Researchers Propose Five New Hallmarks of Aging

This would update and expand a well-respected model of aging.


New HallmarksNew Hallmarks

Publishing in Aging five months after their panel discussion in Copenhagen, many well-known researchers have explained their reasons for wishing to add new hallmarks of aging to the existing paradigm.

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A new addition to an old paradigm

The Hallmarks of Aging, a well-cited and well-respected 2013 paper [1], categorizes the myriad aspects of aging into nine different broad categories. These categories, the Hallmarks, are meant to explain the fundamental, physical reasons why various biological and environmental factors, most notably the passage of time, lead to disease and death in human beings.

However, multiple researchers have argued that the Hallmarks are not complete and that various aspects of aging do not neatly fit into any of these nine categories. To that end, they have proposed five new hallmarks of aging to add to the existing paradigm.

Redrawing the lines

The first proposed new hallmark is compromised autophagy. Autophagy, the process by which cells consume their own components (organelles) for fuel and as a maintenance process, is impaired in aging [2]. This paper notes that it was often categorized as part of proteostasis, but the maintenance of proteins and the maintenance of organelles are two distinct processes.

The second is splicing dysregulation. This refers to the splicing process that constructs RNA from DNA, which is known to be impaired in older people [3]. This is not the same as genomic instability, which refers to the DNA itself, nor is it the same as epigenetic alterations, which refer to the methylation of this DNA.

The third is microbiome disturbance. The gut microbiome is frequently studied as a cause and consequence of advancing age, as it is known to change with aging [4]. We have previously reported on how the gut microbiome is linked to brain health, and the gut-brain axis is a frequent subject of research.

The fourth is altered mechanical properties. Interestingly, the researchers include both intracellular and extracellular changes in this hallmark. Probably the most well-known of the intracellular problems involves the lamina, the nuclear envelope that protects DNA; laminal dysfunction is the key characteristic of progeria, a disease that causes children to rapidly age [5]. This paper also notes how mechanical changes impede the mobility of fibroblasts [6] and immune cells [7].

Of course, the most well-known altered mechanical property is the extracellular cross-linking of collagen through glycation. This results in a loss of tissue elasticity and changes how cells behave [8].

The fifth and final proposed new hallmark is inflammation. The role of systemic inflammation in aging is extremely well-established, to the point that it has its own name: inflammaging [9]. While inflammaging has been considered to be part of the existing hallmark of altered intercellular communication, these researchers propose that its peculiarity and far-reaching effects make it worthy of its own hallmark.


The researchers admit very early in this paper that the Hallmarks are simply a framework and an explanation, not a prescriptive catch-all for everything that constitutes aging. The aspects of aging are heavily interconnected, and much of aging research is built upon explaining this interconnectedness; for example, we know that telomere attrition is a primary cause of cellular senescence in somatic cells.

In a way, adding to the Hallmarks simply admits what most aging researchers already know to be true, altering the governing paradigm to fit the field’s current knowledge. Ultimately, the purpose of the Hallmarks is to explain what aging is in an accurate, relatively complete, and understandable way. The field of aging research is rapidly developing, and the means by which we explain it should develop along with it.

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[1] LΓ³pez-OtΓ­n, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Wong, S. Q., Kumar, A. V., Mills, J., & Lapierre, L. R. (2020). Autophagy in aging and longevity. Human genetics, 139(3), 277-290.

[3] Holly, A. C., Melzer, D., Pilling, L. C., Fellows, A. C., Tanaka, T., Ferrucci, L., & Harries, L. W. (2013). Changes in splicing factor expression are associated with advancing age in man. Mechanisms of ageing and development, 134(9), 356-366.

[4] Wilmanski, T., Diener, C., Rappaport, N., Patwardhan, S., Wiedrick, J., Lapidus, J., … & Price, N. D. (2021). Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nature metabolism, 3(2), 274-286.

[5] Capell, B. C., Erdos, M. R., Madigan, J. P., Fiordalisi, J. J., Varga, R., Conneely, K. N., … & Collins, F. S. (2005). Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proceedings of the National Academy of Sciences, 102(36), 12879-12884.

[6] Walters, H. E., Deneka-Hannemann, S., & Cox, L. S. (2016). Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging (Albany NY), 8(2), 231.

[7] Sapey, E., Patel, J. M., Greenwood, H., Walton, G. M., Grudzinska, F., Parekh, D., … & Thickett, D. R. (2019). Simvastatin improves neutrophil function and clinical outcomes in pneumonia. A pilot randomized controlled clinical trial. American journal of respiratory and critical care medicine, 200(10), 1282-1293.

[8] Jain, N., & Vogel, V. (2018). Spatial confinement downsizes the inflammatory response of macrophages. Nature materials, 17(12), 1134-1144.

[9] Ferrucci, L., & Fabbri, E. (2018). Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nature Reviews Cardiology, 15(9), 505-522.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called β€œreal life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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