A decade of research expands the Hallmarks of Aging from nine to twelve

Aging by the dozen: twelve hallmarks of aging provide comprehensive framework that will be key in the understanding – and delaying – aging.

In 2000, a landmark paper in Cell described the six biological capabilities acquired during the development of cancer tumours in humans – The Hallmarks of Cancer (the six were later expanded to eight capabilities and two enabling capabilities); the idea for identifying discrete biological mechanisms as hallmarks had firmly taken root.

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 discuss strategies to engineer negligible senescence (SENS), but categorise 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, “tentatively” proposing nine hallmarks that represent common denominators of aging in different organisms [3].

The tentativeness was unnecessary, as de Grey et al had laid the groundwork, and 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].

Longevity.Technology: Longevity research moves quickly with new genetic pathways and biochemical processes discovered, explored and therapeutically leveraged. Therefore, extension and improvement of the hallmarks of aging are invaluable for the development of aging research – a longevity work in progress, if you will – and now twelve is the new nine. Categorising aging mechanisms as hallmarks guides researchers in the design of research, and the hallmarks are an excellent starting point for developing longevity interventions, including prevention, diagnostics, treatment and renewal

The originally-proposed nine hallmarks of aging are DNA instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. A decade of research accumulated enough insight and to identify three additional hallmarks: disabled macroautophagy, chronic inflammation, and dysbiosis.

In the previous version, disabled macroautophagy was evaluated in the hallmark loss of proteostasis. Now, disabled macroautophagy is presented as a separate hallmark because macroautophagy attacks non-proteinaceous macromolecules (including lipid vesicles and glycogen) and organelles (such as dysfunctional mitochondria) besides proteins. 

Autophagy declines with age, resulting in intracellular and extracellular waste, including accumulation of dysfunctional organelles, misfolded proteins, reduced pathogen elimination and elevated inflammation. 

Enhanced autophagic activity may increase longevity. The pro-autophagic metabolite spermidine was given to mice as oral supplements, with the result that autophagy increased in multiple organs and mice longevity increased by up to 25% [5], in addition to decreased cardiac aging. Clinical studies have also shown positive impacts of autophagy induced by pharmacological agents such as NAD+ precursors and urolithin A [6,7].

Two other additional hallmarks – chronic inflammation and age-associated dysbiosis – are separated from altered intercellular communication with respect to their specific and significant role in the aging process.

Inflammation increases as people age. Intervention targeting the inflammatory and immune systems has the power to slow down or speed up the aging process. Anti-inflammatory treatments have been shown to improve cognition, motor performance, glucose tolerance and metabolic biomarkers in animal models [8].

Gut microbiota have an important role in health and longevity. Dysbiosis has been shown to contribute to diseases including obesity, type 2 diabetes, cardiovascular diseases, ulcerative colitis, and neurological disorders [9]. 

Microbiota composition varies person by person due to genetics, lifestyle habits and dietary and environmental factors, making evaluating the interaction between microbiota, disease and aging challenging. Studies on humans showed that microbiota changes with aging and a rise in particular bacteria (Alistipes putredinis and Odoribacter splanchnic) had been seen in the gut microbiota of centenarians [10].

Is ‘‘inevitably arbitrary’’ categorisation of the aging mechanism helpful or constraining?

A study by Fraser et al [11] showed that age-related diseases are likely to co-occur if they are associated with the same hallmark, proving the efficacy of hallmarks proposed by López-Otı́n et al.

Aging diseases result from damage accumulation and programming of genetics, environment, and lifestyle. Identifying molecular, cellular and systemic mechanisms underlying aging is key to developing therapeutic strategies to slow or reverse age-related diseases and aging itself. 

Categorisation of aging mechanisms as hallmarks of aging gives a framework to researchers to better break down, evaluate, define, and alternate the aging process. The authors indicated that hallmarks of aging are not disconnected; in fact, they interact with one another. 

This has led the authors to describe aging as a “multiplex” of twelve hallmarks – all hallmarks are interdependent, therefore experimental alteration of one usually affects others. 

But not all hallmarks are created equal.

The authors 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).

The results of the first clinical trials of antiaging interventions may open the floodgates for geroscience research and the authors recommended designing trials to research intervention effectiveness in preventing or mitigating age-associated pathologies. The framework that hallmarks of aging provide may guide researchers to develop effective interventions to expend healthy longevity.

[1] https://pubmed.ncbi.nlm.nih.gov/11976218/
[3] https://www.cell.com/cell/fulltext/S0092-8674(13)00645-4
[4] https://www.cell.com/cell/fulltext/S0092-8674(22)01377-0
[5] https://www.nature.com/articles/nm.4222 
[6] https://www.nature.com/articles/s42255-019-0161-5 
[7] https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(21)00118-0
[8] https://onlinelibrary.wiley.com/doi/10.1111/acel.13050 
[9] https://www.science.org/doi/10.1126/scitranslmed.aaw1815 
[10] https://www.nature.com/articles/s41586-021-03832-5 
[11] https://onlinelibrary.wiley.com/doi/10.1111/acel.13524