The Hallmarks of Aging: A Guide to the Pathways of Aging

What are the hallmarks of aging? The hallmarks of aging are a set of biological processes that scientists have identified as drivers of aging at the cellular level. First defined as nine in 2013 and expanded to twelve in 2023, they offer a framework for understanding why our cells, and our bodies, change over time.

Today we are talking about the hallmarks of aging. Not the visible signals like gray hair, wrinkles, or changing eyesight, but what sits beneath them. In general, what is slowing us down and driving all these changes? To answer that, we have to look at what is happening at the cellular level.

The Hallmarks of Aging Criteria

In an influential paper published in Cell in 2013, López-Otín et al. set out the hallmarks of aging [1]. Aiming to capture the paradigm of aging, they described nine molecular, cellular, and systemic contributors. A decade of research confirmed and extended their importance, and also surfaced new ones. In 2023, López-Otín et al. published a follow-up paper in Cell[2] with twelve hallmarks. The criteria for what counts as a hallmark stayed the same.

To be named a hallmark of aging, a process should meet, to varying degrees, three criteria:

1. It manifests during normal aging.
2. Its experimental acceleration speeds up aging.
3. Its experimental reduction slows aging.

The third criterion is the most exciting: reduce or slow a hallmark, and you may extend healthy lifespan. It is also the hardest to prove in the lab. López-Otín and team account for this, particularly for hallmarks where the third criterion has not been demonstrated, by pointing to the hallmarks' "extensive interconnectedness." In other words, the hallmarks work in combination to drive aging.

What Causes Aging?

Many scientists define aging as "the time-dependent accumulation of cellular damage." As we age, damage builds up inside cells and their ability to function declines. This decline, sometimes called a loss of integrity, is the primary risk factor for many conditions, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases.

Think of a Cell as a Car

Picture a cell as a new car. At first it runs perfectly, but it needs regular maintenance: keeping it clean and replacing worn parts (autophagy) and fixing computer glitches (DNA repair). Over time, wear and tear takes its toll anyway, and parts begin to fail (loss of integrity). If they are not repaired or replaced, the damage spreads. Eventually the car breaks down, blows a gasket (a heart attack, if you will), and the mechanic decides it is beyond repair, so off it goes to the junkyard (cell death). Oversimplified, but that is broadly what happens to cells as they age.

What Drives the Damage?

The damage comes largely from the hallmark processes themselves, working together over time. External factors can accelerate it too. A 2023 brief from the World Heart Federation notes that even moderate alcohol consumption is associated with a loss of healthy life [3].

The hallmarks are grouped into three categories: primary, antagonistic, and integrative. In this series we will explore each hallmark in turn. Here, in the introduction, we will briefly meet the groups.

The Primary Hallmarks of Aging

The primary hallmarks are the initial causes of cellular damage. Take the first one, genomic instability, which is essentially accumulated DNA damage reaching a destabilizing degree. In our car analogy, it is like glitches in the onboard computer piling up until it stops working, or tells you that you are in Bristol when you are, in fact, in Bath.

This group includes:

• Genomic instability
• Telomere shortening
• Epigenetic alterations
• Loss of proteostasis
• Disabled macroautophagy*

The Antagonistic Hallmarks of Aging

The antagonistic hallmarks are the cell's responses to the primary hallmarks, and their effects depend on intensity. At low levels they help mitigate damage; in excess, they become harmful. The eighth hallmark, cellular senescence (cell cycle arrest), is a good example: it can protect against cancer by halting uncontrolled cell division, but in excess it promotes aging.

This group includes:

• Deregulated nutrient sensing
• Mitochondrial dysfunction
• Cellular senescence

As López-Otín et al. put it, these responses are designed to protect the organism from damage or nutrient scarcity, but "when exacerbated or chronic, they subvert their purpose and generate further damage."

The Integrative Hallmarks of Aging

The integrative hallmarks emerge when the damage from the primary and antagonistic hallmarks outpaces the cell's ability to maintain balance through repair and renewal. They lead to the deterioration ultimately responsible for aging.

This group includes:

• Stem cell exhaustion
• Altered intercellular communication
• Chronic inflammation*
• Dysbiosis*

Why the "Hallmarks of Aging" Framework Endures

López-Otín et al.'s 2013 paper became one of the most cited in modern biology and helped inspire a vast body of follow-up research on the molecular mechanisms of aging, including interventions that target one or more hallmarks to support human healthspan. More than a decade later, the number of studies continues to grow.

They are not alone in mapping the paradigm of aging, which is the primary risk factor for most human disease. Other groups have proposed additional hallmarks. A 2022 aging meeting in Copenhagen, for example, agreed on fourteen, adding altered mechanical properties and splicing dysregulation, and leaving room for more as research progresses [4].

We are sticking with López-Otín et al. because, after withstanding a decade of scrutiny, it remains a strong framework, for scientists and aging enthusiasts alike, to explore what we know, how we know it, and how we might live better for longer.

*2023 addition to the hallmarks of aging

This article is for educational purposes only and is not intended as medical advice. It is not intended to diagnose, treat, cure, or prevent any disease. Speak with a qualified healthcare professional before making changes to your diet, supplement routine, or lifestyle.

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References

1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217. doi: 10.1016/j.cell.2013.05.039. PMID: 23746838; PMCID: PMC3836174.
2. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349.
3. The Impact of Alcohol Consumption on Cardiovascular Health (2023). World Heart Federation. Available at: https://world-heart-federation.org/news/no-amount-of-alcohol-is-good-for-the-heart-says-world-heart-federation/(Accessed: 22 May 2024).
4. Schmauck-Medina T, Molière A, Lautrup S, et al. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging (Albany NY). 2022 Aug 29;14(16):6829-6839. doi: 10.18632/aging.204248. PMID: 36040386; PMCID: PMC9467401.