What are the 9 hallmarks of aging?
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Aging was described as “a sustained fall in the age-specific fitness components of an organism due to intrinsic physiological degradation” in the 1991 book Evolutionary Biology of Aging.
The concept of the aging process is somewhat broad.
The difficulty in defining aging is that it is a complex process. There is no one explanation for why we age.
However, throughout the last 30 years, interest in aging research has grown dramatically, with a focus on the cellular and molecular underpinnings of life.
Carlos Lopez-Otn and a group of researchers presented nine signs of aging that are thought to accelerate aging in a review article that was published in Cell.
1) Genomic instability
The buildup of genetic damage throughout the course of life is one factor that causes aging. However, the relevance of these and other progeroid syndromes to normal aging remains unanswered in part because they only replicate specific features of aging. Werner syndrome and Bloom syndrome are two examples of premature aging disorders that are the result of increased DNA damage accumulation. DNA replication mistakes, spontaneous hydrolytic reactions, and reactive oxygen species are just a few of the endogenous hazards that are always posing a danger to the stability and integrity of DNA (ROS). In addition to point mutations, translocations, chromosomal gains and losses, telomere shortening, and gene disruption brought on by the integration of viruses or transposons, the genetic lesions resulting from extrinsic or intrinsic damage are extremely varied. The majority of the damage done to nuclear DNA may be repaired by the intricate network of DNA repair mechanisms that animals have developed to reduce these lesions. The genomic stability systems also contain particular processes for preserving the mitochondrial DNA’s integrity and telomeres’ integrity (which are the subject of a distinct hallmark, see below) (mtDNA). In addition to these direct lesions in the DNA, laminopathies, flaws in the nuclear architecture, can result in genomic instability and early aging.
2) Telomere attrition
Telomeres are ribonucleoprotein structures that guard the integrity of information-carrying DNA throughout the cell cycle and stop chromosomal DNA from losing base pairs during cellular division. Telomere length normally declines during successive cell divisions until it reaches a minimum critical size, which prevents further cell division and results in cellular senescence or death, commonly known as the end replication issue. As an enzyme with a catalytic unit, telomerase provides a solution to the end replication issue by encouraging telomere extension. Nevertheless, the gradual loss of the terminal chromosomal ends and the constrained proliferative ability seen in certain in vitro-cultured cells are both explained by the fact that the majority of mammalian somatic cells did not produce this enzyme. Telomeres are ribonucleoprotein structures that guard the integrity of information-carrying DNA throughout the cell cycle and stop chromosomal DNA from losing base pairs during cellular division. Telomere length normally declines during successive cell divisions until it reaches a minimum critical size, which prevents further cell division and results in cellular senescence or death, commonly known as the end replication issue. As an enzyme with a catalytic unit, telomerase provides a solution to the end replication issue by encouraging telomere extension. Nevertheless, the gradual loss of the terminal chromosomal ends and the constrained proliferative ability seen in certain in vitro-cultured cells are both explained by the fact that the majority of mammalian somatic cells did not produce this enzyme.
Numerous publications have shown that shorter leukocyte telomeres and pro-inflammatory cytokines including tumor necrosis factor (TNF-) and interleukin (IL)-6 are associated with chronic inflammation. TNF- seems to play a specialized function in downregulating telomerase activity, which results in telomere shortening.
3) Epigenetic alterations
Research on aging is not just concerned with DNA. After all, a variety of processes, including the epigenome, depend on your DNA to function. Your body’s cells all share the same DNA. But why do liver cells behave differently from brain cells? The epigenome in you has the key. Your DNA receives instructions from a variety of chemical molecules called epigenomes. Your epigenome is the builder if your DNA is the architect of your body. They make the decisions on what will be built. Gene expression is another name for this process. For instance, in order to identify a cell as a liver cell, the epigenome “turns on” specific regions of your DNA. Unfortunately, environmental exposures and illness can have an impact on your epigenome as you age. These modifications may alter how your epigenome controls gene expression, which may impact how your DNA is processed by the epigenome.
4) Loss of Proteostasis
Impaired protein homeostasis or proteostasis is associated with aging and various age-related illnesses. To maintain the integrity and functionality of their proteomes, all cells make use of a variety of quality control systems. Proteostasis involves both mechanisms for the degradation of proteins by the proteasome or lysosome and mechanisms for the stabilization of correctly folded proteins, most notably the heat-shock protein family. In addition, certain regulators of age-related proteotoxicity, such MOAG-4, function in a manner different from that of molecular chaperones and proteases. Together, these mechanisms work to repair misfolded polypeptides’ structural flaws or entirely eliminate and disintegrate them. This prevents the buildup of defective parts and ensures the ongoing production of intracellular proteins. As a result, numerous studies have shown that proteostasis changes with aging. Additionally, the persistent production of unfolded, misfolded, or aggregated proteins aids in the emergence of various age-related diseases, including cataracts, Parkinson’s disease, and Alzheimer’s disease.
5) Deregulated nutrient sensing
The growth hormone-releasing hormone, which primarily acts in the hepatocytes to trigger the production of insulin-like growth factor 1 (IGF-1), controls the growth hormone (GH), which is generated by the anterior pituitary gland. Additionally, IGF-1 is produced in certain tissues including osteocytes, chondrocytes, and muscle to function in an autocrine or paracrine manner.
The intracellular signaling system used by insulin and IGF-1 is a crucial aging-controlling circuit that has been substantially preserved throughout evolution. In this way, lower GH, IGF-1, and insulin receptor activities, as well as their intracellular effectors, have been linked to increased lifespan (such as Akt and mTOR complexes). Within this context, a number of publications linked food restriction to a longer life expectancy or improved health, which was likely caused by a diminished insulin and IGF-1 signaling pathway.
6) Mitochondrial dysfunction
The obvious link between mitochondrial failure and aging has long been the subject of intense debate, but the precise processes at play are still unknown. Initially, the idea of mitochondrial free radical aging stated that aging was accompanied by a growing malfunction of the mitochondria, an increase in ROS levels, additional mitochondrial degeneration, and widespread cellular damage. However, regardless of ROS levels, malfunctioning mitochondria may speed up the aging process.
The fibers of sarcopenic skeletal muscles in older people frequently lack cytochrome c oxidase and have greater levels of mtDNA mutations. Furthermore, mRNAs that encode mitochondrial proteins are downregulated along with the reduced mitochondrial enzyme activity that is typically observed in elderly people. In this way, resistance exercise has the ability to change the skeletal muscle mtDNA of young and old healthy persons, enhancing mitochondrial function. Along the same lines, a 6-month resistance exercise-training program improved mitochondrial function by reversing aging transcriptional signature levels that were approaching those from younger persons.
7) Cellular senescence
When a cell experiences cellular senescence, it loses the capacity to divide and inevitably dies.
Senescence of cells happens naturally. Your body can often manufacture more new cells than senescent ones. But as people age, their number of senescent cells rises.
Consider cellular senescence as a built-in safety measure. Cellular senescence stops those defective features from replicating further when a cell experiences irreversible DNA damage or telomere malfunction.
It’s your body’s final defense against a buildup of environmental stresses. According to a paper that appeared in Nature Reviews Molecular Cell Biology, “endogenous and exogenous stressors induce cellular senescence.”
A review paper in Nature Reviews Endocrinology, however, highlights evidence that cellular senescence contributes to the development of age-related diseases.
Cellular senescence can become troublesome if it continues to proliferate in the absence of fresh cell replacement. For instance, a review article from Nature Medicine describes new data that shows senescence results in a decrease in the ability to heal tissue and the production of proinflammatory chemicals.
Nevertheless, studies into cellular senescence aim to decipher the senescence mechanism for useful therapeutics, notably in halting the growth of troublesome cells.
8) Stem cell exhaustion
The relative importance of cell-intrinsic pathways compared to cell-extrinsic ones is a key topic of discussion regarding the reduction in stem-cell function. Recent research has offered considerable evidence in favor of the latter. In instance, DR enhances cell-extrinsic processes of intestine and muscular stem activities. Even in tissues where donor cells cannot be seen, transplanting muscle-derived stem cells from young mice into progeroid mice increases lifespan and ameliorates degenerative changes in these animals, indicating that their therapeutic benefit may come from systemic effects brought on by secreted factors. Furthermore, parabiosis studies have shown that systemic substances from young mice can restore the loss in brain and muscular stem cell activity in elderly animals.
One of the primary causes of tissue and organismal aging is likely stem cell depletion, which develops as the integrative result of several aging-related impairments. Stem cell rejuvenation may be able to reverse the aging phenotype at the organismal level, according to recent promising findings.
9) Altered intercellular communication
Beyond changes to cells themselves, aging also entails adjustments to endocrine, neuroendocrine, or neuronal intercellular communication. Thus, as inflammatory responses increase, immunosurveillance against pathogens and premalignant cells declines, and the composition of the peri- and extracellular environment changes, neurohormonal signaling (e.g., renin-angiotensin, adrenergic, insulin-IGF1 signaling) tends to be deregulated in aging, affecting the mechanical and functional properties of all tissues.
The importance of inflammatory pathways in aging has also been emphasized by international studies on the transcriptional landscape of aged tissues. One of these transcriptional signatures of aging is the over-activation of the NF-B pathway, and restricted expression of an NF-B inhibitor in the aging skin of transgenic mice results in both phenotypic rejuvenation and the restoration of the transcriptional signature associated with young age. Similarly, in other animal models of accelerated aging, genetic and pharmacological suppression of NF-B signaling prevents age-associated characteristics. The recent discovery that inflammatory and stress responses activate NF-B in the hypothalamus and initiate a signaling cascade that leads in decreased generation of gonadotropin-releasing hormone (GnRH) by neurons suggests a novel connection between inflammation and aging.
Numerous aging-related changes, including bone brittleness, muscular weakness, skin atrophy, and decreased neurogenesis, can be attributed to this GnRH reduction. Treatment with GnRH consistently inhibits aging-impaired neurogenesis and slows the progression of aging in mice. These results imply that the integration of NF-kB-driven inflammatory responses with GnRH-mediated neuroendocrine actions via the hypothalamus may influence systemic aging.
Other types of intercellular communication
The inter-organ coordination of the aging phenotype is explained by the fact that, in addition to inflammation, aging-related alterations in one tissue can result in aging-specific degradation of other tissues. Along with inflammatory cytokines, there are also instances of “contagious aging” or “bystander effects” in which senescent cells cause the senescence of nearby cells by mechanisms involving ROS and gap junction-mediated cell-cell interactions. The age-related functional deficits of CD4 T cells are influenced by the microenvironment, as determined using an adoptive transfer paradigm in mice. Similarly, diminished kidney function can raise a person’s chance of developing heart disease. On the other hand, lifespan-extension techniques that focus on a specific tissue can slow down the aging of that tissue.
Restoring defective intercellular communication
Genetic, dietary, or pharmaceutical therapies that may enhance the cell-cell communication qualities that are lost with age are only a few approaches for reversing the poor intercellular communication that underlies aging processes. The DR techniques for extending healthy longevity and the rejuvenation tactics based on the utilization of blood-borne systemic components discovered in parabiosis investigations are of particular relevance in this respect. Additionally, long-term use of anti-inflammatory drugs like aspirin may lengthen the lifespan of mice and promote healthy aging in humans. Additionally, it appears potential to lengthen longevity by modifying the make-up and activity of the complex and dynamic intestinal bacterial ecology of the human body, given that the gut microbiome influences host immune system function and has systemic metabolic impacts.