Hallmarks of aging

Hallmarks of aging are something we reference a lot – and with good reason. Here’s what we’re on about…

An increasing number of studies suggest the presence of a “metabolic clock” that controls aging. This clock involves the accumulation of metabolic alterations and a decline in metabolic homeostasis and biological fitness. The key to tackling aging and promoting longevity lies in targeting the underlying age mechanisms.

The Hallmarks of Aging is a way of categorising these underlying age mechanisms; a set of biological processes that are thought to contribute to the overall process of aging, the hallmarks were first proposed in 2013, and they have since become a widely-accepted framework for understanding the molecular basis of aging.

A brief history of hallmarks

In Time to Talk SENS: Critiquing the Immutability of Human Aging (published in the Annals of the New York Academy of Sciences in 2002), de Grey et al not only discussed strategies to engineer negligible senescence (SENS), but categorised nine major molecular and cellular changes associated with aging [1].

By 2004, this had been streamlined to seven, and as Dr de Grey puts it, this way of categorising the accumulation of molecular or cellular side effects of metabolism that were thought to contribute to age-related mammalian physical or cognitive decline had become “an established school of thought within contemporary biogerontology [2].”

Then in 2013, López-Otı́n et al published the first edition of the Hallmarks of Aging, proposing nine hallmarks that represent common denominators of aging in different organisms [3].

Researchers and the wider longevity space were quick to integrate the language of the hallmarks into their discussions and papers. Since then, a decade of research has endorsed the importance of identified hallmarks in the aging process. However, new aging mechanisms discovered demanded both the extension of existing hallmarks and the addition of three hallmarks [4].

All about hallmarks

The hallmarks of aging are determined mainly by our genetics, but environmental factors can cause or exacerbate them also. Each hallmark contributes to the damage that occurs and accumulates with age and is ultimately responsible for age-associated pathologies. The hallmarks of aging determine the difference between chronological age (how many years since you were born) and biological age (how the aging process has affected your body’s physical and mental functions and appearance, in short, a time-dependent decline).

The nine cellular hallmarks of aging originally put forward were: telomere attrition, genomic instability, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, loss of proteostasis, deregulated nutrient sensing, epigenetic alterations, and altered intercellular communication [3]. Metabolic alterations have been implicated in each of these processes [4].

 A decade of research accumulated enough insight to identify three additional hallmarks bringing the total to twelve [5]. The new hallmarks are: disabled macroautophagy, chronic inflammation, and dysbiosis.

But not all hallmarks are created equal

The authors of the 2013 update suggested a hierarchy among the twelve hallmarks of aging; the primary hallmarks (the result of the accumulation of genome, telomeres, epigenome, proteome, and organelles damage) are followed by the antagonistic hallmarks (responses to damage), then the integrative hallmarks (stem cell exhaustion, intercellular communication alterations, chronic inflammation and dysbiosis as a result of unrepaired damage).

And while hallmarks of aging are super-useful for understanding the mechanisms of aging, aging, aging itself has yet to be recognised as a target for drug development or treatment (although the work of Nir Barzilai and the TAME trial could change that).

Understanding the molecular basis of aging and the role of these twelve hallmarks is important for the development of therapies to promote healthy aging and extend lifespan. Research into interventions that target these hallmarks, such as calorie restriction and certain dietary interventions, is an active area of investigation.

Extra reading!

[1] https://pubmed.ncbi.nlm.nih.gov/11976218/
[2] https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0020187
[3] https://www.cell.com/cell/fulltext/S0092-8674(13)00645-4
[4] https://www.cell.com/cell/pdf/S0092-8674(16)30981-3.pdf
[5] https://pubmed.ncbi.nlm.nih.gov/36599349/

Hallmarks of aging graphic courtesy of Carlos Lopez-Otin, et al., “The Hallmarks of Aging”, Cell 153, 2013 28