Hallmarks of Ageing
The inevitability of aging has fascinated humanity since antiquity.Despite remarkable scientific advances, the complexity of aging continues to impede a complete understanding. In 2013, the Hallmarks of Aging were introduced to establish an organized, systematic, and integrative framework for research in this field. More than a decade later, advancements in the area prompted an updated version that incorporated three additional hallmarks while preserving the original conceptual structure. This review aims to explain the underlying biological mechanisms, highlight recent insights and emerging key players, and provide high-quality antibodies and proteins to support further research on these critical antigens.
Fig. 1: Hallmarks of Ageing based on López-Otín et al.. Click on a hallmark for further information.
The hallmarks of ageing are classified into three categories: primary, antagonistic, and integrative hallmarks. Primary hallmarks directly contribute to the onset of damage and consistently exert detrimental effects. Antagonistic hallmarks have context-dependent roles, offering protective effects at moderate levels but becoming harmful when excessively activated. Integrative hallmarks emerge when the body's compensatory mechanisms fail to maintain tissue homeostasis in response to accumulated damage.
Hallmarks of Ageing: Definition
Based on the “The hallmarks of cancer” by Hanahan and Weinberg, López-Otín et al. established three criteria that a biological process must fulfil to be considered as a hallmark of aging: it has to appear during physiological aging, it has to accelerate aging when aggravated experimentally, and its experimental alleviation has to slow aging, thus increasing healthy lifespan.
Genome Instability
Genome instability refers to an increased tendency for alterations in the genome, like mutations and chromosomal rearrangement. As organisms age, several cellular processes that maintain genomic integrity become impaired, including DNA damage recognition (ATM) and DNA repair pathways like homologous recombination and non-homologous end joining (ATR, BRCA1). The result is a higher burden of DNA lesions and mutations in somatic cells, which not only contributes to cellular senescence and functional decline but also increases the risk of malignant transformation. Therefore, genome instability is also a hallmark of cancer. Accumulated mutations over time can inactivate tumor suppressor genes (TP53) or activate oncogenes.
Telomere Attrition
Telomeres are repetitive nucleotide sequences (TTAGGG repeats in humans) located at the ends of linear chromosomes, serving to protect chromosomal DNA from deterioration or fusion with neighboring chromosomes. Telomere attrition is a cumulative process driven over time by replicative cell divisions (mitotic clock), oxidative stress or inflammatory environments. Telomeres are protected by shelterin, a specialized multi-protein complex that binds specifically to telomeric DNA, protecting chromosome ends and regulating telomere maintenance.
With each round of DNA replication, telomeres progressively shorten in somatic cells, unless compensated by telomerase activity. Critically shortened telomeres lose their protective function. They have fewer binding sites for TRF1 and TRF2, leading to partial or complete dissociation of shelterin components.
Reprogramming Rejuvenation Strategies
Genetic reprogramming-induced rejuvenation introduces specific transcription factors (such as Yamanaka factors: Oct4, Sox2, Klf4, and c-Myc) into somatic cells to revert them to a more youthful or pluripotent state. This process resets epigenetic markers associated with aging and can partially reverse cellular aging without fully inducing pluripotency.
Chemical reprogramming-induced rejuvenation, by contrast, uses small molecules or drug-like compounds to modulate signaling pathways and epigenetic regulators to achieve similar rejuvenating effects without genetic manipulation. These compounds can induce a youthful gene expression profile and reverse aging markers with potentially lower risk and greater controllability.
Epigenetic Alterations
Epigenetic mechanisms emerged as key contributors to the alterations of genome structure and function that accompany aging. The three pillars of epigenetic regulation are DNA methylation, histone modifications, and noncoding RNA species. Alterations of these epigenetic mechanisms affect the vast majority of nuclear processes, including gene transcription and silencing, DNA replication and repair, cell cycle progression, and telomere and centromere structure and function. Transcription factors can induce cellular age reversal though epigenetic reprogramming.
The Circadian Clock
The circadian clock is an intrinsic time-keeping system that regulates daily physiological and metabolic rhythms in alignment with the 24-hour day-night cycle. Disruption of circadian rhythms contributes to age-related decline in cellular function, increased inflammation, and impaired tissue regeneration. Aging is associated with dampened circadian gene expression and reduced amplitude of clock-controlled biological processes, which may accelerate functional deterioration and disease susceptibility.
BMAL1 (Brain and Muscle ARNT-Like 1): A transcription factor that forms a heterodimer with CLOCK to activate the transcription of circadian target genes, including those involved in metabolism, DNA repair, and oxidative stress response. BMAL1 is essential for maintaining circadian rhythm and its deficiency is linked to premature ageing phenotypes. PER2 (Period Circadian Regulator 2): Part of the negative feedback loop that inhibits the activity of the BMAL1:CLOCK complex. PER2 helps regulate the timing and robustness of the circadian cycle. Dysregulation of PER2 has been associated with disrupted sleep patterns and age-related disorders.
Loss of Proteostasis
Loss of proteostasis is a critical hallmark of ageing due to its central role in maintaining protein quality control, which is essential for cellular function and organismal health. Proteostasis involves a tightly regulated network of molecular chaperones, proteolytic systems (e.g., the ubiquitin-proteasome system and autophagy-lysosome pathway), and stress response pathways that collectively ensure proper protein folding, prevent aggregation, and mediate the degradation of damaged or misfolded proteins.
With age, this proteostasis network becomes progressively impaired, leading to the accumulation of dysfunctional proteins and aggregates that can disrupt cellular homeostasis. This proteotoxic stress contributes to cellular senescence, impaired stress responses, and chronic inflammation, and is implicated in the pathogenesis of various age-associated diseases, particularly neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Thus, the decline in proteostasis is not only a marker of cellular ageing but also a driver of systemic functional decline across tissues.
Disabled Macroautophagy
With advancing age, macroautophagy becomes progressively compromised. Autophagosome formation is reduced, lysosomal degradation only functions inefficient and expression or activity of key autophagy-related proteins is altered. This decline compromises the cell’s ability to clear damaged organelles and aggregated proteins, contributing to cellular dysfunction and age-related pathologies.
LC3 plays a central role in autophagosome biogenesis. During autophagy, cytosolic LC3-I is lipidated to form LC3-II, which associates with the autophagosomal membrane and is widely used as a marker of autophagosome formation. In ageing cells, reduced LC3-II levels often reflect impaired autophagosome maturation or increased turnover due to defective lysosomal fusion. p62/SQSTM1 functions as a selective autophagy receptor that binds ubiquitinated cargo and delivers it to autophagosomes via LC3 interaction. Under normal conditions, p62 is degraded during autophagy. In aged cells, its accumulation indicates impaired autophagic flux and serves as a marker of dysfunctional cargo clearance.
The antagonistic hallmarks exert dual effects depending on their activity levels—being beneficial at low or transient levels but becoming harmful when chronically activated or excessively intensified, as typically observed with advancing age. Among the initially proposed hallmarks of ageing, deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence are classified within this category.
Deregulated Nutrient Sensing
Deregulated nutrient-sensing occurs when the cell mechanisms for determining the presence or absence of nutrients fail, so instead of protecting against nutrient scarcity they produce deleterious effects. With advancing age, the IGF-1 and mTOR pathways often become hyperactivated, promoting anabolic processes and inhibiting autophagy, which contributes to cellular damage and reduced stress resistance. Conversely, longevity-associated pathways such as AMPK and sirtuins, which support catabolic metabolism and stress resilience, are often downregulated. On the other hand, inhibition of MTORC1 complex, a master regulator of nutrient-sensing mechanisms, increases lifespan in model organisms
Mitochondrial Dysfunction
Mitochondrial dysfunction in ageing arises from cumulative damage to mitochondrial DNA, impaired electron transport chain (ETC) function, and altered dynamics of mitochondrial biogenesis and mitophagy. These defects lead to reduced ATP production, increased production of reactive oxygen species (ROS), and disruption of redox homeostasis.
These harmful species, together with the decay in the mitochondrial function, can promote the permeabilization of the mitochondria, causing inflammation and cell death. However, when this occurs only at a low-grade during youth, it triggers what is called “mitohormesis”, which promotes cell survival and adaptation to stress.
Mitohormesis
Mitohormesis refers to a biological concept in which mild mitochondrial stress induces an adaptive cellular response that ultimately promotes health and longevity. Specifically, low levels of mitochondrial ROS, traditionally considered damaging, can serve as signaling molecules that activate protective pathways such as antioxidant defense systems, mitochondrial biogenesis, and autophagy.
This adaptive response enhances cellular resilience, improves metabolic homeostasis, and may delay the onset of age-related dysfunction. Importantly, mitohormesis underscores the idea that not all ROS are deleterious—in controlled amounts, they are essential for triggering beneficial stress responses. Thus, mitohormesis offers a mechanistic explanation for why certain interventions, such as caloric restriction or physical exercise, can extend lifespan by transiently increasing mitochondrial stress to induce long-term cellular adaptation.
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References
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