Why do we age? Introducing the Hallmarks of Ageing
Welcome to our new monthly deep dive into the science of ageing!
We are all familiar with the classic visual signs of ageing like grey hair, wrinkles, or failing eyes. But, besides that relentless mistress called time, what exactly is going on inside our bodies to cause ageing? Orchestrating the ageing process behind the scenes of visual signs, is the gradual accumulation of damage in our cells. Every cell in our body - from those in our skin to those in our organs - experiences this deterioration over time, compromising cellular integrity and overall functionality.
Scientists have identified 12 key factors that contribute to this cellular decline, termed the ‘hallmarks of ageing’. To conceptualise, think of your body as a city, with cells working together like interconnected areas, each playing a crucial role in keeping you healthy. Just as a city ages through deterioration of different components; infrastructure, interrupted communication networks, and declining maintenance systems, our cells face similar challenges. Over time, crucial processes begin to falter - DNA repair mechanisms miss important fixes, cellular cleanup crews work less efficiently, and the biological networks that keep cells communicating break down. These cellular changes eventually manifest as the visible and physical signs of ageing we’re all familiar with. all familiar with. More importantly, this progressive deterioration serves as the primary driver for many diseases that become increasingly common with age, from cardiovascular disease to cancer.
Over the next year, we’ll explore these key factors, known rather as the 12 Hallmarks of Ageing—the fundamental biological processes that drive how we age. These hallmarks, first outlined in a landmark 2013 paper by award-winning biochemist and molecular biologist Carlos López-Otín and his team and updated in 2023, serve as a framework for understanding why and how our bodies change over time. Each month, we’ll break down one hallmark in clear, accessible language, exploring how it affects our bodies and discussing the latest research on potential interventions.
Before we dive into the individual hallmarks, let’s start with an overview of this groundbreaking concept and why it has become so central to the field of ageing research. Understanding these hallmarks isn’t just academic—it’s key to developing strategies to promote healthier, longer lives.
I. Criteria for Defining a Hallmark
In their first paper, López-Otín and his team established three criteria that a biological process must meet, to varying degrees, to be considered a hallmark of ageing:
1. It should naturally occur as part of the ageing process.
2. Experimental acceleration or increase of the biological process should measurably speed up the ageing process.
3. Mitigating the process (actionably reducing or slowing it down) should, in turn, slow down normal ageing.
The third criterion is obviously the most exciting— a method to target something directly to slow ageing and extend healthspan? A dream come true! Unfortunately, it’s not quite that simple. This goal remains one of the most challenging to achieve or prove in research, largely because many of these hallmarks are deeply interconnected in their contributions to the ageing process. López-Otín and his team often emphasise this point, particularly when discussing hallmarks that are difficult to isolate or validate, highlighting their “extensive interconnectedness.” Meaning, as you might expect, pinpointing a singular 'cause' of ageing is a profoundly complex, perhaps impossible, endeavor.
II. The 12 Hallmarks of Ageing: Categorised
The 12 Hallmarks of Ageing are organized into three key categories that describe how ageing progresses in our bodies. The first category, primary hallmarks, includes the fundamental forms of cellular damage like genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, and disabled macroautophagy – these represent the initial cellular breakdowns. The second category, antagonistic hallmarks, comprises deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence – these are biological responses that are initially protective but become harmful when excessive or chronic. Finally, the integrative hallmarks represent the ultimate consequences of the previous two categories, including stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis, which together manifest as the systemic breakdown we recognize as ageing.
The Primary Hallmarks
The primary hallmarks represent the fundamental forms of cellular damage that accumulate with time. Think of these as the initial points of failure in our cellular city:
Genomic instability - Our DNA gets damaged and cells become less able to repair these errors, leading to genetic mistakes.
Telomere shortening - The protective caps at the ends of our chromosomes get shorter with each cell division, eventually leaving our genetic material vulnerable.
Epigenetic alterations - The way our genes are switched on and off becomes disrupted, changing how cells read and use genetic instructions.
Loss of proteostasis - Cells lose their ability to make and maintain proteins correctly, leading to buildup of damaged or misfolded proteins.
Disabled macroautophagy - The cell’s recycling system breaks down, meaning cellular waste and damaged components aren’t properly cleared away. (added in 2023)
The antagonistic hallmarks
In contrast to the primary hallmarks, antagonistic hallmarks have opposite effects depending on their intensity- “when exacerbated or chronic, they subvert their purpose and generate further damage”. They’re like a city’s emergency response systems - initially protective but potentially destructive when overactive. At low levels, these responses help manage the damage caused by the primary hallmarks, much like how a city’s repair crews and emergency services handle daily problems. However, when these responses become excessive, they create problems of their own. Included in this group are the following:
Deregulated nutrient sensing- Cells become worse at detecting and using nutrients. It’s like losing the ability to properly process food and energy, disrupting important metabolic processes.
Mitochondrial dysfunction- Our cells’ power plants (mitochondria) become less efficient at producing energy. Over time, they not only produce less energy but also create more harmful by-products.
Cellular senescence- Damaged cells stop dividing but don’t die. Instead, they linger and release harmful substances that affect nearby healthy cells. While this initially helps prevent cancer, too many of these "zombie cells’ cause problems.
Integrative Hallmarks:
Think of these final hallmarks as the citywide problems that emerge when multiple systems break down at once. Just as a city can't function when its infrastructure crumbles and communication networks fail, our body begins to show widespread dysfunction when cellular damage accumulates. Here are the final consequences:
Stem Cell Exhaustion - The body’s supply of repair cells becomes depleted, reducing its ability to heal and maintain tissues.
Altered Intercellular Communication - Cells stop communicating effectively with each other, leading to uncoordinated responses and increased inflammation.
Chronic Inflammation - The body remains in a constant state of low-level inflammation, gradually damaging tissues over time. (added in 2023)
Dysbiosis - The healthy balance of bacteria in our gut becomes disrupted having widespread consequences in the body. (added in 2023)
The Future of Ageing Research
Understanding these hallmarks of ageing opens up exciting possibilities for the future of health. Rather than just treating age-related diseases after they develop, we might be able to prevent or delay them by addressing their root causes. Over the next year, we’ll be discussing each of these hallmarks individually. You’ll learn not only how they influence your health, but also what current research tells us about monitoring and potentially influencing them. Whether you’re interested in the science of ageing or simply want to better understand your own body’s ageing process, tune in to the next blog posts in this series!
References:
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.0392.
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278. https://doi.org/10.1016/j.cell.2022.11.001
Authors: Katsume Stoneham & Georgia Pilling
The Hallmarks of Ageing (Source: Cell, 2023)
