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9 Hallmarks of aging

Aging is scientifically defined as a progressive loss of physiological functions and increased vulnerability to immune conditions. The decline of integrity of the normal biochemical functions of the cells of the body poses a major risk of developing age-related maladies like cancer, diabetes, cardiovascular diseases and neurodegenerative diseases like Alzheimer’s disease. While today’s approaches in medicine focus more on predictive and preventive measures, it is conspicuous that we pay attention to any ‘red flags’ that have been disposed of. In this article we will review some of the major hallmarks of aging backed by modern gerontology research.

 

Genomic instability
One major contributor to aging is accumulation of DNA damage. The DNA damage is normally repaired by the sirtuins. Why this damage occurs is because of some exogenous as well as endogenous factors. The former can be anything like physical, chemical and biological agents while the latter includes reactive oxygen species, errors in DNA replication and spontaneous hydrolytic reactions in the cells. These agents can cause mutations, deletions, chromosome aneuploidies and copy-number variations in both nuclear and mitochondrial DNA. These damages are proven to cause genetic disorders and accelerate aging in mice. When the expression of DNA damage repairing genes was increased in transgenic mice, it was shown that it delayed aging. This marks the first hallmark of aging to be instability in the genome.

Telomere attrition
Telomeres are the regions of chromosomes that are normally linked to aging. These consist of terminal end DNA which general DNA polymerases cannot replicate completely. These regions can only be replicated by telomerase enzymes. With age, humans and mice experience telomere shortening as most of the somatic cells do not express telomerase. Shelterins are a type of nucleoprotein complexes that hide the telomeres that cannot be replicated even in the presence of telomerase. This leads to deteriorating effects on cells such as senescence and apoptosis. This telomere dysfunction is thought to accelerate aging in both mice and humans.

Epigenetic alterations
Epigenetic changes are another major hallmark associated with aging. They involve alterations in DNA methylations, chromatin remodeling as well as post-translational modifications in histones. These abnormal modifications affect genes which contribute towards longevity in many model organisms. SIRT6 is a common example of epigenetic alterations whose loss-of-function reduces longevity in mice and makes them vulnerable to genetic disorders. The experiments suggest that manipulating the epigenome can help eliminate the age-related pathologies and promote longevity in mice and humans.

Loss of proteostasis
Protein homeostasis is referred to as proteostasis. Proteostasis helps stabilize the correctly folded proteins and degradation of proteins by proteasome or lysosome. There are other mechanisms than molecular chaperons and proteases which act coordinatively to remove and restore any proteins avoiding accumulation of cellular waste. With age, these processes are disturbed causing age-related diseases. Genetic manipulations in proteostasis in mammals are seen to delay aging.

Deregulated nutrient-sensing
IGF-1 and insulin (IIS) pathway is the most evolutionarily conserved nutrient sensing pathway linked to the extension of lifespan. This pathway is integrated with other nutrient sensing systems like mTOR, AMPK and sirtuins. These systems sense amino acids, low energy states by high AMP levels and high NAD⁺ levels. The latter two pathways sense catabolism and hence work in the opposite direction of former two. Experiments have shown that their up-regulation favors healthy aging. Based on these studies it is believed that manipulation of these pathways with the help of CR mimetics such as rapamycin can promote health and longevity in mice.

Mitochondrial dysfunction
There are different theories of mitochondrial dysfunction such as reactive oxygen species (ROS) and Mito hormesis. The efficacy of the respiratory chain in mitochondria decreases and it starts to leak electrons thereby reducing ATP generation. According to the ROS theory as age proceeds, the production of ROS is increased in mitochondria further deteriorating the mitochondria and causing overall cellular damage. This phenomenon promotes aging as cellular damage interferes with cellular signaling. Mito hormesis suggests that mild toxic treatments stimulate responses that contribute to cellular fitness and may increase lifespan.

Cellular senescence
Cellular senescence is the arrest of a cell cycle at a particular stage which leads to certain phenotypic changes in the cell. Senescence is caused by the accumulation of telomeric DNA damage as well as non-telomeric DNA damage. This causes the accumulation of senescent cells in the tissues. With age, the rate of accumulation of these cells increases and the rate of their clearance decreases. This effect accelerates aging.

Stem cell exhaustion
Telomere shortening and some other mechanisms cause the decline in regeneration potential of stem cells. Losing the ability to differentiate proves detrimental to the long-term maintenance of the body. This effect applies in case of hematopoiesis as well as immune cells proliferation which generates susceptibility against age-related diseases. Stem cell exhaustion results in tissue and organismal aging. Studies suggest that stem cell rejuvenation therapies might be helpful in reversing the effects of aging.

Altered intracellular communication
The final hallmark of aging is intracellular communication. This suggests that the phenomenon of aging is not strictly cellular but it also depends on intracellular communication which is generally carried out in the form of signaling pathways. This implies that cell signaling can be improved to modulate aging. Examples of altered cell signaling with age are inflammatory cytokines, neurochemical signaling and IGF-1 signaling.

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