The 12 Hallmarks of Aging

Aging can be defined as the time-related decline of the physiological functions necessary for survival. The functional deterioration that drives aging at the whole-body (i.e., systemic) level is caused primarily by cellular aging, i.e., the gradual decline in cell function resulting from cellular damage that accumulates throughout life [1,2]. As cell function declines, so does tissue function, and these age-related modifications gradually start to impact our body systemically. 

How old your cells and tissues are is your biological age. Although it correlates with your chronological age—how long you’ve been alive—they happen at different rates because many of the cellular changes that are typical of aging can be influenced by and modifiable through lifestyle patterns, including diet, physical activity, and psychological stress. 

There are several cellular and molecular changes that are regarded as hallmarks of the aging process. In 2013, nine hallmarks of aging were proposed [3]. In the meantime, aging research has expanded significantly, and in 2023, the hallmarks of aging were extended to twelve [4]. 

Three criteria have been proposed for a process to be considered a hallmark of aging [4]:

1. The time-dependent manifestation of alterations accompanying the aging process; 
2. The possibility of accelerating aging by experimentally accentuating the hallmark; 
3. The opportunity to decelerate, halt, or reverse aging by therapeutic interventions on the hallmark.

These are the current twelve hallmarks of aging:

• Genomic instability
• Telomere attrition
• Epigenetic alterations
• Loss of proteostasis
• Deregulated nutrient-sensing
• Mitochondrial dysfunction
• Cellular senescence
• Stem cell exhaustion
• Altered intercellular communication
• Disabled macroautophagy
• Chronic inflammation
• Dysbiosis

Genomic Instability

DNA is the molecule that encodes the genetic information needed for the development and functioning of an organism. Nuclear DNA, i.e., the DNA contained in the nucleus of cells, carries most genetic information. A smaller portion of DNA is found in mitochondria (mitochondrial DNA) and it encodes for proteins involved in the oxidative phosphorylation process, which produces cell energy as ATP.

DNA is susceptible to lesions caused by endogenous factors, such as DNA replication errors and oxidative stress, as well as environmental factors, such as radiation and pollution. Mitochondrial DNA is particularly susceptible to damage because its repair and protection mechanisms are less efficient than those of nuclear DNA and because mitochondria have a microenvironment prone to oxidative stress [5]. Changes in nuclear and mitochondrial DNA are common and contribute to aging [5,6], but cells have several mechanisms of DNA repair and quality control to maintain genetic stability. 

However, DNA repair and maintenance mechanisms become less efficient as we age, which allows for growing genetic instability and the accumulation of DNA damage in aged cells [7]. These changes in DNA can affect genes that are essential for healthy cell function, which may lead to tissue dysfunction and affect organismal homeostasis. DNA damage in stem cells can be particularly detrimental because it can contribute to stem cell exhaustion (another hallmark of aging described below) and impair tissue renewal, which in turn may accelerate the aging process [4,8]

Telomere Attrition

Telomeres are DNA sequences at the ends of chromosomes that shorten slightly each time a cell divides, which means they get shorter as we age [9]. This process is known as telomere attrition or telomere shortening [10,11]. When telomeres reach a critical length, cell division stops and cells enter into replicative senescence (cellular senescence is another hallmark of aging described below) [12]. 

Some cells are able to circumvent telomere shortening through the activity of an enzyme called telomerase, which elongates telomeres when cells divide to maintain their adequate length [13,14]. But telomerase is expressed only in cells that must divide extensively, such as stem cells, as well as sperm cells, epidermal cells of the skin, and lymphocytes (a type of immune cell). The vast majority of cells do not express telomerase and undergo progressive telomere shortening throughout life [15]. 

Telomeres have protective functions over chromosomes and their shortening induces genomic instability and, ultimately, cellular senescence or cell death. These can cause changes in gene expression and signaling pathways that may lead to a progressive decline in tissue function and contribute to organismal aging and age-related dysfunctions [4,16].

Epigenetic Alterations

Epigenetic alterations are a set of mechanisms that regulate gene expression based on lifestyle and environment [17]. Epigenetic alterations are heritable but they are not changes in DNA sequence. Rather, epigenetic modifications are regulatory changes to DNA, some of them reversible, that alter DNA accessibility and chromatin structure (chromatin is a complex of DNA and proteins that condenses long DNA molecules into more compact structures) and impact gene expression and other cellular processes [18]. 

Epigenetic alterations include DNA methylation, histone modifications (histones are proteins that help condense DNA into chromatin), chromatin remodeling, and synthesis of non-coding RNAs (ncRNAs, transcripts that do not produce proteins). They involve an extensive array of enzymes that generate and maintain epigenetic patterns [18–20]. 

Patterns of epigenetic alteration change with age and can lead to significant gene expression changes that especially affect biological processes that are significantly deregulated in aging, such as inflammation, protein folding, extracellular matrix (ECM) regulation, and mitochondrial function [4,21,22]. This can result in loss of cellular homeostasis, changes in stem cell behavior, metabolic health decline, and the development and progression of age-related dysfunctions [19,20,23,24]. The so-called epigenetic clocks that assess biological age are based on patterns of epigenetic alterations with DNA methylation that occur with aging.

Loss of Proteostasis

Cells have several mechanisms to maintain proteostasis (i.e., protein homeostasis), including processes that regulate protein translation, assist in protein folding, and degrade damaged proteins. Protein quality control mechanisms decay with aging and lead to the production of incorrectly translated or incomplete proteins, incorrect folding of proteins, or inefficient elimination of damaged proteins, for example [4,25,26]. 

Loss of cellular proteostasis thus results in the accumulation of misfolded or damaged proteins [27,28]. These changes accelerate aging because they impact cells’ ability to produce healthy proteins required for proper cellular function and can saturate cellular mechanisms of protein repair, degradation, and turnover required to maintain cellular fitness. As a result, damaged proteins may form aggregates that deposit within cells and compromise cellular and tissue function [27,29,30]. 

Protein aggregates can be removed by autophagy, but this is another process whose efficiency is also affected by aging (see below) [28,31]. 

Disabled Macroautophagy

Autophagy is a cellular process through which cells degrade and recycle dysfunctional or damaged cell organelles (including dysfunctional mitochondria—mitophagy), protein aggregates, or unused proteins and other macromolecules (e.g., DNA, lipid vesicles, and glycogen) [31].

Macroautophagy is the main pathway of autophagy (which also includes microautophagy and chaperone-mediated autophagy). This form of autophagy involves the formation of a double-membrane vesicle called autophagosome around the cellular structure or molecule targeted for degradation, which then fuses with the lysosome (a cell organelle specialized in digesting cellular structures and molecules), where the contents of the vesicle are degraded through the activity of enzymes [32]. 

The expression of autophagy-related genes declines with age, which contributes to the accumulation of protein aggregates and dysfunctional organelles, and to the reduced elimination of proteins involved in inflammatory processes, thereby also enhancing inflammation (another hallmark of aging, see below) [4,33,34]. 

Genetic inhibition of autophagy in model organisms causes the premature degeneration and senescence of multiple organ systems and accelerates the aging process [35]. In humans, reduced autophagy has been causally linked to age-related dysfunctions resembling premature aging [31,36]. Stimulation of autophagy and mitophagy in model organisms reduces age-associated dysfunctions and increases healthspan [37–40]. 

Deregulated Nutrient-Sensing

The nutrient-sensing network is a central regulator of cellular activity, including autophagy, protein synthesis and degradation, glucose and lipid metabolism, and mitochondrial biogenesis. The nutrient-sensing network responds to nutrition, energy availability, and stress by activating anabolism (i.e., the production of macromolecules) if nutrients and cell energy are available and stress is low, or by inducing catabolism (i.e., the breakdown of macromolecules into small molecules to produce energy) and cellular defense pathways if nutrient and cell energy availability is low and stress is high [41]. 

The nutrient-sensing network modulates the activity of numerous proteins, including transcription factors that can modulate gene expression and influence cellular function. The main nutrient sensors of the network include the mTOR Complex (mTORC1), which senses the availability of leucine and other amino acids [42], AMP-activated kinase (AMPK), which is a sensor of ATP availability [43], and the sirtuins SIRT1 and SIRT3, which respond to NAD+ levels, an indication of cellular energy status [44].

These and other sensors, along with other signaling molecules, work together to modulate cellular metabolism according to energy availability. For example, in a context of overnutrition, MTORC1 is activated and AMPK, SIRT1, and SIRT3 are inhibited, which leads to an inhibition of catabolic reactions with consequent suppression of adaptive cellular stress responses, including autophagy, antioxidant defenses, and DNA repair. Conversely, calorie restriction and fasting inhibit MTORC1 and activate AMPK, SIRT1, and SIRT3, leading to a promotion of adaptive cellular stress responses [45].

With aging, increases in oxidative stress, inflammation, epigenetic modifications, genomic instability, and disruption of enzymatic activity can contribute to a deregulation of the nutrient-sensing network, and consequently, poorer regulation of adaptive cellular stress responses. This can make a homeostatic metabolic regulation network acquire pro-aging properties [4,41].

The activity of the nutrient-sensing network has a marked influence on healthspan and aging [42,46,47]. Healthy aging benefits and extended lifespan can be achieved through dietary changes, namely by calorie restriction, time-restricted feeding, and adjustments to dietary composition [48–50].

Mitochondrial Dysfunction

Mitochondria are a type of cell organelle (i.e., specialized cellular structure) that participate in a wide range of processes with crucial roles in cellular function and health maintenance. The key function of mitochondria is the extraction of energy from nutrients and the generation of cell energy as ATP. But mitochondria have many other roles, including in inflammation and immunity and in cell survival and cell death pathways [51].

Mild mitochondrial stress can promote an adaptive stress response that enhances the health, viability, and functionality of a cell, tissue, or organism [52,53]. This response is called mitohormesis (from mitochondria + hormesis) and it is a specific form of hormesis—a biological adaptive response that’s beneficial at a low stressor dose and damaging at a high stressor dose [54]. 

With aging, mitochondria are exposed to growing levels of stressors and their responses become detrimental. Mitochondrial function declines due to exposure to multiple linked processes, including an accumulation of mitochondrial DNA mutations, loss of proteostasis, and loss of mitochondrial quality control mechanisms that maintain mitochondrial fitness by repairing or eliminating damaged molecules and organelles and by creating new functional proteins and mitochondria [55,56].

These changes compromise the efficiency of the electron transport chain, mitochondrial metabolism, and cell energy production, enhance the production of reactive oxygen species (ROS), and can permeabilize mitochondrial membranes and trigger signaling pathways that lead to inflammation and cell death. Together, these changes lead to a progressive deterioration of cell and tissue function and, consequently, to an acceleration of the aging process [4,57].

Cellular Senescence

Cellular senescence is a stress response characterized by a permanent state of growth arrest (i.e., cells stop dividing, but don’t die) and the production of chemical mediators that influence tissue function and immune responses, collectively known as senescence-associated secretory profile (SASP) [58,59]. Cells become senescent in response to different types of stress (some of which are other hallmarks of aging), such as mitochondrial dysfunction, oxidative stress, genomic instability, epigenetic alterations, and telomere attrition, for example [60]. 

Senescence occurs as part of healthy tissue function to suppress the proliferation of dysfunctional cells, promote tissue regeneration and repair, and recruit immune cells that remove dysfunctional cells. After carrying out these functions, senescent cells are promptly removed by the immune system. However, when immune clearance fails, senescent cells can linger in tissues, gradually accumulate, and continue to secrete SASP mediators whose actions were meant to be restricted and that may now interfere with tissue repair and regeneration [61–63]. 

With aging, several cellular stressors that induce senescence increase, and the immune system becomes less efficient at finding and clearing senescent cells, allowing a growing accumulation of senescent cells [58,64,65]. Cellular senescence burden in tissues and organs can drive age‐related dysfunctions and contribute to functional decline with aging [66,67]. 

All cell types can undergo senescence during aging, but fibroblasts, endothelial cells, and immune cells are the most affected [68]. Even cells in non-proliferating or slowly proliferating tissues, such as the brain or the heart can become senescent [68–70]. Studies in mice with accelerated aging and naturally aged have demonstrated that the elimination or disruption of senescent cells can ameliorate several age-associated conditions and delay health decline during aging [71–73].

Stem Cell Exhaustion

Stem cells are undifferentiated or partially differentiated cells, i.e., cells that haven’t yet developed into a specific type of cell. Stem cells can differentiate into different types of cells and have the capacity to divide indefinitely to self-renew, thereby maintaining a stem cell pool [74]. 

There are two major types of stem cells: embryonic stem cells, which can originate all cell types of the adult body, and non-embryonic or somatic stem cells, commonly known as adult stem cells, which are found within tissues and organs and can differentiate only into the specialized cell types of that tissue or organ [74]. These tissue-specific stem cells play a key role in tissue regeneration and repair and in maintaining tissue homeostasis throughout life [75].

Because stem cells persist throughout life, they are particularly susceptible to the accumulation of cellular damage and age-related changes, including oxidative damage, DNA damage, epigenetic modifications, mitochondrial dysfunction, and aggregation of damaged proteins. Consequently, with aging, stem cells exhibit a marked decline in their capacity to proliferate and either become senescent or die by apoptosis, leading to a decline in the stem cell pool, or stem cell exhaustion. These changes manifest as a reduced capacity to renew and repair tissues that is associated with, and contributes to, the aging process [4,75].

Altered Intercellular Communication

Aging is associated with progressive changes in intercellular communication that compromise the homeostatic regulation of tissues and organs. These changes affect the main pathways of intercellular communication—neural, endocrine, and immune signaling pathways— as well as short-lived extracellular signaling molecules (such as ROS, nitric oxide, and prostaglandins), mediators released from tissues, cell-bound ligands, and receptors, as well as cell-to-cell interactions through tight junctions or gap junctions [4,76]. 

Altered intercellular communication can change the properties of tissues in ways that may favor the aging process [77,78]. For example, it can affect the function of fibroblasts (the main cells of connective tissues), leading to the activation of pro-senescence and pro-inflammatory pathways and to increased secretion of molecules that promote modifications in proteins of the extracellular matrix (ECM) that supports tissues, such as elastin fragmentation and collagen crosslinking [79]. This in turn can lead to increased ECM stiffness and tissue fibrosis and contribute to tissue aging (a process known as fibroaging) [80–82].

Alterations in intercellular communication are mostly driven by changes within cells (e.g., senescence, genomic instability), but they allow the amplification of age-related changes occurring at the cellular level to the tissue, organ, or even whole-body level. This can occur by promoting systemic inflammation, a decline in immune efficiency, detrimental metabolic adaptations, and alterations in the communication between the human genome and the microbiome, for example [4]. 

Chronic Inflammation

Inflammation increases and can become chronic during aging [83]. This process is known as inflammaging and it’s caused by a progressive increase in the levels of pro-inflammatory mediators in blood and tissues. Inflammaging occurs as a consequence of changes driven by other hallmarks, such as genomic instability, disabled autophagy, epigenetic modifications, loss of proteostasis, altered intercellular communication, and SASP signaling. Inflammaging can also be promoted by perturbations of circadian rhythms and by intestinal barrier dysfunction [84].

In association with enhanced inflammation, immune function also declines [85], leading to excessive activation of pro-inflammatory immune cells, inefficient immunosurveillance and elimination of infected, damaged, or senescent cells, loss of self-tolerance, enhanced autoimmune responses, and reduced maintenance and repair of biological barriers, all of which amplify systemic inflammation [86].

Chronic inflammation manifests at the systemic level and contributes to the development of several age-related dysfunctions, including neuroinflammation, cardiovascular changes, metabolic dysfunction, and joint degeneration, for example [83,87]. 

Dysbiosis

The gut microbiota and its genes, metabolites, and signaling molecules (i.e., the gut microbiome) are key players in multiple human physiological processes, such as metabolism, immunity, and neural signaling. Therefore, the gut microbiome can have a strong impact on the maintenance of our health and the aging process [88]. 

The composition of the gut microbiota changes gradually during aging, leading to a general decrease in ecological diversity. This change influences the levels of microbial metabolites, which can in turn influence physiological processes in the human body. On the other hand, age-related host cellular changes and alterations in intercellular communication can also affect the composition and activity of the gut microbiota, creating a feed-forward loop of disruption of the bidirectional host-microbiota communication. This can result in dysbiosis, i.e., an imbalance in the composition of the gut microbiota and a disruption of microbial metabolism that changes human-microbiota interactions and can contribute to several age-related dysfunctions [89,90].

Analyses of the gut microbiome of adults of all ages have indicated that there are age-related shifts in the abundance of specific microbial populations that are associated with changes in the levels of microbial metabolites involved in inflammation, immune regulation, and aging [91,92].

Although there is marked heterogeneity in the patterns of microbial composition described in aging, specific age-related shifts in gut microbiota composition have been identified and linked to frailty, inflammation, and poorer cognition and mood with aging [91]. On the other hand, a higher abundance of health-promoting bacterial species, including Akkermansia, have been found in healthier older adults [93].

How the Hallmarks Contribute to the Aging Process

The hallmarks of aging are all interconnected and sometimes even overlap. Each can play a part in the development of amplification of other hallmarks and, together, they contribute to the complex process of aging. Nevertheless, some degree of hierarchy can be established between them, resulting in their grouping into three categories: primary, antagonistic, and integrative hallmarks.

The primary hallmarks—genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and disabled macroautophagy—can be regarded as initiating triggers within cells whose damaging consequences progressively accumulate with time. They are unambiguously negative. 

On the other hand, antagonistic hallmarks—deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence—are biological stressors that can have opposite effects depending on their dose. They are hormetic responses: at low levels, they promote beneficial and protective adaptations, but when they are exacerbated or chronic, they become damaging [54]. The antagonistic hallmarks start out as beneficial processes, but become progressively detrimental with aging, partly due to or accelerated by the primary hallmarks. 

Finally, integrative hallmarks—stem cell exhaustion, altered intercellular communication

chronic inflammation, and dysbiosis—develop when the damage caused by the primary and antagonistic hallmarks accumulates beyond a point that cannot be managed by tissue homeostatic mechanisms. Integrative hallmarks have a direct effect on tissue function and systemic health.

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