The genes that influence our longevity

Prof. Jacques Proust

Nescens, Clinique de Genolier

March 21, 2022

There is no way to avoid ageing, not yet anyway. As we age, the progressive malfunction of our cells, organs, etc., leads to having a higher risk factor for diseases. Those diseases include cancer, neuro-degenerative problems, cardiovascular diseases, rheumatism, and more. The speed at which we age closely correlates with our genes alongside environmental and lifestyle factors. The average genetic component in determining life expectancy is around 25% and has been maintained as such throughout evolution. The ApoE gene is the first gene to be linked with longevity. Foxo and Clotho are also genes that influence our longevity by taking care of our bodies. 

If you want to learn more, keep on reading the article from Prof. Jacques Proust.

Ageing is an inevitable, progressive biological process that manifests itself through malfunction and eventual destruction of tissues and organs. The progressive malfunctioning of cells, organs, systems and the whole organism, is a high risk factor for age-related pathologies such as cancer, cardiovascular diseases, neuro-degenerative problems, rheumatism and inflammation. The appearance of these diseases, physical deterioration and the dwindling of reserve capacities, reduces our life expectancy.

The speed and intensity of the ageing process are closely correlated with genetic, environmental and lifestyle factors. Genetic antecedents, life history and risk factors make the difference in how some people resist better and longer the physiological degeneration that is typical of ageing. In a population with average life expectancy, the genetic component in determining life expectancy is 25%. This percentage increases with age to 33% for centenarian women and 48% for centenarian men. After more than 20 years of scientific research, it has been found that longevity is determined by genes and metabolic pathways that have been highly maintained throughout evolution. The same genes encoding the same metabolic pathways determine longevity in species as diverse as yeasts, worms, flies and mice.

Let’s take a closer look at some of these genes:

ApoE: the gene associated with unusual longevity

The ApoE gene (apolipoprotein E gene) is the very first gene known to link to high longevity, at least as far as its alleles are concerned. Alleles are variants of the gene, here the forms E2 and E3. E2 and E3 are found more frequently in the 100-year-olds, while the variant E4 is found more in connection with diseases typical of old age, such as cardiovascular disorders and Alzheimer’s disease, and is therefore associated with a higher mortality. Depending on the genotype present (E2, E3 or E4), the products of the ApoE gene in Positive or negative fundamental biological mechanisms at the root of the ageing process:

– Stabilisation and dissolution of lipoproteins (proteins that transport fats in the blood), partly responsible for regulating cholesterol levels

– Oxidative stress and production of free radicals (highly reactive oxidised molecules produced by our metabolism , partly responsible for molecular deterioration in old age).

– Activity and renewal of the mitochondria (power plants in the cells whose energy production decreases with time) – Rejection of damaged and unusable mitochondria (mitophagy)

– Rejection of damaged molecules (autophagy), the accumulation of which massively disrupts the function of the cell

– The immune function, the efficiency of which decreases with age

– Inflammations that overshoot the target and become harmful with age, phenomenon called “inflamm-aging”.

Foxo: the gene family of longevity

Recent research shows the important role of Foxo (Forkhead box O) genes in ageing and longevity, through the processes encoded in them. The invertebrate genome contains only one Foxo gene, while mammals have 4. The only foxo gene found in the hydra (freshwater polyp) is responsible for its (near) immortality: it ensures that its stem cells are constantly renewed. In the more complex organisms, the foxo genes have multiplied and fulfil various functions.

In mammals, this gene family directly or indirectly controls biochemical mechanisms that are necessary for the optimal functioning of the organism. The Foxo genes are particularly involved in:

– Repairing molecular damage and especially DNA

– Elimination and recycling of damaged molecules (autophagy)

– Protection from oxidative stress caused by free radicals

– Rejection of non-functional cells (apoptosis)

– Maintenance of stem cells

– Regulation of the immune system and inflammatory mechanisms

– Inhibition of cancer cell division.

Family Foxo’s maintenance and repair work defies the basic mechanisms underlying ageing.

Processes and strategic position on the intracellular biochemical metabolic pathways, make Foxo gene 3 the major player in the molecular mechanisms involved in high longevity. In humans, a link is found between certain Foxo gene 3 variants and longevity. 11 independent studies in populations of different genetic origins, in different countries, have confirmed this link. All that remains is to find out exactly which functions of this gene variant support resistance to ageing processes.

Clotho: the anti-ageing gene

Klotho is the name of one of the three Moirs of Greek mythology who determined everyone’s lifespan. Klotho stretched the thread of life, Lachesis measured it and Atropos cut it.

The gene Klotho, when spontaneously mutated, “loss of function”, leads to accelerated ageing in a certain type of mice. Mice with this mutation had growth retardation and physio-pathological changes normally attributed to the ageing process, such as vascular calcification, osteoporosis and various organic damages. Instead of the usual 2 years of life, these mice had a shorter life expectancy of 2 or 3 months.

Conversely, a Klotho gene enhanced by genetic engineering increases the life expectancy of the mouse. Like the Foxo genes, the Klotho gene has been highly conserved throughout evolution. The product of the Klotho gene (the Klotho protein) either binds to the cell membrane or exists in soluble form: the latter functions like a hormone and exerts its effect on various organs and systems from a distance. The concentration of Klotho protein in blood plasma decreases with advancing age. Deficient production of Klotho is associated with many diseases typical of old age, cancer, chronic kidney failure, diabetes, hypertension, skin atrophy.

How exactly Klotho acts against ageing is still being researched in many studies. However, it is known what Klotho is involved in:

– Control of inflammatory processes

– Inhibition of the production of free radicals (reactive oxidation products)

– Amelioration of the phenomenon of cellular ageing (definitive dormancy of cells and arrest of cell division)

– Preservation of the supply of stem cells that take care of cell division

– Interruption of the signalling pathways of the activators of ageing growth factors

As for Foxo, one establishes a link between the human ageing process and certain functional variants of the Klotho gene.

TOR, the genetic pathway to the ageing process

One of the main roles of TOR (Target of Rapamycin) is to adapt growth and cell metabolism to environmental conditions, especially nutrients and growth factors. When TOR is derailed, it is involved in cancer formation, diabetes, but also in the ageing process.

Among other biological effects, TOR activation:

– increases protein synthesis

– inhibits the autophagy process and the activity of the proteasome involved in the elimination and recycling of damaged molecules or molecules no longer needed by the cell

– decreases the renewal of certain stem cells

– affects the transcription of genes involved in protection against oxidative stress

Inhibition of TOR by rapamycin significantly increases lifespan in yeasts, worms, flies and, dose-dependently, in mice. Rapamycin is a molecule with immunosuppressive and anticancer properties that was discovered in the soil of Easter Island in the 1970s. The Easter Islands are also called Rapa Nui, hence the name.

The anti-ageing effect of TOR inhibition does not seem to depend on lower cancer rates or protein synthesis, but rather on maintaining the quality of intracellular proteins by activating autophagy mechanisms. As for stem cell maintenance, it is more attributable to protection from oxidising molecules than to any other anti-ageing activity.

Other genes regulating different players in the biochemical pathways, each with pro- and anti-ageing effects, (among them the sirtuins, AMP kinase, insulin-like growth factors) have been discovered in recent years.

Apart from the intellectual fascination with the advances made in recent years in understanding the fundamental mechanisms of ageing, there is also a greater interest in the possibility, through pharmacological or nutritional intervention, of modifying the activity of these genes and the biochemical pathways they encode. In the near future, these interventions could strengthen our resistance to ageing and contribute to the preservation of our health capital in old age.

Medical Director, Centre for Preventive Medicine, Nescens, Clinique de Genolier, 1272 Genolier

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