Replenish NAD+ to Protect Telomeres from Age-Related Damage and Dysfunction: Recent Research

As the length of your telomeres is directly related to biological age, it’s imperative to consider ways to protect these structures that reside on the tips of our chromosomes. While chronological age reflects the date on your birth certificate, biological age represents how old your cells, tissues, and DNA are. 

A biological age greater than your chronological age will manifest as premature aging, both internally — think dysfunctional cells and mitochondria — and externally, with wrinkled skin and greying hair. 

Not surprisingly, many researchers are looking for ways to turn back this biological clock — and they may have found it through replenishing NAD+ stores. NAD+ is an essential compound needed by every cell in the body; unfortunately, its levels decline with age. These declining levels are thought to be a driving force behind telomere shortening, accelerated aging, and chronic disease development. 

A recent study from September 2020 dove deeper into the relationship between telomere length and NAD+ levels, as well as how boosting NAD+ stores affects telomere and mitochondrial function. 

In this article, read more about the details of this study, the basics of telomeres and cellular senescence, and how replenishing NAD+ through its precursors may help to protect telomeres from the damage and dysfunction that accelerates aging. 

Telomeres and Cellular Senescence: The Basics  

Telomeres play an essential role in the aging process, as they protect our cells and DNA from damage. Shorter telomere lengths are linked to accelerated aging and earlier onset of disease. Research has found that people with shorter telomeres have shorter lifespans and an increased risk of chronic diseases. 

Telomeres are the “caps” at the ends of the DNA molecules inside our chromosomes, which can be imagined as the plastic casing protecting the tip of a shoelace. Similar to how the shoelace cap protects it from fraying, telomeres protect the chromosome from the damage that leads to premature aging. 

These protective endcaps are also necessary to ensure DNA gets copied correctly during cell division. During normal DNA replication, the strand gets shorter with each cell division. The telomeres ensure that critical genetic information doesn’t get snipped off during this process. Essentially, the telomeres get shorter with each cell division to save the DNA. The enzyme telomerase adds length to the telomeres and ensures that telomeres don’t become too short prematurely. 

However, when a cell reaches the end of its telomere, it can no longer replicate and is considered senescent. Cellular senescence is another marker of aging, which occurs when cells stop dividing, lose function, and trigger a cascade of inflammatory compounds that accelerate aging. 

A genetic disease called dyskeratosis congenita (DC) is a rare form of bone marrow failure, meaning that the bone marrow cannot produce enough blood cells. People with DC experience rapid telomere shortening at a young age due to a mutation in the genes that control telomerase activity. 

Without proper telomerase functioning, the telomeres become shorter more quickly, causing cellular senescence at a young age. In people with DC, fast-dividing cells are affected the most, including the skin, bone marrow, and gastrointestinal cells. 

Due to their rapid telomere shortening, people with DC are often involved with research on cellular senescence and premature aging. 

What Did This Study Look At?

This study, which was published in The EMBO Journal in September 2020, looked at skin fibroblast cells from people with DC and compared them to healthy skin cells. The researchers analyzed many different aspects of cellular and mitochondrial health, including the activity of three enzymes: CD38, PARPs, and SIRTs (sirtuins). 

Briefly, sirtuins are a family of proteins nicknamed “longevity genes”; they are involved in mitochondrial repair, reducing cellular senescence, and slowing down the aging process. PARP1 is an enzyme that helps with DNA repair, and CD38 is a glycoprotein that is highly expressed in inflammatory cells and disease states. 

These three enzymes all utilize and require NAD+ to function; however, they all compete for NAD+. Therefore, if one enzyme is overactive — specifically, CD38 — the other two have limited activity and function.  

Animal studies have shown that mice without CD38 have significantly higher NAD+ concentrations and sirtuin activity. Other research has found that CD38 activity increases alongside the aging process; researchers think that elevated CD38 contributes to the age-related decline in NAD+ levels.

After looking at levels of these enzymes, the researchers cultured the cells with a precursor to NAD+, nicotinamide riboside (NR). NR is one of two primary precursors to NAD+, with the other being NMN (nicotinamide mononucleotide). 

What Were the Results?

As expected, DC cells exhibited significantly lower NAD+ levels, sirtuin activity, and ATP production compared to healthy controls. The DC cells also had considerably elevated CD38 expression, which contributes to NAD+ decline in cells with shortened telomeres. 

After NR supplementation, PART and SIRT activity was restored. The same was seen when CD38 was inhibited. The NAD+ precursor also mitigated telomeric DNA damage, mitochondrial dysfunction, and reactive oxygen species (ROS) buildup in the mitochondria. An accumulation of ROS indicates oxidative stress, which occurs when inflammatory molecules aggregate and damage cells and DNA. 

Notably, the NAD+ precursor slowed down the onset of cellular senescence in the DC cells. Although this study did not look at the effects of NMN, it’s possible that the results seen with NR would also be seen with NMN, as they are both precursors to NAD+. 

Telomere shortening, CD38 expression, and low NAD+ levels participate in a vicious cycle of sorts. When telomeres shorten or fray, CD38 is overexpressed, which reduces NAD+ levels. From there, NAD+ is not available for sirtuins or PARP to function properly, which causes DNA damage, mitochondrial dysfunction, and accelerated aging. This damage and dysfunction cause further telomere shortening, and the cycle continues. 

Key Takeaway From This Research: 

• Shortened telomeres cause accelerated aging, mitochondrial dysfunction, DNA damage, and cellular senescence. 
• This study found that supplementing with NAD+ precursors — in this case, NR — restored low NAD+ levels in people with shortened telomeres.
• In addition, NAD+ precursors mitigate mitochondrial and telomeric DNA damage, restore sirtuin and PARP activity, and delay the onset of cellular senescence in people with dyskeratosis congenita, a genetic condition that prematurely shortens telomeres. 

References: 

Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003;361(9355):393-395. doi:10.1016/S0140-6736(03)12384-7

Gramatges MM, Bertuch AA. Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy. Transl Res. 2013;162(6):353-363. doi:10.1016/j.trsl.2013.05.003

Sun C, Wang K, Stock AJ, et al. Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction. EMBO J. 2020;39(21):e103420. doi:10.15252/embj.2019103420