Hallmarks of Ageing
In this article, we review the hallmarks of ageing : 12 interconnected biological processes that drive ageing. By better understanding the underlying processes of ageing, we can look for targeted solutions that mitigate these processes and tackle ageing at a fundamental level. This can help prevent ageing-associated health issues such as metabolic, neurodegenerative and cardiovascular disease.
What does ‘hallmarks of ageing’ mean?
The hallmarks of ageing describe the 12 underlying biological changes that collectively contribute to the ageing phenotype, the ageing body that we can observe. In this framework, ageing is conceptualized as a progressive decline in tissue homeostasis and functionality, leading to external signs of ageing like development of ageing-associated disease, wrinkles, muscle loss and other associated developments..
These hallmarks were first articulated in a seminal review by López-Otín et al. and have undergone refinement and expansion in subsequent works (López‐Otín et al., 2013; López‐Otín et al., 2023). The current version of the hallmarks of ageing, published in 2023, includes 12 hallmarks of ageing, which are broadly accepted in the global ageing and longevity research community.
The Three Types of Hallmarks of Ageing
Ageing manifests at multiple levels in the body, from genomic, to cellular, tissue and whole body. The hallmarks of ageing describe changes at all four levels. They are divided into three types:
- Primary: fundamental changes, for example DNA damage accumulated over time. The root causes of cellular damage.
- Antagonistic: Resulting from the primary hallmarks, responses to the cellular damage. For example, mitochondrial dysfunction.
- Integrative: End-stage consequences of the primary and antagonistic hallmarks, which drive the ageing phenotype.
Primary
The primary hallmarks of ageing include genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis. Genomic instability means that DNA damage and mutations build up over time, caused by environmental and internal stresses. Such stresses can cause small changes in the DNA. Over time, the DNA accumulates more and more changes. This is also referred to as increasing genomic instability. This instability can lead to detrimental effects on cellular function and is observed widely in ageing tissues (Hunt et al., 2019; Frenk & Houseley, 2018; Giudici, 2021).
Telomere attrition, the progressive shortening of chromosomal ends, contributes to replicative senescence. Replicative senescence means that cells are no longer able to divide themselves. Replicative senescence due to telomere attrition underscores a critical limit to cellular division influencing organismal ageing (Giudici, 2021). Epigenetics, the way that genes are – or aren’t– expressed, also changes. Epigenetic alterations involve changes in gene expression regulation without modifying the underlying DNA sequence, leading to a drift in cellular identity and function across age (Aunan et al., 2016; Jin et al., 2023). Moreover, loss of proteostasis relates to the failure of cellular mechanisms that maintain protein homeostasis, the balance of protein states (folded, unfolded and so on) in the cell. This results in the accumulation of damaged and misfolded proteins, which can alter cellular functions (Salimi & Hamlyn, 2020).
As these primary hallmarks accumulate, the body's compensatory responses may further drive ageing.
Antagonistic
Antagonistic hallmarks are responses to damage that arise from the primary hallmarks, including cellular senescence, deregulated nutrient sensing and mitochondrial dysfunction. Cellular senescence is characterized by a permanent state of cell cycle arrest that acts as a protective mechanism against cancer; by stopping the normal life cycle of the cell, which includes cell division, cancer cells are stopped. However, the necessary cell division for tissue repair and replacement of cells is also stopped, though stem cells can still provide new replacement cells. In addition, senescence contributes to ageing and tissue dysfunction through the senescence-associated secretory phenotype (SASP), by sending out specific molecules that influence other cells around it (Leonardi et al., 2018; Wen et al., 2023).
Mitochondrial dysfunction means that the cell’s ‘power plants’ no longer work properly, leading to less energy and more stress in the cell. As mitochondria produce energy for the cell and tissue functioning, mitochondrial dysfunction contributes to systemic metabolic dysfunction in ageing tissues (Salimi & Hamlyn, 2020; Mattson & Arumugam, 2018). Additionally, deregulated nutrient sensing affects cellular health and metabolism. Nutrient sensing is important, as the cell needs to respond to each nutrient in specific ways to utilize it. Deregulated nutrient sensing impacts pathways like insulin signaling for blood sugar regulation, and mTOR (mechanistic target of rapamycin), which are critical for growth and energy homeostasis (Aunan et al., 2016; Giudici, 2021).
Over time, both primary and antagonistic processes converge into integrative hallmarks that visibly drive ageing.
Integrative
Resulting from the cumulative effects of the primary and antagonistic mechanisms described above, the integrative hallmarks of ageing include stem cell exhaustion and altered intercellular communication. Stem cell exhaustion means stem cells lose their ability to repair and replace damaged tissue as effectively as before. This results in reduced tissue repair and reduced homeostasis (internal balance of the body) (Hunt et al., 2019; Wen et al., 2023). Altered intercellular communication, marked by chronic inflammation (inflammageing) and dysregulated signaling between cells, can compromise tissue function and promote age-related diseases (Leonardi et al., 2018; Gems & Magalhães, 2021). This interplay among hallmarks underlines the complex network of ageing processes that collectively culminate in the ageing phenotype.
Conclusion
In conclusion, the hallmarks of ageing provide a comprehensive framework for understanding the biological complexities underpinning ageing. Ageing happens at multiple levels, from cellular to whole-body, and in multiple intertwined processes, from primary hallmarks, resulting in antagonistic and ultimately, in integrative hallmarks. Progress in identifying and dissecting these hallmarks not only enhances our fundamental knowledge of ageing but also offers opportunities to intervene in the biological processes of ageing. This way, ageing can be slowed down and ageing-associated health issues can be prevented at a fundamental level, expanding healthy lifespan.
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