Telomerase-Mediated Anti-Ageing Interventions

Abstract

The ageing process involves a gradual decline of chromosome integrity throughout an organism's lifespan. Telomeres are protective DNA-protein complexes that cap the ends of linear chromosomes in eukaryotic organisms. Telomeric DNA consists of long stretches of short "TTAGGG" repeats that are conserved across most eukaryotes including humans. Telomeres shorten progressively with each round of DNA replication due to the inability of conventional DNA polymerase to completely replicate the chromosome ends, known as the "end-replication problem". The telomerase enzyme counteracts the telomeric DNA loss by de novo addition of telomeric repeats onto chromosomal ends. Germline and stem cells maintain significant levels of telomerase activity to maintain telomere length and can divide almost indefinitely. However, the differentiation of stem cells accompanies the inactivation of telomerase gene expression, resulting in the progressive shortening of telomeres in somatic cells over successive divisions. Critically short telomeres elicit and sustain a persistent DNA damage response leading to permanent growth arrest of cells known as cellular senescence, a hallmark of cellular ageing. The accumulation of senescent cells in tissues and organs contributes to organismal ageing. Thus, the prevention of telomere shortening is a promising means to delay or even reverse cellular ageing. In this chapter, we summarize potential anti-ageing interventions that mitigate telomere shortening through increasing telomerase level or activity and discuss these strategies' risks, benefits, and future outlooks.

Keywords: Cell senescence; DNA replication; End replication problem; Hayflick limit; Ribonucleoprotein; Telomerase activation; Telomere shortening.