One of the most significant biochemical changes observed with ageing is the decline in nicotinamide adenine dinucleotide (NAD⁺), a molecule central to cellular metabolism and survival. Beyond its classic role in redox reactions, NAD⁺ is a critical cofactor for enzymes that govern DNA repair, gene expression, energy metabolism, and protein maintenance. As NAD⁺ levels fall with age, numerous biological systems begin to fail, accelerating the cellular damage associated with the nine hallmarks of ageing.

Genomic instability is one of the first hallmarks influenced by NAD⁺ depletion. The enzymes responsible for detecting and repairing DNA damage particularly poly(ADP-ribose) polymerases (PARPs) and sirtuins require NAD⁺ to function effectively. When NAD⁺ is lacking, DNA lesions go unrepaired, leading to mutations and chromosomal aberrations. This gradual build-up of genomic damage undermines genomic integrity and increases the risk of age-related diseases such as cancer (Covarrubias et al., 2020; Lautrup et al., 2023).

The process of telomere attrition is also accelerated by a reduction in NAD⁺. Telomeres are repetitive DNA sequences at the ends of chromosomes that shorten with each cell division. SIRT1, a NAD⁺-dependent sirtuin, plays a key role in maintaining telomere structure and function. With diminished NAD⁺, SIRT1 activity is compromised, hastening telomere shortening and pushing cells into senescence prematurely (Christiano et al., 2023). This process contributes directly to the biological clock of ageing and impairs tissue regeneration.

Another consequence of NAD⁺ decline is the disturbance of epigenetic regulation, where changes in gene expression occur without alterations in the DNA sequence itself. Sirtuins, particularly SIRT1 and SIRT6, depend on NAD⁺ to modify histones and regulate chromatin structure. Insufficient NAD⁺ results in disorganised epigenetic patterns, disrupting gene expression and impairing cellular identity and function (Verdin, 2015; Covarrubias et al., 2020). This epigenetic drift is increasingly recognised as a driver of ageing and age-related dysfunction.

The hallmark of loss of proteostasis the cellular capacity to maintain a healthy, functional proteome is also influenced by NAD⁺ levels. Autophagy and the heat shock response are two NAD⁺-dependent processes critical for degrading misfolded or damaged proteins. When NAD⁺ levels fall, these systems fail, leading to the accumulation of toxic protein aggregates. This is especially relevant in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease (Srivastava, 2016; Campbell, 2022).

Perhaps most well-studied is the role of NAD⁺ in preventing mitochondrial dysfunction. Mitochondria, the powerhouses of the cell, rely on NAD⁺ to carry out oxidative phosphorylation and produce ATP. With age, NAD⁺ availability declines, impairing energy production and increasing the generation of reactive oxygen species (ROS). This not only reduces cellular energy but also promotes oxidative stress and inflammation. Additionally, NAD⁺ is required for mitochondrial maintenance mechanisms such as mitophagy, which eliminates damaged mitochondria. When NAD⁺ is scarce, these dysfunctional mitochondria accumulate, further contributing to cellular ageing (Prolla and Denu, 2014; Lautrup et al., 2019; Christiano et al., 2023).

The age-related reduction in NAD⁺ has been attributed to both lifestyle and biological factors. One of the major contributors is the enzyme CD38, which is upregulated in ageing tissues and depletes NAD⁺ levels, particularly in response to chronic inflammation and factors secreted by senescent cells (Chini et al., 2019). Additionally, reduced biosynthesis and recycling of NAD⁺ precursors exacerbate the decline, especially in metabolically active tissues like the brain, liver, and muscles.

Given its central role in so many pathways, restoring NAD⁺ levels has become a compelling target in the field of anti-ageing and regenerative medicine. Supplementation with NAD⁺ precursors such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) has shown potential in boosting mitochondrial function, improving cognitive health, and slowing epigenetic drift in both animal models and early-stage human trials (Song et al., 2023; Iqbal and Nakagawa, 2024). While long-term effects remain under investigation, the rejuvenating potential of NAD⁺ restoration is increasingly supported by clinical and biochemical data.

In summary, declining NAD⁺ is not just a consequence of ageing it is a key driver of many degenerative changes observed across tissues. From faulty DNA repair and chromosomal instability to impaired mitochondrial performance and protein mismanagement, NAD⁺ depletion lies at the core of cellular ageing. Its restoration holds promise as one of the most targeted and potentially effective strategies in the emerging science of longevity.

References

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