José Antonio Rodríguez Piedrabuena-- Why do we age?

Ageing is a factor mainly due to the dysregulation of the systems intended to prevent, repair and regenerate our body. Since the aim of a geroprotectant is to increase life expectancy, treatment should start before any chronic disease appears and delay the onset of age-related diseases.

The best anti-ageing methods

The Mediterranean diet, not smoking, getting plenty of sleep on time, a life in which we do not seek to stress or be stressed, having a personal improvement project, eliminating disorder and lack of discipline and thinking of others are key elements in delaying natural ageing. Feeding our brain with cultural stimuli, eliminating alcohol and tobacco, as well as exercising help to preserve our health.

Full-week daily exercise reduces neuroinflammation, increases mitochondrial function, improves proteostasis, rescues impaired neurogenesis and activates the immune system.

These methods should be supported by various senolytic substances that can delay ageing and reduce senescence, inflammation and mortality. These may include:

• Fisetina: A natural flavonoid found in many fruits and vegetables that prolongs life when eaten. It improves tissue homeostasis, reverses age-related tissue damage and prolongs life. Fisetin inhibits the activity of several pro-inflammatory cytokines and has no adverse side effects, and all clinical tests resulted in much longer survival. The treatments were accompanied by a decrease in the expression of senescence and SASP markers. In addition, treated patients showed improved antibody responses against coronavirus and partial rejuvenation of the immune system through elimination of senescent immune cells.
• Curcuminhydrophobic polyphenol found in the rhizome of turmeric. It has widely studied pharmacological activities such as anticancer, anti-inflammatory, antioxidant and antimicrobial (Maheshwari et al., 2006). Due to its polyphenolic nature, it has also been studied for its enormous therapeutic potential to delay ageing (Bielak-Zmijewska et al., 2019). It has also shown very promising results in cancer treatment, being able to inhibit the growth and proliferation of cancer cells in a variety of cancers, including breast cancer, pancreatic cancer, head and neck squamous cell carcinoma, prostate cancer, colorectal cancer, brain cancer and glioblastoma.

Its more than obvious anti-ageing capabilities are:

1. Improves the effectiveness of physical activity.
2. It maintains the diversity and viability of the microbiome. In this regard, the microbiota has the capacity to secrete an enzyme, b-glucuronidase, which through deglucuronidation improves its bioavailability.
3. It has anti-tumour activity, so it can reduce the progression of existing tumours.
4. Modulates the process of autophagy, which destroys senescent cells, and may prevent cellular senescence.
5. It inhibits the activity of proteins such as mTOR and NF-kB, which are considered to be pro-ageing proteins.
6. It has senolytic activity and therefore destroys senescent cells.
7. It has anti-inflammatory activity superior to many prescription drugs.

In addition, the study published in the journal Nature MedicineThe study also concludes that urolithin A, a metabolite produced by our intestinal flora from compounds found in pomegranates, is capable of boosting the renewal of mitochondria, the organelles responsible for generating energy in cells, thus preventing age-related muscle deterioration.

Mechanisms by which ageing occurs

Ageing is due to the loss of proteostasis, mechanisms used by the cell to maintain the protein population by eliminating misfolded or degraded proteins. It is a network of 1400 proteins. However, it can also be due to deregulation of nutrient-sensing systems, epigenetic alterations, mitochondrial dysfunction, stem cell depletion, altered intercellular communication. Such accumulation of cellular damage is the main cause of ageing.

Aberrant activation of oncogenes (genes that mutate and generate cancer), oxidative stress, solar ionising radiation or altered autophagy (the process by which the cell breaks down and destroys old, damaged or abnormal proteins and other substances in its cytoplasm - the liquid inside the cell - and the breakdown products are recycled for important cellular functions) create telomeric or non-telomeric DNA damage that alters chromatin structure.

In these situations, when the cellular repair mechanisms are overwhelmed due to the damage generated in the DNA, the cell enters the cellular senescence phase through the phosphorylation of a protein, p53, one of the main responsible for the permanent arrest of the cell cycle, which is the cause of cells entering senescence, although not the only one. (Kritsilis et al., 2018).

Senescence is a triggered cell fate, which results in transcription factor cascades that can cause extensive changes in gene expression, histone modifications and cell organelle function, elevated protein production and profound morphological and metabolic changes. The histones bind to DNA, help shape chromosomes and help control gene activity. A significant fraction of these senescent cells (SnC) release inflammatory factors, chemokines and growth factors, proteases, bioactive lipids, extracellular vesicles and procoagulant factors, producing a senescence-associated secretory phenotype or SASP. It acts as a chemoattractant that stimulates immune cell-mediated killing of senescent and neighbouring cells in healthy organisms. However, with advancing age and many chronic diseases, senescent cells accumulate in most tissues, presumably due to ineffective clearance by the immune system and resistance to their cell death. This accumulation leads to chronic sterile inflammation, which in turn leads to loss of resilience and predisposition to many diseases.

Also as we get older our gut flora is affected. So one way to slow physical and mental decline is to include foods for our gut bacteria such as prebiotics (found in foods like whole grains, bananas, vegetables, onions, garlic, artichokes, pistachios and garlic) and probiotics.

"Gut bacteria are capable of producing substances that regulate cardiovascular balance, so a heart-healthy diet ensures that we have a good gut microbiota," says DR. Julián Pérez Villacastin, Head of the Department of Cardiology, San Carlos Hospital

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