Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. Thehallmarks of aging are the types ofbiochemical changes that occur in all organisms that experiencebiological 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 ofbiological aging and its underlying mechanisms.
The following three premises for the interconnected hallmarks have been proposed:[2]
"their age-associated manifestation"
"the acceleration of aging by experimentally accentuating them"
Over time,almost all living organisms experience a gradual and irreversible increase insenescence and an associated loss of proper function of the bodily systems. As aging is the primary risk factor for major human diseases, includingcancer,diabetes,cardiovascular disorders, andneurodegenerative diseases, it is important to describe and classify the types of changes that it entails.[citation needed]
After a decade, the authors of the heavilycited original paper updated the set of proposed hallmarks in January 2023.[3][2] In the newreview, three new hallmarks have been added:macroautophagy,chronic inflammation anddysbiosis, totaling 12 proposed hallmarks.[2]
The nine hallmarks of aging of the original paper are grouped into three categories as below:[1]
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.[citation needed]
Each hallmark was chosen to try to fulfill the following criteria:[1]
manifests during normal aging;
experimentally increasing it accelerates aging;
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.[citation needed]
Proper functioning of thegenome is one of the most important prerequisites for the smooth functioning of a cell and the organism as a whole. Alterations in thegenetic code have long been considered one of the main causal factors in aging.[4][5] In multicellular organisms genome instability is central tocarcinogenesis,[6] and in humans it is also a factor in someneurodegenerative diseases such asamyotrophic lateral sclerosis or the neuromuscular diseasemyotonic dystrophy.
Telomere shortening is associated with aging, mortality andaging-related diseases. Normal aging is associated with telomere shortening in both humans and mice, and studies ongenetically modified animal models suggest causal links between telomere erosion and aging.[10]Leonard Hayflick demonstrated that a normalhumanfetal cell population will divide between 40 and 60 times incell culture before entering asenescence phase. Each time a cell undergoesmitosis, thetelomeres on the ends of eachchromosome shorten slightly. Cell division will cease once telomeres shorten to a critical length.[11] This is useful when uncontrolledcell proliferation (like in cancer) needs to be stopped, but detrimental when normally functioning cells are unable to divide when necessary.[citation needed]
An enzyme calledtelomerase elongates telomeres ingametes andstem 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] Theshelterin protein complex regulates telomerase activity in addition to protecting telomeres from DNA repair ineukaryotes.[citation needed]
DNA condensation–the DNA chain is wrapped aroundhistones, which form into coils, which wrap into ever larger coils that ultimately make up thechromosome.
Out of all the genes that make up a genome, only a subset areexpressed at any given time. The functioning of a genome depends both on the specific order of itsnucleotides (genomic factors), and also on which sections of theDNA chain are spooled onhistones and thus rendered inaccessible, and which ones are unspooled and available fortranscription (epigenomic factors). Depending on the needs of the specific tissue type and environment that a given cell is in, histones can bemodified 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 ofprotein deacetylases that promote the binding of DNA onto histones and thus turn unnecessary genes off.[17] These enzymes useNAD as acofactor. 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]
Proteostasis is thehomeostatic 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 undesiredpost-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 continuallyremoved 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 bycaloric restriction[23] or by administration ofrapamycin, both through inhibiting themTOR pathway.[24]
Nutrient sensing is acell's ability to recognize, and respond to, changes in the concentration of macronutrients such asglucose,fatty acids andamino acids. In times of abundance,anabolism is induced through variouspathways, the most well-studied among them themTOR pathway.[25] When energy and nutrients are scarce, theAMPK receptor senses this and switches off mTOR to conserve resources.[26]
In a growing organism, growth and cell proliferation are important and thus mTOR isupregulated. 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 likedietary restriction or administeringrapamycin have been shown to be one of the most robust methods of increasing lifespan in worms, flies and mice.[29][30]
Themitochondrion is the powerhouse of the cell. Different human cells contain from several up to 2500 mitochondria,[31] each one converting carbon (in the form ofacetyl-CoA) andoxygen into energy (in the form ofATP) andcarbon dioxide.
During aging, the efficiency of mitochondria tends to decrease. The reasons for this are still quite unclear, but several mechanisms are suspected: reducedbiogenesis,[32] accumulation of damage and mutations inmitochondrial DNA, oxidation of mitochondrial proteins, and defective quality control bymitophagy.[33]
Dysfunctional mitochondria contribute to aging through interfering with intracellular signaling[34][35] and triggering inflammatory reactions.[36]
Under certain conditions, a cell will exit thecell 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 theimmune 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:
The proportion of senescent cells increases with age.[40]
Stem cells areundifferentiated or partially differentiated cells with the unique ability to self-renew and differentiate into specialized cell types. For the first few days after fertilization, theembryo 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).[citation needed]
Loss ofregenerative 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]
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-gradeinflammation throughout the body with advanced age.[47] The normal role of inflammation is to recruit the body'simmune 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 theSASP (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]
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 varioushallmarks 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 proposedhallmarks of health, which include organizational features of spatial compartmentalization, maintenance ofhomeostasis, and adequate responses to stress".[2][56]
^Moskalev, Alexey; Shaposhnikov, Mikhail; Plyusnina, Ekaterina; Zhavoronkov, Alex; Budovsky, Arie; Yanai, Hagai; Fraifeld, Vadim (March 2013). "The role of DNA damage and repair in aging through the prism of Koch-like criteria".Ageing Research Reviews.12 (2):661–684.doi:10.1016/j.arr.2012.02.001.PMID22353384.S2CID26339878.
^Malaquin, Nicolas; Martinez, Aurélie; Rodier, Francis (2016-09-01). "Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype".Experimental Gerontology.82:39–49.doi:10.1016/j.exger.2016.05.010.ISSN0531-5565.PMID27235851.S2CID207584394.
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