While aging is not yet considered a disease, there is no longer any doubt that attacking it can combat, delay or even prevent age-related illnesses, including cancer. The explosion of activity in the science of aging over the past decade has now generated nearly 80 experiments in mammals, including humans, confirming that prolonging healthy life is possible. An article published in Cell co-authored by Maria A. Blasco, scientific director of the CNIO, analyses how much progress has been made and outlines the next steps.

A decade ago, the relationship between the molecular causes of aging and various diseases was still an unexplored concept. At the time, a group of researchers published a study in Cell that reviewed the current state of knowledge on the subject. That paper served as a roadmap for the field and had a significant impact on the scientific community. The same authors have now updated their analysis with new insights and findings.

With the new review they aim to “provide an improved framework for the development of effective interventions aimed at the extension of healthy longevity,” they write.

“It will be important to intervene in human aging”

“Aging is not yet a recognized target for drug development or for treatment,” but the “spectacular progress” made in recent years to increase longevity in model organisms, including in mammals, indicates that “it will be important to develop rational strategies for intervening into human aging.”

Maria A. Blasco is a renowned expert in the study of telomeres, the structures that make up the ends of chromosomes. The shortening of telomeres has been identified as one of the primary causes of aging. The other authors are Carlos López-Otín (University of Oviedo), Manuel Serrano (IRB Barcelona), Linda Partridge (University College London, UK), and Guido Kroemer (Centre de Recherche des Cordeliers, France).

The 2013 paper summarized for the first time the molecular markers of aging in mammals. It was entitled The Hallmarks of Aging and was considered by Cell to be one of the most significant publications of the year. Since then, some 300,000 more papers have been published on the topic, “as many as during the previous century,” write Blasco and co-authors in the new study, entitled Hallmarks of aging: An expanding universe.

Four “primary causes” of aging

The recent advancements in scientific research have validated the findings of the 2013 analysis, reaffirming its correctness. In that paper, the researchers identified nine hallmarks of aging, molecular signatures that mark the progression of the aging process. They also indicated which ones can be acted upon to prolong life.

They pointed to four “primary causes of aging”: genomic instability, telomere shortening, epigenetic alterations, and the imbalance between protein synthesis and degradation. These indicators of aging are intricately interconnected processes, which collectively contribute to the overall aging of the organism. This is why there are multiple approaches that can be taken to target the aging process.

These findings “have withstood scrutiny by tens of thousands of aging researchers” over the past ten years, Blasco and her co-authors write in Cell. 

“Closer to applying basic knowledge to treat disease”

“What we put forward has been confirmed,” says Blasco, who says that in this area of research “there is now much more investment, and we are now closer to applying basic knowledge to new ways of treating diseases.”

In 2013, it had already been established that the excessive shortening of telomeres is a significant contributing factor in the development of age-related diseases. This new paper emphasizes that the “generation of mouse models with short telomeres has demonstrated that telomere attrition is at the origin of telomere syndromes and prevalent age-associated diseases, such as pulmonary and kidney fibrosis.”

The newly published paper reviews “novel interventions on aging and age-related pathologies” that act on telomeres. “As an example, telomerase activation using a gene therapy strategy has shown therapeutic effects on mouse models of pulmonary fibrosis and aplastic anemia.”

Aging and diet

A table in the new paper lists nearly 80 recent experimental interventions in mammals, mostly mice, in which life extension or the treatment of age-related diseases has been achieved. Some of these studies—those investigating how to delay aging through diet—involve humans.

“Diet is one of the most practical targets for interventions into human aging,” say the authors in Cell. They explain that this is because one of the key indicators of aging is the dysregulation of the nutrient-sensing mechanism, which is the sophisticated network of molecular signals that all mammals—and many other creatures—use to alert the organism that food is available.

“Nutrient sensors constitute targets for potential longevity drugs,” the authors write, “but health benefits and extended lifespan might also be achieved by dietary interventions.” However, the results obtained in this line of research for our species are still unclear: “In humans, clinical assays based on dietary restriction are complicated by poor compliance, yet suggest positive effects on immunity and inflammation.”

Nine to twelve markers of aging

For Blasco and the other co-authors, the markers of aging are measurable processes that change with the age of the organism and that, when experimentally manipulated, induce an acceleration or, conversely, an interruption—or even a regression—of the aging process.

In the new paper, the authors expand the hallmarks of aging from nine to twelve: genomic instability; telomere attrition; epigenetic alterations; loss of proteostasis; disabled macroautophagy; deregulated nutrient-sensing; mitochondrial dysfunction; cellular senescence; stem cell exhaustion; altered intercellular communication; chronic inflammation; and imbalances in the microbiome (dysbiosis).

“Each of the hallmarks should be considered as a point-of-entry for future exploration of the aging process, as well as for the development of new anti-aging medicines,” the researchers conclude.