Hallmarks of aging

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Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The hallmarks of aging are the types of biochemical changes that occur in all organisms that experience biological aging and lead to a progressive loss of physiological integrity, impaired function and, eventually, death. They were first listed in a landmark paper in 2013 [1] to conceptualize the essence of biological aging and its underlying mechanisms.

Contents

The following three premises for the interconnected hallmarks have been proposed: [2]

Overview

The hallmarks of aging The Hallmarks of Aging.jpg
The hallmarks of aging

Over time, almost all living organisms experience a gradual and irreversible increase in senescence and an associated loss of proper function of the bodily systems. As aging is the primary risk factor for major human diseases, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases, it is important to describe and classify the types of changes that it entails.

After a decade, the authors of the heavily cited original paper updated the set of proposed hallmarks in January 2023. [3] [2] In the new paywalled review, three new hallmarks have been added (not included or categorized below): disabled macroautophagy, chronic inflammation and dysbiosis, totaling 12 proposed hallmarks. [2]

The nine hallmarks of aging of the original paper are grouped into three categories as below: [1]

Primary hallmarks (causes of damage)

Antagonistic hallmarks (responses to damage)

Integrative hallmarks (culprits of the phenotype)

Primary hallmarks are the primary causes of cellular damage. Antagonistic hallmarks are antagonistic or compensatory responses to the manifestation of the primary hallmarks. Integrative hallmarks are the functional result of the previous two groups of hallmarks that lead to further operational deterioration associated with aging. [1]

There are also proposed further hallmarks or underlying mechanisms that drive multiple of these hallmarks.

The hallmarks

Each hallmark was chosen to try to fulfill the following criteria: [1]

  1. manifests during normal aging;
  2. experimentally increasing it accelerates aging;
  3. experimentally amending it slows the normal aging process and increases healthy lifespan.

These conditions are met to different extents by each of these hallmarks. The last criterion is not present in many of the hallmarks, as science has not yet found feasible ways to amend these problems in living organisms.

Genome instability

Proper functioning of the genome is one of the most important prerequisites for the smooth functioning of a cell and the organism as a whole. Alterations in the genetic code have long been considered one of the main causal factors in aging. [4] [5] In multicellular organisms genome instability is central to carcinogenesis, [6] and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

Abnormal chemical structures in the DNA are formed mainly through oxidative stress and environmental factors. [7] A number of molecular processes work continuously to repair this damage. [8] Unfortunately, the results are not perfect, and thus damage accumulates over time. [4] Several review articles have shown that deficient DNA repair, allowing greater accumulation of DNA damages, causes premature aging; and that increased DNA repair facilitates greater longevity. [9]

Telomere shortening

Human chromosomes (gray) capped with telomeres (white) Telomere caps.PNG
Human chromosomes (gray) capped with telomeres (white)

Telomeres are regions of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. They protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the ends of the DNA strand for a double strand break.

Telomere shortening is associated with aging, mortality and aging-related diseases. Normal aging is associated with telomere shortening in both humans and mice, and studies on genetically modified animal models suggest causal links between telomere erosion and aging. [10] Leonard Hayflick demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase. Each time a cell undergoes mitosis, the telomeres on the ends of each chromosome shorten slightly. Cell division will cease once telomeres shorten to a critical length. [11] This is useful when uncontrolled cell proliferation (like in cancer) needs to be stopped, but detrimental when normally functioning cells are unable to divide when necessary.

An enzyme called telomerase elongates telomeres in gametes and stem cells. [12] Telomerase deficiency in humans has been linked to several aging-related diseases related to loss of regenerative capacity of tissues. [13] It has also been shown that premature aging in telomerase-deficient mice is reverted when telomerase is reactivated. [14] The shelterin protein complex regulates telomerase activity in addition to protecting telomeres from DNA repair in eukaryotes.

Epigenomic alterations

DNA condensation-the DNA chain is wrapped around histones, which form into coils, which wrap into ever larger coils that ultimately make up the chromosome. DNA ORF.png
DNA condensation–the DNA chain is wrapped around histones, which form into coils, which wrap into ever larger coils that ultimately make up the chromosome.

Out of all the genes that make up a genome, only a subset are expressed at any given time. The functioning of a genome depends both on the specific order of its nucleotides (genomic factors), and also on which sections of the DNA chain are spooled on histones and thus rendered inaccessible, and which ones are unspooled and available for transcription (epigenomic factors). Depending on the needs of the specific tissue type and environment that a given cell is in, histones can be modified to turn specific genes on or off as needed. [15] The profile of where, when and to what extent these modifications occur (the epigenetic profile) changes with aging, turning useful genes off and unnecessary ones on, disrupting the normal functioning of the cell. [16]

As an example, sirtuins are a type of protein deacetylases that promote the binding of DNA onto histones and thus turn unnecessary genes off. [17] These enzymes use NAD as a cofactor. With aging, the level of NAD in cells decreases and so does the ability of sirtuins to turn off unneeded genes at the right time. Decreasing the activity of sirtuins has been associated with accelerated aging and increasing their activity has been shown to stave off several age-related diseases. [18] [19]

Loss of proteostasis

Proteostasis is the homeostatic process of maintaining all the proteins necessary for the functioning of the cell in their proper shape, structure and abundance. [20] Protein misfolding, oxidation, abnormal cleavage or undesired post-translational modification can create dysfunctional or even toxic proteins or protein aggregates that hinder the normal functioning of the cell. [21] Though these proteins are continually removed and recycled, formation of damaged or aggregated proteins increases with age, leading to a gradual loss of proteostasis. [22] This can be slowed or suppressed by caloric restriction [23] or by administration of rapamycin, both through inhibiting the mTOR pathway. [24]

Deregulated nutrient sensing

Nutrient sensing is a cell's ability to recognize, and respond to, changes in the concentration of macronutrients such as glucose, fatty acids and amino acids. In times of abundance, anabolism is induced through various pathways, the most well-studied among them the mTOR pathway. [25] When energy and nutrients are scarce, the AMPK receptor senses this and switches off mTOR to conserve resources. [26]

In a growing organism, growth and cell proliferation are important and thus mTOR is upregulated. In a fully grown organism, mTOR-activating signals naturally decline during aging. [27] It has been found that forcibly overactivating these pathways in grown mice leads to accelerated aging and increased incidence of cancer. [28] mTOR inhibition methods like dietary restriction or administering rapamycin have been shown to be one of the most robust methods of increasing lifespan in worms, flies and mice. [29] [30]

Mitochondrial dysfunction

Mitochondrion Mitochondrion mini.svg
Mitochondrion

The mitochondrion is the powerhouse of the cell. Different human cells contain from several up to 2500 mitochondria, [31] each one converting carbon (in the form of acetyl-CoA) and oxygen into energy (in the form of ATP) and carbon dioxide.

During aging, the efficiency of mitochondria tends to decrease. The reasons for this are still quite unclear, but several mechanisms are suspected: reduced biogenesis, [32] accumulation of damage and mutations in mitochondrial DNA, oxidation of mitochondrial proteins, and defective quality control by mitophagy. [33]

Dysfunctional mitochondria contribute to aging through interfering with intracellular signaling [34] [35] and triggering inflammatory reactions. [36]

Cellular senescence

Under certain conditions, a cell will exit the cell cycle without dying, instead becoming dormant and ceasing its normal function. This is called cellular senescence. Senescence can be induced by several factors, including telomere shortening, [37] DNA damage [38] and stress. Since the immune system is programmed to seek out and eliminate senescent cells, [39] it might be that senescence is one way for the body to rid itself of cells damaged beyond repair.

The links between cell senescence and aging are several:

Stem cell exhaustion

Stem cells are undifferentiated or partially differentiated cells with the unique ability to self-renew and differentiate into specialized cell types. For the first few days after fertilization, the embryo consists almost entirely of stem cells. As the fetus grows, the cells multiply, differentiate and assume their appropriate function within the organism. In adults, stem cells are mostly located in areas that undergo gradual wear (intestine, lung, mucosa, skin) or need continuous replenishment (red blood cells, immune cells, sperm cells, hair follicles).

Loss of regenerative ability is one of the most obvious consequences of aging. This is largely because the proportion of stem cells and the speed of their division gradually lowers over time. [43] It has been found that stem cell rejuvenation can reverse some of the effects of aging at the organismal level. [44]

Altered intercellular communication

Different tissues and the cells they consist of need to orchestrate their work in a tightly controlled manner so that the organism as a whole can function. One of the main ways this is achieved is through excreting signal molecules into the blood where they make their way to other tissues, affecting their behavior. [45] [46] The profile of these molecules changes as we age.

One of the most prominent changes in cell signaling biomarkers is "inflammaging", the development of a chronic low-grade inflammation throughout the body with advanced age. [47] The normal role of inflammation is to recruit the body's immune system and repair mechanisms to a specific damaged area for as long as the damage and threat are present. The constant presence of inflammation markers throughout the body wears out the immune system and damages healthy tissue. [48]

It's also been found that senescent cells excrete a specific set of molecules called the SASP (Senescence-Associated Secretory Phenotype) which induce senescence in neighboring cells. [49] Conversely, lifespan-extending manipulations targeting one tissue can slow the aging process in other tissues as well. [50]

Further hallmarks

These may constitute further hallmarks or underlying mechanisms that drive multiple of these hallmarks.

Alternative conceptual models

The Seven Pillars of Aging Model The seven pillars of aging.jpg
The Seven Pillars of Aging Model

In 2014, other scientists have defined a slightly different conceptual model for aging, called 'The Seven Pillars of Aging', in which just three of the 'hallmarks of aging' are included (stem cells and regeneration, proteostasis, epigenetics). [53] The seven pillars model highlights the interconnectedness between all of the seven pillars which is not highlighted in the nine hallmarks of aging model. [54]

Authors of the original paper merged or linked various hallmarks of cancer with those of aging. [55]

The authors also concluded that the hallmarks are not only interconnected among each other but also "to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress". [2] [56]

See also

Related Research Articles

<span class="mw-page-title-main">Telomere</span> Region of repetitive nucleotide sequences on chromosomes

A telomere is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Telomeres are a widespread genetic feature most commonly found in eukaryotes. In most, if not all species possessing them, they protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double-strand break.

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. Whole organism senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

<span class="mw-page-title-main">Telomerase</span> Telomere-restoring protein active in the most rapidly dividing cells

Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.

Biological immortality is a state in which the rate of mortality from senescence is stable or decreasing, thus decoupling it from chronological age. Various unicellular and multicellular species, including some vertebrates, achieve this state either throughout their existence or after living long enough. A biologically immortal living being can still die from means other than senescence, such as through injury, poison, disease, predation, lack of available resources, or changes to environment.

<span class="mw-page-title-main">Hayflick limit</span> Limit to divisions of a normal human cell

The Hayflick limit, or Hayflick phenomenon, is the number of times a normal somatic, differentiated human cell population will divide before cell division stops. However, this limit does not apply to stem cells.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

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<span class="mw-page-title-main">Telomerase reverse transcriptase</span> Catalytic subunit of the enzyme telomerase

Telomerase reverse transcriptase is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.

<span class="mw-page-title-main">Cellular senescence</span> Phenomenon characterized by the cessation of cell division

Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things.

The stem cell theory of aging postulates that the aging process is the result of the inability of various types of stem cells to continue to replenish the tissues of an organism with functional differentiated cells capable of maintaining that tissue's original function. Damage and error accumulation in genetic material is always a problem for systems regardless of the age. The number of stem cells in young people is very much higher than older people and thus creates a better and more efficient replacement mechanism in the young contrary to the old. In other words, aging is not a matter of the increase in damage, but a matter of failure to replace it due to a decreased number of stem cells. Stem cells decrease in number and tend to lose the ability to differentiate into progenies or lymphoid lineages and myeloid lineages.

<span class="mw-page-title-main">Biomarkers of aging</span> Type of biomarkers

Biomarkers of aging are biomarkers that could predict functional capacity at some later age better than chronological age. Stated another way, biomarkers of aging would give the true "biological age", which may be different from the chronological age.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

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Judith Campisi was an American biochemist and cell biologist. She was a professor of biogerontology at the Buck Institute for Research on Aging. She was also a member of the SENS Research Foundation Advisory Board and an adviser at the Lifeboat Foundation. She was co-editor in chief of the Aging Journal, together with Mikhail Blagosklonny and David Sinclair, and founder of the pharmaceutical company Unity Biotechnology. She is listed in Who's Who in Gerontology. She was widely known for her research on how senescent cells influence aging and cancer — in particular the Senescence Associated Secretory Phenotype (SASP).

Senotherapy is an early-stage basic research field for development of possible therapeutic agents and strategies to specifically target cellular senescence, an altered cell state associated with ageing and age-related diseases. The name derives from intent of the proposed anti-aging drug to halt "senescence". As of 2019, much of the research remains preliminary and there are no drugs approved for this purpose.

The disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. Formulated by Thomas Kirkwood, the disposable soma theory explains that an organism only has a limited amount of resources that it can allocate to its various cellular processes. Therefore, a greater investment in growth and reproduction would result in reduced investment in DNA repair maintenance, leading to increased cellular damage, shortened telomeres, accumulation of mutations, compromised stem cells, and ultimately, senescence. Although many models, both animal and human, have appeared to support this theory, parts of it are still controversial. Specifically, while the evolutionary trade-off between growth and aging has been well established, the relationship between reproduction and aging is still without scientific consensus, and the cellular mechanisms largely undiscovered.

Cell cycle withdrawal refers to the natural stoppage of cell cycle during cell division. When cells divide, there are many internal or external factors that would lead to a stoppage of division. This stoppage could be permanent or temporary, and could occur in any one of the four cycle phases, depending on the status of cells or the activities they are undergoing. During the process, all cell duplication process, including mitosis, meiosis as well as DNA replication, will be paused. The mechanisms involve the proteins and DNA sequences inside cells.

Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases. SASP may also consist of exosomes and ectosomes containing enzymes, microRNA, DNA fragments, chemokines, and other bioactive factors. Soluble urokinase plasminogen activator surface receptor is part of SASP, and has been used to identify senescent cells for senolytic therapy. Initially, SASP is immunosuppressive and profibrotic, but progresses to become proinflammatory and fibrolytic. SASP is the primary cause of the detrimental effects of senescent cells.

Telomeres, the caps on the ends of eukaryotic chromosomes, play critical roles in cellular aging and cancer. An important facet to how telomeres function in these roles is their involvement in cell cycle regulation.

<span class="mw-page-title-main">Relationship between telomeres and longevity</span>

The relationship between telomeres and longevity and changing the length of telomeres is one of the new fields of research on increasing human lifespan and even human immortality. Telomeres are sequences at the ends of chromosomes that shorten with each cell division and determine the lifespan of cells. The telomere was first discovered by biologist Hermann Joseph Muller in the early 20th century. However, experiments by Elizabeth Blackburn, Carol Greider, and Jack Szostak in the 1980s led to the successful discovery of telomerase and a better understanding of telomeres.

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