fundamental component of biological identity, but gene activity is regulated by numerous molecular mechanisms that also respond to the environment and physiological conditions. These include DNA methylation, histone modifications, chromatin structure, and the action of non-coding RNAs.
These processes constitute part of epigenetic regulation.
Epigenetics does not necessarily modify the DNA sequence: rather, it modifies how genetic information is made accessible and utilized by cells.
This helps explain why cells with the same genetic makeup can have profoundly different functions and why the biological environment can influence gene expression throughout life.
The most important consequence is that genetics and epigenetics do not represent two opposing systems. The former provides a fundamental part of the biological architecture; the latter helps regulate its use in relation to the cellular state and the stimuli received.
The 12 Hallmarks of Aging
Current aging research uses the Hallmarks of Aging model as a conceptual framework to organize the main biological mechanisms involved.
The updated version includes 12 hallmarks:
- genomic instability;
- telomere shortening;
- epigenetic alterations;
- loss of proteostasis;
- impaired macroautophagy;
- altered nutrient sensing;
- mitochondrial dysfunction;
- cellular senescence;
- stem cell exhaustion;
- altered intercellular communication;
- chronic inflammation;
- dysbiosis.
However, these processes should not be considered independent compartments.
On the contrary, they are strongly interconnected. Mitochondrial dysfunction can increase cellular stress; inflammation can promote senescence; epigenetic alterations can modify the expression of genes involved in metabolism and stress response; dysbiosis can influence metabolism and immunity.
The hallmarks model is therefore above all a biological map of aging, not an individual diagnostic test.
This distinction is also essential from the perspective of precision medicine: not everyone presents the same biological processes with the same intensity, and there is currently no single universal profile of "correct aging". The literature itself emphasizes that the hallmarks constitute an integrative conceptual framework, while the causal relationships between the different processes remain a subject of research.
The Epigenome: the Meeting Point Between Genes and the Environment
The epigenome can be imagined as a regulatory system that helps determine which genetic programs are activated or repressed in a given cell.
During aging, this system undergoes modifications.
Among the studied phenomena are changes in DNA methylation patterns, alterations in histone modifications, and changes in chromatin structure. These changes can influence fundamental cellular processes, including metabolism, stress response, DNA repair, and inflammation.
A particularly interesting aspect is represented by epigenetic clocks, mathematical tools that use specific DNA methylation patterns to estimate a form of biological age.
However, it is important not to confuse an epigenetic clock with an absolute measure of the biological age of the entire organism.
Epigenetic clocks are extremely interesting research biomarkers, but their individual clinical interpretation, their ability to predict future events, and the meaning of variations induced by specific interventions are still under study.
Can Lifestyle Influence the Epigenome?
One of the most interesting questions in contemporary research is whether daily habits can modify the epigenetic processes associated with aging.
Biological evidence indicates that physical activity, diet, metabolism, sleep, and other environmental factors can be associated with epigenetic modifications.
Physical exercise represents one of the most studied examples.
A recent review synthesized the evidence that physical activity can modulate DNA methylation, histone modifications, and non-coding RNAs, influencing processes associated with cellular homeostasis and aging. However, the epigenetic response depends on the type, intensity, and duration of the exercise, as well as the tissue considered.
This means that it is not scientifically correct to state that "exercise rejuvenates DNA".
It is more appropriate to say that exercise constitutes a biological stimulus capable of modifying numerous molecular pathways, some of which involve epigenetic regulation.
Inflammaging: When Inflammation Becomes Chronic
Among the most important processes associated with aging is inflammaging, a term used to describe a state of chronic systemic inflammation, generally low-grade, associated with age.
It is not acute inflammation that appears in response to an infection or injury.
Inflammaging is more subtle and persistent and can be fueled by multiple factors: the accumulation of senescent cells, immune alterations, mitochondrial dysfunction, metabolic changes, intestinal permeability, visceral adiposity, and changes in the microbiota.
Chronic inflammation, in turn, can interfere with numerous physiological processes.
Thus, a network of interactions is created in which different hallmarks reinforce each other.
This is one of the reasons why aging cannot be addressed through a single biomarker or a single intervention.
Muscle as an Endocrine Organ
Physical activity is of particular interest because skeletal muscle is not simply an apparatus dedicated to locomotion.
During exercise, muscle produces and releases signaling molecules, including myokines, which can exert autocrine, paracrine, and endocrine effects.
The broader concept of exerkines, on the other hand, includes a set of molecules released or modulated by exercise from various tissues, including muscle, liver, adipose tissue, and other biological compartments.
These molecules participate in communication between organs and can influence metabolism, inflammation, cardiovascular function, and the nervous system.
Research on exerkines is particularly interesting for geroscience because it suggests that exercise can act as a systemic stimulus and not simply as muscle training.
However, many of the biological relationships identified still stem from experimental and observational studies. The translation of these mechanisms into specific clinical prescriptions therefore requires further studies in humans.
The Importance of Chronobiology
The timing at which a biological stimulus is applied can also influence its effects.
The organism is regulated by circadian rhythms involving metabolism, hormone secretion, body temperature, sleep-wakefulness, and response to physical activity.
This has led to the development of exercise chronobiology, a field of research that studies the possible interaction between the circadian clock, physical activity, and metabolism.
However, it is necessary to avoid turning experimental results into universal rules.
There is, in fact, no exercise timing prescription valid for all people with diabetes, obesity, or other metabolic conditions.
The response depends on the individual, pharmacological treatment, type of exercise, diet, sleep-wake rhythm, and individual metabolic profile.
Personalization is therefore more important than searching for a "perfect time".
The Microbiota: An Ecosystem, Not a Snapshot
The intestinal microbiota represents another meeting point between the environment, metabolism, immunity, and aging.
The composition of the microbial community is dynamic and is influenced by diet, medications, physical activity, the environment, age, and numerous other factors.
Dysbiosis was included among the 12 hallmarks of aging precisely because alterations in the microbiota can interact with metabolism, immunity, and inflammation.
But this does not mean that a "perfect" microbiota exists.
The great interindividual variability makes it extremely difficult to define a single optimal microbial composition valid for everyone.
It is therefore necessary to distinguish between the growing evidence on the biological role of the microbiota and the numerous commercial proposals that attribute generalized effects on longevity to individual microorganisms or supplements.
Current research rather suggests considering the microbiota as a dynamic ecosystem, whose functionality must be interpreted in the context of the entire organism.
Genetics, Epigenetics, and Precision Medicine
Overcoming genetic determinism does not mean that genes are irrelevant.
On the contrary, genetics remains fundamental to understanding individual predispositions, hereditary diseases, and response to numerous environmental and pharmacological factors.
The point is different: the presence of a genetic variant does not automatically equate to the development of a disease.
Biological risk emerges from the interaction between genetic makeup, the epigenome, the environment, behavior, and other factors.
This is one of the conceptual foundations of precision medicine.
The same genetic information can have different meanings in people with different clinical histories, environmental exposures, and metabolic conditions.
For this reason, a genetic result must be interpreted within the clinical context.
The Limitation of "Do-It-Yourself" Genetic Tests
The increasing availability of commercial genetic tests has made genomic information easily accessible to the public.
This can have positive aspects, but also presents significant challenges.
An isolated genetic result does not necessarily constitute clinically useful information.
To interpret it correctly, personal and family medical history, phenotype, relevant laboratory tests, assessment of risk factors, and, when indicated, genetic counseling may be required.
Predictive medicine, therefore, does not consist in collecting as much genetic data as possible.
It consists in identifying which information is actually clinically useful for that specific person.
This principle is particularly important when a result could change behaviors, generate anxiety, or influence the taking or discontinuation of medications.
A genetic test should therefore not be interpreted as a biological verdict, but as a possible source of information that must be contextualized.
Healthspan: living longer or living better?
Aging research is progressively shifting focus from mere lifespan to healthspan, that is, the years lived maintaining good functional capacity and a satisfactory state of health.
The WHO defines healthy aging as the process of developing and maintaining the functional capacity that enables well-being in later life. This capacity includes, among other aspects, mobility, autonomy, the ability to learn and make decisions, relationships, and social participation.
The topic is particularly relevant in Italy as well.
According to Istat, in 2024 life expectancy at birth was 83.4 years, while healthy life expectancy at birth was estimated at 58.1 years.
These data do not mean that after 58 a person necessarily lives in poor health. Healthy life expectancy is a population indicator constructed according to specific methodologies.
The data does, however, show a central issue: extending life and extending healthy life are related but not equivalent goals.
From epigenetics to personalized prevention
The great prospect opened by epigenetics does not consist in the promise of being able to completely control aging.
Its value is rather that of having helped demonstrate how complex and dynamic the interaction between genetic heritage and the environment is.
Diet, movement, sleep, stress, environmental exposures, and metabolic conditions can influence numerous biological pathways. The final effect, however, depends on the individual context and the interaction between multiple systems.
For this reason, aging prevention cannot be reduced to a single genetic test, an epigenetic biomarker, or a supplement.
It is necessary to simultaneously consider metabolism, body composition, functional capacity, physical activity, diet, sleep, cardiovascular health, mental health, microbiota, environmental factors, and medical history.
The hallmarks model helps to understand this complexity, while epigenetics shows how sensitive the biological system is to environmental stimuli.
The challenge of contemporary medicine is to transform this knowledge into truly useful, measurable, and personalized interventions.
Longevity, in this perspective, is not simply a matter of how many years we can live.
It is the ability to preserve biological function, autonomy, and quality of life for as long as possible, by intervening on modifiable factors without turning the science of aging into a commercial promise of eternal youth.
Essential bibliographic references
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of Aging: An Expanding Universe. Cell. 2023;186(2):243-278.
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of Aging: An Expanding Universe. The updated model identifies 12 interconnected biological processes of aging.
- Hallmarks of Aging: Causes and Consequences. Critical review of the model and the causal relationships between the processes of aging.
- The hallmarks of aging as a conceptual framework for health and longevity research. Review of the utility of the hallmarks as a conceptual framework for longevity research.
- Exercise-Induced Epigenetic Modifications: Implications for Healthy Aging. Review of the mechanisms through which exercise can modulate DNA methylation, histone modifications, and non-coding RNA.
- World Health Organization. Healthy ageing and functional ability. Definition of healthy aging and functional capacity.
- Istat. SDGs Report 2025 – Statistical information for the 2030 Agenda in Italy. 2024 data on life expectancy and healthy life expectancy.
