Because we get old? In the last ten years, this question has been answered with nine keys. But since yesterday there are twelve. A study led by the professor of Biochemistry and Molecular Biology at the University of Oviedo carlos lopez otín and the researcher at the University of Paris guido cromer has defined three new molecular and cellular processes that cause human aging. They are the alterations in autophagy, which is an efficient process of cellular and molecular recycling; chronic inflammation, which has significant consequences for the body; and dysbiosis, which is the loss of dialogue between the human genome and that of all the microorganisms that inhabit us. This finding, published in the American magazine «Cell», opens the door, according to Otín, to design intervention strategies on each of the mechanisms that influence old age, so that we can improve our quality of life and extend longevity.

The first nine keys to aging came to light in 2013 and that research, also directed by Carlos López Otín, became the most cited work in history in this scientific field. In this revolutionary study, nine factors were discussed that jointly contribute to our cellular and functional deterioration associated with the passage of time., and which are classified into three main categories: primary, antagonistic and integrative. The primary factors –the triggers of the process– are genomic instability, telomere shortening, epigenetic alterations and loss of proteostasis. The antagonistic factors –refer to the organism’s responses to reduce the damage produced by the primary factors, and which, if exacerbated or chronic, become harmful– are deregulation of nutritional sensors, cellular senescence and mitochondrial dysfunction. Finally, the integrating factors –the main ones responsible for aging– are the depletion of progenitor cell reserves and alterations in intercellular communication mechanisms.

Now a team coordinated by Otín and Kromer –and made up of manuel serrano (IRB, Barcelona), maria blasco (CNIO, Madrid) and cute partridge (Max Planck Institute, Cologne) – has just shown that there are three more processes involved in aging. Some, Otín explains to LA NUEVA ESPAÑA, have already known each other «for a long time». This is the case of alterations in autophagy and chronic inflammation, but it remained to be demonstrated. And that they have done. «In recent years, ‘in vivo’ experiments have been carried out, some in our own laboratory, which have demonstrated the direct and causal relevance of these phenomena in the functional deterioration of our organism during aging», he affirms.

The case of dysbiosis, explains the prestigious scientist, «is much more recent and transformative.» «We have gone from being unaware of the fundamental molecular details of the process to discovering the relevance of this pathological phenomenon in multiple aspects of health: from obesity, longevity and aging, to cancer and the response to chemotherapy. In a work by my then brilliant student and now renowned researcher Clea Barcena and other members of our laboratory, published in ‘Nature Medicine’ in 2019, already we show that longevity can be extended in animal models of normal and pathological aging through interventions in the microbiome. In addition, with the help of IPLA researchers, we defined the existence of prolongevity bacteria. This type of work is what has determined the ascending status of some of the key processes of aging». And, without a doubt, a note, more will appear. In fact, they already have «two or three on the waiting list».

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The ultimate goal of this research is to define specific intervention strategies for each of the twelve keys in the future. «To cite a few examples, genetic instability can begin to be addressed through new editing methods; epigenetic changes, through cellular reprogramming with Yamanaka factors; and dysbiosis, through nutrition and physical exercise appropriate or by supplementing with components of the microbiota that favor health”, says Otín.

The researcher from the University of Oviedo, who is temporarily staying in a laboratory in Paris, introduces in another recent study, published in the journal «Cell Metabolism» and again together with Kromer, the concept of metakeys in the field of biomedicine. «They are the determining processes common to two or more biological or pathological processes. In this case, the metakeys of aging and cancer were those molecular or cellular factors that are equivalent in these two complex processes, despite the general tendency to assume that both they are antagonistic in all their aspects,» he reflects. Scientists have identified four of these common mechanisms between old age and tumors: epigenetic alterations, chronic inflammation, and dysbiosis.

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