Fight Aging!

Writing a succinct few page introduction to present scientific thought on the driving mechanisms of aging and the present landscape of development of means of treating aging seems quite the tall order. The field is complex, aging is complex, much is in flux and important updates to present understanding arrive every few years. Where to start, what to include, and what to leave out? Today's open access paper is, for its short length, a good attempt. It is important for those on the inside who have access to every last fine detail to be able to summarize at least the shape of the field to those on the outside. Knowledge is a set of concentric rings, from the laypeople at the outside to researchers at the cutting edge in the very center. The primary task of those in each ring, often neglected, is not to look inward and learn, but to look outward and explain well.

The authors of today's paper put forward their view on what we should take away from the data obtained to date on mechanisms of aging and their treatment, which is that the growing burden of cellular senescence in aged tissues plays a central, important role in degenerative aging. While numerous companies are developing forms of senolytic therapy to selectively destroy senescent cells, few have yet undertaken clinical trials. While novel approaches to clearing senescent cells or modulating their harmful behavior are discovered every year, the number of startup biotech and pharmaceutical companies focused on cellular senescence seems to have plateaued for now. This is a part of the field that, while well funded, could justifiably be funded to a much higher level than is presently the case. The mountain of animal data, that repeatedly, in scores of studies, demonstrates the capacity to rejuvenate tissues throughout the body and turn back the progression of age-related conditions, should be justification enough.

Biological mechanisms of ageing and potential therapeutic targets

Ageing is a natural and complex process that can be generally characterized by a slow and progressive physical and cognitive decline during adulthood, leading to impaired autonomic functioning and increased vulnerability to disease and death. It results from a series of biological changes that drive the accumulation of molecular and cellular damage over time, affecting cells, tissues, organs, and ultimately the entire organism. Thus, the classic view of ageing is linked to disease: one is the door that leads to the other, to the point that, socially, we associate both concepts and we see old people as sick and frail by default. Separating ageing from disease, and thus promote healthy ageing, is one of the biggest challenges of both science and the health systems.

Despite the growing insights into the biology of the ageing process, our current understanding on the complexity of multi-organ ageing and its dynamics is still limited. The first challenge is defining biological ageing itself. Currently, there is no consensus set of markers that can produce a list of organ-specific figures related to their actual biological age. Measurements of telomere length or epigenetic clocks are routinely used to estimate biological ageing, despite only covering one of the many facets of ageing. Moreover, although these are powerful tools to describe health associations in large populations, they are not designed for prediction of health at individual level, mostly due to their large variability. Thus, better makers of biological ageing are needed in order to have predictive tests with clinical impacts, and this will only come with a better understanding of the enormous complexity of the underlying molecular mechanisms of ageing.

Two major groups of theories to explain the mechanisms that lead to ageing have been proposed: the error-based and the program-based theories. The first consider ageing as a stochastic process caused by the accumulation of errors and damage in cells and tissues, both as a consequence of intracellular and external damages, as well as a less-effective system repair with time. This would include molecular processes like DNA damage, mitochondrial dysfunction, or telomere attrition. On the other hand, the program-based theories consider that individuals are partly genetically and developmentally quasi-programmed organisms and that healthy ageing would be the result of extending this programmed correctly functioning phase. As an example, there would be developmental pathways that keep working even past adulthood or mechanisms that are beneficial during the reproduction stage, like genes or certain hormones, that can be detrimental in the later stages.

There have been several attempts to classify the molecular mechanisms and biological processes associated with ageing. A landmark paper proposed 9 initial hallmarks of ageing, which were later expanded to 12, defined as factors that manifest with ageing and that, when aggravated or ameliorated experimentally, worsen or improve the ageing process. These hallmarks cover a wide variety of biological processes (from DNA damage to loss of stem cells or shortening of telomeres), but must of them seem to converge in what could be considered one of the most relevant hallmarks: the accumulation of senescent cells.

Most of the hallmarks related to stress (such as increased genomic instability, telomere shortening, metabolic changes, epigenetic changes, etc.) are potent inducers of senescence. In turn, senescence contributes essentially to other hallmarks, such as the alteration in intercellular communication or the depletion of stem cells. Moreover, the accumulation of senescent cells provides a clinically relevant target and is currently the hallmark that has more advanced therapeutic options in study. Although significant improvement of ageing phenotypes will undoubtedly require multimodal approaches, strategies to address the buildup of senescent cells in organs is likely to be the first pharmacological intervention to delay biological ageing that will be available to treat age-related diseases.