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Currently, there is enormous scientific interest in understanding the aging process in order to slow it down or even avoid it. Large corporations are hiring leading researchers from around the world for significant sums of money to delve into this hot field of cellular rejuvenation.
It is a mission that can be compared to the space race, the human genome project, the fight against cancer, the study of the brain or artificial intelligence.
Inexorable destiny or curable disease?
Among the preventive proposals of the researchers are various actions at a nutritional level, calorie restriction , blood dilution (with transfusions of young people or serums) or microbiota transplantation .
At a therapeutic level, we find drugs to destroy senescent (aged) cells and antioxidant, hormonal or anti-inflammatory agents, among others. The dream of eternal youth is still valid, although the results, we anticipate, are not very satisfactory.
In the academic field, many think that aging is programmed (deterministic model), while others – such as the Australian biologist David Sinclair – believe that it is a disease. According to his theory, if we know the bases of aging well, we can alter it, delay it or even prevent it. And, perhaps, achieve immortality.
The truth is that in recent decades there has been a great increase in life expectancy. According to the World Health Organization , between 2015 and 2050 the population over 60 years of age will double: from 12 to 22%. But this also represents a challenge, since chronic diseases related to aging will increase at the same time.
The signature of aging
We are talking about a process influenced by many factors, especially age. As the years go by, a series of common characteristics appear in aging individuals.
In 2013, in an approach similar to that done with the characteristics of cancer, nine common features of aging were defined :
- Shortening of the ends of chromosomes (telomeres).
- Gene instability.
- Epigenetic alterations.
- cellular senescence.
- Loss of protein renewal (proteostasis).
- Appetite dysregulation.
- Dysfunction of the energy factories in the cell (mitochondria).
- Stem cell depletion.
- Defective intercellular communication.
In March 2022, several researchers proposed including five more features :
- Inflammation.
- Dysbiosis (alteration of balance) of the microbiome.
- Alteration of cell renewal and cleaning (autophagy)
- Alteration in the process of RNA joining or splicing ( splicing ) that prevents the correct expression of proteins.
- Alteration of cellular mechanical properties.
The researchers who had suggested the original nine signs updated them to a total of 12 in 2023 , incorporating inflammation, dysbiosis and alteration of cellular autophagy.
Ailing cells
Of these twelve distinctive signals, the concept of cellular senescence is key. It refers to the morphological and functional changes of aged cells. One of the most important is the cessation of cell division, but these decaying cells also increase in size, resist dying, express proteins associated with senescence and are metabolically active.
It is documented that senescent cells accumulate in aged tissues and participate in the decrease in muscle mass, frailty and other diseases associated with aging. On the other hand, they secrete growth factors and pro-inflammatory proteins – called cytokines . Both produce alterations in tissues that can lead to cancer.
Under normal conditions, these declining cells are recognized and eliminated by immune cells . But as we age, the immune system also deteriorates, and the consequences that this entails – greater number and severity of infections, more autoimmune diseases and cancer, worse response to vaccines… – must be added the accumulation of senescent cells in the body. .
Recently, a work in which the Spanish researcher Juan Carlos Izpisúa participated detected the reactivation of endogenous retroviruses (virus genetic material integrated into our DNA) during aging. According to his study, this “resurrection” generates particles capable of inducing senescence in young cells.
The good news is that the researchers showed that this process can be blocked with monoclonal antibodies , opening the door to possible therapeutic actions. In addition, diluting harmful particles in the blood would also help reduce cellular aging.
This is how senolytic drugs work
From a therapeutic point of view, there are various drugs whose objective is precisely to eliminate senescent cells . Called senolytics, they could delay or alleviate frailty, cancer and other diseases related to senescence. The following stand out:
- Quercetin . It is a natural flavonoid substance from plants present in products such as grapes, apples or tea leaves. Studies show promising results as an agent with antioxidant and anti-inflammatory properties, in combination with the drug dasatinib .
- Fisetina. This flavonol is located in different plants and trees, fruits such as strawberries, apples or grapes and tea leaves. It is a powerful activator of sirtuins, enzymes that regulate various cellular processes, as well as gene expression. Clinical trials are currently being conducted to confirm whether it slows aging and can help improve physical function, especially in cancer patients.
- Navitoclax . This antitumor agent is an inhibitor of BCL-2 , a protein that prevents cells from dying. Indicated to treat lymphomas, it also eliminates senescent cells.
- Dasatinib. It inhibits an activation pathway that affects senescent fat cell progenitor cells (adipocytes).
- UBX0101 . It is an inhibitor of a protein that acts on senescent synovial cells and could be used to treat osteoarthritis. It is being tested in clinical trials.
- Fenofibrate . Reduces triglycerides and cholesterol. It has been observed that it acts as a senolytic and promotes cell renewal in chondrocytes, the cells that make the structural components of cartilage.
Currently, many of them are being tested – alone or in combination – in clinical trials, although some tests have been completed because they did not achieve the expected results.
An arsenal of new drugs
There are also drugs that do not eliminate senescent cells, but rather modify their state. They highlight resveratrol, a polyphenol present especially in grapes; metformin, an antidiabetic drug; the monoclonal antibodies lutikizumab and cankinumab, which block the proinflammatory cytokine IL-1; the protein etanercept, which blocks another inflammatory cytokine, and inhibitors of proteins called JAK, whose effect is fundamentally anti-inflammatory.
Rapamycin – a substance obtained from the soil bacteria Streptomyces hygroscopicus – and its analogues deserve a separate chapter , which increase cell renewal and alter cellular metabolism by inhibiting the mTOR protein .
Experiments have revealed that such inhibition increases the half-life of yeast, flies, worms and mice. Furthermore, a recent review indicates that this compound improves parameters of the immune, vascular and skeletal systems in humans.
However, it is not without side effects: rapamacin increases cholesterol and triglyceride levels, as well as the risk of contracting infections .
Finally, “cocktails” are being tested such as the combination of the hormone dehydroepiandrosterone with metformin and growth hormone, which seems to regenerate , in part, the thymus (small organ where white blood cells known as T lymphocytes are differentiated). Other studies use nicotinamide precursors (a form of vitamin B3), antioxidants, senolytic drugs, vitamins, and anti-inflammatory drugs in different combinations.
Many of these promising drugs are being tested in people, so we will have to wait to see their beneficial effects, as well as analyzes of their possible toxicity and side effects. For now, there is no drug that can be recommended for human use until convincing results are shown in clinical trials.
Advances and challenges
Although there is still no consensus on the bases of aging, important advances are being made in understanding both this process and the one that produces the deterioration of the immune system, immunosenescence.
Regarding the research of new drugs and therapies, there is potential, but still few certainties. Another key will be to determine more accurately our biological age (there is no consensus among the biological clocks designed by various researchers) and also, why not, our immunological age. This will make it possible to act as soon as possible, to try to slow down the deterioration and improve the quality of life during the third (or fourth) age.
