In this diverse world, Mayflies have only a 24-hour lifespan, the shortest lifespan of any animals. Greenland sharks live for an average of 300 years while Homo sapiens have an average life expectancy of 70 years which proves that we humans have evolved from our ancestors. This also proves that how ageing and life expectancy isn’t the same for every species thereby providing an opportunity to question its variability and necessity. Ageing or Aging is a multifaceted biological process defined as the deterioration of physiological function throughout time which are essential for the maintenance of homeostasis leading to the early disposition of many diseases including cancer, cardiac disease and neurodegenerative disorders eventually ensuing in early mortality.

 Life seems too short in this swiftly changing world but what if we grow old and choose to pause and start again rather than dying? Though it may sound bizarre many scientists across the globe are working to make this possible by comprehending the hallmark of ageing, the epigenetic alteration. This article will provide brief insights on how altered DNA outdoes the ageing process.

HOW AND WHY DO WE AGE?

Over the years, scientists have been concentrating on the molecular and cellular basis in comprehending the mechanism of ageing. Single-celled entities like bacteria and amoeba easily divide into daughter cells throughout their life span without losing the ability to proliferate, unlike human cell which can divide 50 times before succumbing to death. These observations led to the raise of two theories in the process of understanding ageing.

The first theory proposed the ageing is due to Programmed factors where genes determine the longevity of cells which will lead to the cell’s inability to divide accurately over a while. The second theory proposed that over years DNA gets ruptured until it can no longer function accordingly due to Damage related factors ultimately leading to the ageing of cells.

THEORIES OF AGEING

Ageing

Every day the DNA’s stability is attacked by various physical, chemical, biological factors and various endogenous processes including DNA replication inaccuracy, reactive oxygen species which are treated by a DNA repair system. The incurred damages of the DNA accumulated over a while influence the rate of ageing.

There are several theories like ‘Mutation accumulation theory’, ‘Antagonistic pleiotropy theory’ and ‘Disposable Soma theory’ which were proposed to understand ageing on the molecular level.

Lopez -Otin C and colleagues postulated nine characteristic features of ageing which is the consequence of cellular vandalization inflation which includes

  1. Genomic instability
  2. Telomere alterations
  3. Epigenetic alterations
  4. Cellular senescence
  5. Mitochondrial dysfunction
  6. Deprivation of proteostasis
  7. Uncontrolled nutrient sensing
  8. Exhaustion of stem cells
  9. Modified intercellular communication.

TELOMERES AND DNA DAMAGING IN AGEING:

  • The nuclear genome is incessantly attacked by genotoxic chemicals in high frequency in the form of exogenous and endogenous hazards like Ultraviolet radiation, Ionising radiation, Reactive oxygen species (ROS), hydrolysing, alkylation of DNA molecules spontaneously.
  • When there is damage to the DNA various cells entails an extensive and highly regulated mechanism known as DNA repair mechanism or DNA Damage Response (DDR) which distinguishes and signal DNA lesions aiding in their repair.
  • Generally, DNA can be affected in various ways like bulky adducts, Single-strand breaks (SSB), Double-Strand break (DSB), nucleotide mismatching and so on. But Genome maintenance hypothesis of ageing pegs that DNA repair can be subject to age-related changes and decline to approve the damage accumulation.
  • Cells with defective key proteins involved in the DDR mechanism have invariably reported the increased ageing phenotypes due to mutation accumulation and epimutation which ultimately leads to cell senescence or apoptosis.
  • The recurrent DNA sequences at each end of chromosomes are known as Telomeres which prevent chromosome instability.
  • During every cell division, the telomeres instead of getting replicated by the action of DNA polymerase will get shorten with age (as reported in lymphocytes, HSC and fibroblasts) without the action of Telomerase which maintains the telomeres by adding telomers onto to chromosome       .                      
  • This leads to the proposal that Telomere shortening can serve as a ‘Clock’, an indication for the cells to stop dividing anymore. While Cristofalo and his colleagues pegged that there is no interrelation between the life span of human who has shorter telomeres than mice to telomere length.
  • The studies of Collado.M and colleagues have shown how telomerase-deficient mice had shorter telomeres and age prematurely.
  • Few Studies have pegged that telomere-dependent inhibition of cell division would rather aid as a primary defence against cancer than as an ‘ageing clock’ while there are various studies that serve as evidence in linking the telomere length and cell senescence and how inflammation contributes to the rate of telomere length alteration.
  • These contradictory results from studies emphasize the need to understand the pathway that employs DNA sequence alteration in somatic cell ageing which remains uncertain.

HORVATH CLOCK

HORVATH CLOCK OF AGEING
  • While the first part of this article listed the various theories and few conclusions in understanding the mechanism of ageing, it is essential to recognize the impeccable observation and studies conducted by scientists, one of them being Steve Horvath who devised a biochemical test which goes by the name ‘Horvath clock’ to estimate age using DNA methylation level.
  • Chronological age is the number of years the person is alive (your current age). Biological age is the measure of the health of a person which is dependent on various external factors like diet, exercise, diseased condition and so on.
  • The chronological and biological age may not be similar, for instance, consider a sibling wherein the elder one is an alcoholic while the younger one is a teetotaler. Though chronologically the firstborn would be elder but his/her biological age will be certainly older than the younger sibling due to the habits they possess.
  • This change in biological age can be found by studying DNA Methylation which bears a significant influence in not the only ageing process but also the various physical, chemical and biological process. Horvath’s clock employs by contrasting the DNA methylation age with chronological age which is also known as Age acceleration
  • The estimated age is also known as DNA methylation age rely on 353 epigenetic markers on DNA which measure the CpG nucleotides or methylation. The most significant feature of this clock is its applicability to the diverse spectrum of cell and tissue types.
  • In a recent interview, Steve Horwath stated that changing epigenetics will represent the new frontier for extending the life span and DNA methylation explains more at least 50% differences in longevity across mammals indicating if all goes well by 2035, we will be introduced to anti-ageing pills which will provide extended lifespan!

RESOURCES

The University of Edinburgh. (2019, September 3). Body’s ageing process accelerated by DNA changes. ScienceDaily. Retrieved May 29, 2021 from www.sciencedaily.com/releases/2019/09/190903101455.html

Telomeres: What causes biological ageing? (2021). Retrieved 29 May 2021, from https://www.medicalnewstoday.com/articles/318764

Francisco Alejandro Lagunas-Rangel and Rosa María Bermudez-Cruz (March 22nd 2019). The Role of DNA Repair in Cellular Aging Process, DNA Repair- An Update, Maddalena Mognato, IntechOpen, DOI: 10.5772/intechopen.84628. Available from: https://www.intechopen.com/books/dna-repair-an-update/the-role-of-dna-repair-in-cellular-aging-process

Bergsma, T., & Rogaeva, E. (2020). DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan. Neuroscience insights15, 2633105520942221. https://doi.org/10.1177/2633105520942221

Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Ageing: The Biology of Senescence. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10041/

Rodríguez-Rodero, S., Fernández-Morera, J. L., Menéndez-Torre, E., Calvanese, V., Fernández, A. F., & Fraga, M. F. (2011). Ageing genetics and ageing. Ageing and Disease2(3), 186–195.

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