• A Research led by the University of Oviedo describes the nine keys to aging in our organism

    June 06, 2013

    The work, published in the prestigious journal ‘Cell' and led by Carlos López-Otín, defines for the first time all the molecular indicators of aging and relates this process to diseases like cancer. This research work may contribute to the identification of pharmacological targets which improve human health.

    Living longer, and being healthy, only depends on a few genes in some species. This was discovered, working on worms, three decades ago, and that was the beginning of the golden age of research on aging, which has provided lots of interesting results, but has also created some confusion. The prestigious journal Cell will publish next Thursday a thorough review in this regard, in order to "create a useful framework for future works". For the first time, all the molecular indicators of aging in mammals are defined, the nine matters that set the advance of the process. It is also explained which ones we can work on to prolong life; and it refutes some myths, like the thought that antioxidants slow aging.

    The authors are the Spanish researchers Carlos López-Otín (University of Oviedo); Maria Blasco (National Center for Oncological Research, CNIO); and Manuel Serrano (CNIO), with Linda Partridge ( Max Planck Institute for Biology of Aging) and Guido Kroemer (Descartes University of Paris). This work is modeled on a previous publication in Cell in 2000, The Hallmarks of Cancer, and it is a turning point concerning research on cancer.

    This research has refuted a few myths, like the belief that antioxidants rejuvenate, and it has also revealed that it is possible to delay aging of organs and tissues working on only one indicator.

    "The current situation of research on aging is very similar to that of cancer research a few decades ago.", it is stated in the resulting work, entitled The Hallmarks of Aging. According to López-Otín, "it was the right moment to present in an organized and understandable way, the molecular keys of a process that, despite the thousands of scientific articles published about it every year, it is not well understood yet". "In the field of aging it was obvious that there were more theories than experimental evidences", Blasco points out, and he adds: "This review is not about theories, but about molecular and genetic evidences".

    The connection of this work with cancer goes beyond a formal parallelism. This is because one of the main conclusions of The Hallmarks of Aging is that understanding and fighting aging imply fighting cancer and other diseases that mainly affect the developed world. The connection is clear: aging results from the accumulation of damage in the DNA throughout life, and that process is also what originates cancer, diabetes, cardiovascular diseases, and also neurodegenerative diseases like Alzheimer´s.

    "Aging is what causes diseases when we grow older", Blasco explains. "Identifying the molecular markers of aging helps us find the cause of other diseases, like cancer. This is highly relevant", he points out. This article states that "cancer and aging may share a common origin", and it explains that both may be understood as "two different manifestations of the same underlying process".

    "It is not about not having wrinkles"

    According to Serrano, this aspect removes the "frivolity" so often present when dealing with research on aging: "It is not about not having wrinkles or living a hundred years at any cost, but about prolonging life with no diseases". In Cell, researchers are explicit when stating their ultimate goal: contributing to "identify pharmacological targets that improve human health during the aging process".

    Another milestone of this work is that it not only defines the nine molecular indicators of aging, but it also arranges them as primary—the triggering cause—; those that make up the body´s response to those causes; and finally the resulting functional failures. Hierarchy is very important, because the effect obtained applying one process or another is different. Working on a single mechanism, in case it is primary, makes it possible to delay the aging of many organs and tissues.

    Four primary causes of aging

    There are four primary causes of aging: genomic instability; telomeres shortening; epigenetic alterations; proteostasis deficiency.

    Genomic instability deals with the mutations that are built up in genes over the years, due to intrinsic or extrinsic causes. The shortening of telomeres-segments that occur at the ends of chromosomes- is one of these mutations, although it is considered an independent hallmark due to its relevance. Epigenetic alterations result from vital experience –environmental exposure-.

    Proteostasis deficiency is related to the non-removal of defective proteins, that once gathered together, lead to pathologies related to aging- in Alzheimer´s disease for example, neurons die because of the formation of protein plates, that should have been removed-.

    The body´s responses to the triggering causes are mechanisms that try to remediate damage, but if they become chronic or worse, they may become harmful. In the case of cellular senescence: it induces the cell to stop dividing itself when many defects are brought together and therefore prevents cancer, but if this happens in excess, tissues and organism suffer aging.

    There are another two processes that are a double-edge sword, and are very present when discussing about aging theories: the so called oxidative damage, related to the popular free radicals; and mechanisms resulting from metabolism, related in turn to evidences –not yet confirmed in human beings – that prove that caloric restriction prolongs life.

    Everything suggests that reality is more complex than just taking antioxidants and stop eating to live longer. Large amounts of free radicals may be harmful, but they also trigger a protective response. As regards antioxidants, authors are conclusive: There is no genetic evidence that increasing antioxidant defenses delays aging. And, if it is true that deficiency of nutrients in our organism launches protective strategies- presumably, the reason why caloric restriction seems to be successful-, "over the time, and in excess, they may become pathological", they declare.

    The third group of indicators emerges when the damage caused by the two above cannot be compensated. This is the case of the depletion of tissue stem cells which cease their regenerative function; or mistakes in intercellular communication, which lead to inflammation –a process that when chronic, is related to cancer-.

    Strategies to stop aging

    One of the main challenges nowadays is to understand the connection among all the hallmarks. And of course, to develop research to find the way to control these processes. Authors review the therapeutic targets already identified, and suggest answers to stop aging.

    One of the therapeutic strategies already tested on mice, successfully, is to avoid telomere shortening. "This process may be slowed down, and even reversed on mice", Blasco says, expert in this field. She believes that, in general terms, "we still have lots of possibilities to fight aging and live longer in a healthy way".

    López-Otín is confident that "There are diverse opportunities to extend longevity in the relatively near future. Actions aimed at reducing or correcting genomic damage due to age are still distant, but those related to metabolic regulation systems are much more accessible". And he concludes: "We cannot aim to immortality, but to the possibility of having a better life for all of us".

    Reference article:
    The Hallmarks of Aging. Carlos López-Otín, Maria A. Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer. doi: 10.1016/j.cell.2013.05.039