Telomere shortening is probably the most famous hallmark of aging, but what is the telomere’s original function?
Telomeres protect the ends of chromosomes
Every complex organism is based on the proliferation of the cells. The cells must duplicate themselves to support growth and replace damaged cells. There is one problem in this process, however. Due to imperfections in DNA replication, there tend to be errors replicating the end of DNA strands.
Usually the ends of DNA would be lost, which could be a big problem as the genes located near the ends of the DNA strand can be truncated during the process. Luckily, a special, replicative DNA sequence is located at each of the chromosome’s ends. We call it “the telomere”. Although telomeres becomes shorter after each replication, it can be restored by an enzyme called telomerase.
Beyond that, the telomere also prevents the end of the chromosome from being misrecognized as a DNA double-strand break and thus, prevents the chromosomes from being ligated together by DNA repair machinery, a phenomenon usually observed in a cancer cell.
Telomeres becomes shorter during aging
Most cells do not express telomerase, which leads to the cumulative loss of telomere-protective sequences from chromosome ends. Telomere exhaustion explains the limited proliferative capacity of cultured cells, the so-called replicative senescence or Hayflick limit (Hayflick and Moorhead, 1961). Importantly, telomere shortening is observed during normal aging both in humans and mice (Blasco, 2007).
Telomeres becomes shorter in older people (Blasco, 2007).
Telomere length is related to health and lifespan
Telomerase deficiency in humans is associated with the premature development of diseases, which involve the loss of the regenerative capacity of different tissues. Telomere loss is also linked to cellular senescence, another hallmark of aging, as well as organismal aging.
Thus, mice with shortened or lengthened telomeres exhibit decreased or increased lifespans, respectively (Armanios et al., 2009; Blasco et al., 1997). Research evidence also indicates that aging can be reverted by telomerase activation. In particular, the premature aging of telomerase-deficient mice can be reverted when telomerase is genetically reactivated in these aged mice (Jaskelioff et al., 2011).
Moreover, normal physiological aging can be delayed without increasing cancer incidence in adult wild-type mice by systemic viral transduction of telomerase (Bernardes de Jesus et al., 2012). In humans, observational studies have supported the existence of a strong relationship between short telomeres and mortality risks (Boonekamp et al., 2013).
There is also an interesting study that shows that the telomere shortening rate is anti-correlated with the lifespan across mammals (Whittemore et al., 2019).
Telomere shortening rate is anti-correlated with lifespan (Whittemore et al., 2019).
Telomeres and NAD+
Technically speaking, telomere attrition is a form of genetic instability, a hallmark we introduced in the previous article in this series (https://alivebyscience.com/nad-and-the-hallmarks-of-aging-series-1-genomic-instability-2/). The telomere stands out because it is especially susceptible to age-related damage compared to other genomic regions. Also, similar to genomic instability, telomere attrition is also closely related to cellular NAD+ levels. In fact, it is a bi-directional relationship.
Telomere dysfunction decreases NAD+ levels and suppresses sirtuin activity
A recent study found that dyskeratosis congenita patients, a disease stemming from short telomeres and telomerase knockout mice both display lower nicotinamide adenine dinucleotide (NAD) levels, as well as an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced PARP and SIRT1 activities (Sun et al. 2020).
Another study by Amano et al. shows that all seven sirtuin proteins (also known as longevity protein) are suppressed after the shortening of telomeres in a mouse liver.
Telomere shortening decreased NAD+ levels (Sun et al. 2020).
NAD+ precursors stabilize telomeres to slow aging
Supplementation with NAD precursors improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence (Sun et al. 2020). The second study also shows that administration of the NAD+ precursor nicotinamide mononucleotide (NMN) maintains telomere length, dampens the DNA damage, improves mitochondrial function, and functionally rescues liver fibrosis (Amano et al. 2019).
These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and also establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing NAD levels stabilizes telomeres and mitigates telomere-dependent disorders.