Aging may be inevitable, but a study of the various Hallmarks of Aging and some newer mechanisms, will help us to increase the ‘healthy lifespan’ and lead a relatively disease-free life up to our genetic potential. There are 100’s of theories of Aging, which have been proposed based on man’s search for immortality since 1000s of years. Till date, the search for the ‘fountain of youth’ continues.
Carlos Lopez-Otin and others (2013) have published an extensive review, which describes the ‘9 Hallmarks of Aging’. Each hallmark involves the intrinsic (internal and genetically programmed factors) and the extrinsic or external factors that influence the aging process. The external factors can be modulated and a factor is called a hallmark if it accelerates aging or if its reversal ameliorates the aging process. [1]
These 9 hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.[1]
Brief Overview of the 9 Hallmarks of Aging
- Genomic Instability – Accumulation of genetic changes and damages throughout life.
- Telomere Attrition – Loss of the protective Telomeres at the end of chromosomes during cell division.
- Epigenetic alterations – Methylation of Histones and Chromatin (proteins that cover DNA) alters the expression of genes.
- Loss of proteostasis – Impairment of protein homeostasis leading to formation and accumulation of unfolded and misfolded proteins, which cannot perform their critical functions.
- Deregulated nutrient-sensing – The mechanisms that detect nutrient scarcity, induce catabolism and increase longevity; whereas nutrient abundance induces anabolism and accelerated aging.
- Mitochondrial dysfunction – The efficiency of energy production (ATP) is reduced and the generation of reactive oxygen species (ROS) is increased. The critical signals for intracellular communication are also disrupted and the survival responses diminished.
- Cellular Senescence – Is the arrest of the cell’s ability to divide. One mechanism is Telomere Attrition but there are many other mechanisms leading to cellular senescence.
- Stem Cell Exhaustion – The decline of ‘stem cells’ in multiple tissues of the body, leading to a reduced capacity for repair of various tissues and organs.
- Altered Intercellular Communication – Aging induces changes in intercellular communication and disrupts the hormonal balance. There is an underlying smouldering proinflammatory state known as ‘inflammaging’. This is accompanied by reduced immunity and reduced responses by the elaborate cellular defences mediated by Sirtuins.
Aging or senescence in one tissue, can lead to deterioration in other tissues, a process known as ‘contagious aging’ or the ‘bystander effect’. Conversely, lifespan-extending manipulations targeting one single tissue can retard the aging process in other tissues.[1]
Intracellular Communication
Disruption of intracellular communication is fast emerging as another fundamental aspect of aging. These developments are centred around mitochondrial function, autophagy and mitochondrial communication with the nucleus and other organelles (like lysosomes) inside the cell.
The activities of the two principal proteolytic systems implicated in protein quality control, namely, the autophagy-lysosomal system and the ubiquitin-proteasome system, decline with aging
Autophagy involves the degradation and recycling of dysfunctional intracellular debris (mainly proteins) by the lysosome, for recycling substrates and restoring homeostasis. Autophagy is cytoprotective and its disruption leads to accelerated aging. When autophagy is restored it has an anti-aging effect. Calorie restriction and Resveratrol help to restore autophagy via the Sirtuin, AMPK and mTOR pathways. Curcumin also has a salutary effect due to its range of anti-inflammatory actions. [2]
Intracellular communication between mitochondria and the nucleus is critical for maintaining homeostasis under normal and stressful conditions. A decline in the communication process accelerates aging. Apart from generating energy (ATP), mitochondria are involved in iron-sulfur cluster biogenesis, nucleotide biosynthesis, and amino acid metabolism. Almost all mitochondrial proteins are encoded in nuclear genes. The cross-talk between them ensures that mitochondria get their structural components as and when it is necessary, to maintain mitochondrial function and also biogenesis as per the energy demands of the cell and tissues. [3]
Accumulating evidence demonstrates an age-dependent decline in NAD+ levels and associate its depletion to several hallmarks of aging and age-related diseases. NAD+ is one of the important compounds involved in communication between mitochondria and the nuclear genome. Intracellular NAD+ is closely linked to the Sirtuins, PGC 1alpha and other pathways that cause mitochondrial biogenesis and restore mitochondrial function. NAD (Nicotinamide Adenine Dinucleotide) levels can be increased by oral consumption of NR (Nicotinamide Riboside) or NMN (Nicotinamide Mononucleotide) administration. NMN has been shown to have remarkable beneficial effects that counter normal aging. [4]
Numerous anti-aging trials are in progress and hopefully some effective anti-aging remedies will emerge. In the meanwhile, calorie restriction, diets rich in antioxidants and flavonoids, exercise and stress reduction are wise options to delay aging and increase healthy lifespan.
Prolong Youth by leading an ‘enlightened and balanced life’
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- Ref 1: Carlos Lopez Otin et al, Cell. 2013 June 6; 153(6): 1194–1217
- Ref 2: Rubinsztein DC et al, Cell 146, September 2, 2011: p 682-695
- Ref 3: Eisenberg-Bord et al, The FEBS Journal 284 (2017) 196–210
- Ref 4: Aman Y et al, Translational Medicine of Aging 2 (2018) 30-37
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