Aging characterized by gradual loss of physiological integrity
Aging is characterized by a gradual loss of physiological integrity, resulting in impaired biological function and increased vulnerability to diseases and death.
In 2013, Lopez-otin et al first summarized the hallmarks of aging into nine categories (Lopez-otin et al, 2013), which were later widely accepted by the field of aging research.
These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
In this series of articles, I will go through all nine of these tentative hallmarks of aging and their relationship with NAD+ metabolism or other pro-longevity therapeutic strategies that are currently available to the public. Note that all of this information is just for scientific purposes and is not medical advice. Please consult your doctor before you start to try any new drug/interventions mentioned in the articles.
The complexity of the human genome
In each human cell, there are 23 pairs of chromosomes residing in the nucleus, which carry all of the information needed for life and dictates the synthesis of protein machinery and other metabolic processes. We call these 46 chromosomes the human genome.
The genome is stable when we are young
In young people, the genome is relatively stable, as the damage has not accumulated in the DNA. Exceptions are premature aging diseases, such as Werner syndrome and Bloom syndrome.
In these patients, an important protein (lamin) which is a key component of nucleus, is mutated. As a consequence, the nucleus becomes leaky and it fails to protect the genome inside of it. The DNA damage rapidly accumulates in the genome, resulting in genomic instability and accelerated aging.
One study published recently shows that correcting this mutation by in vivo (meaning in living animals), gene-editing successfully extends the lifespan of the mouse model by 200%. Read more here:
Aging decreases the integrity and stability of DNA
During aging, as one might imagine, the integrity and stability of DNA are continuously challenged by exogenous physical (such as X-rays), chemical (carcinogens), biological agents, or by endogenous threats, including DNA replication errors and reactive oxygen species (ROS).
These genetic lesions include point mutations, translocations, chromosomal gains and losses, telomere shortening, and gene disruptions caused by the integration of viruses or transposons (the “jumping” DNA element).
As more and more damages accumulate, the system becomes more chaotic, and more errors tend to happen. This forms a vicious cycle and will eventually result in various aging phenotypes, cancer, and cellular senescence.
Accumulation of DNA damage and its consequences
So what exactly is the pathological consequence of DNA damage? First of all, the mutations caused by environmental factors such as UV and X-ray will accumulate across the genome and will lead to cancer if the mutation happens in critical genes (also known as driver genes).
Only ~1% of the genome is the protein-coding region and only a small proportion of them are the driver genes, so there is a very small chance for a mutation to occur in the driver gene. That is why most cancer happens in old people – it takes a long time for cells to accumulate all the required mutations.
PARP repairs DNA but consumes large amounts of NAD+
The second consequence is that to repair the DNA damage, such as strand breaks, a protein called PARP must be activated, however PARP is a major consumer of NAD+, causing cellular NAD+ levels to drop dramatically as more DNA damage occurs. This is what happens during aging (genomic instability) or exposure to radiation, and the loss of NAD+ and acetyl-CoA, resulting in mitochondrial dysfunction and neurodegeneration.
The third consequence is when the mutation happens to the tumor suppressors, age-related cancer might also occur. And finally, due to the protective mechanism of the stem cell, the cell will stop dividing and die (apoptosis) or become a senescent cell.
This will result in the depletion of stem cells and the accumulation of senescent cells, which are two other hallmarks of aging. These will contribute to the dysfunction of replicating tissues such as gonad, hair, and bone marrow.
Increasing NAD+ levels can alleviate aspects of aging
As mentioned above, DNA damage will result in the hyper-activation of PARP and decreased cellular NAD+ levels. One study shows that inhibition of PARP1 leads to lifespan extension in certain C. elegans (https://www.sciencedirect.com/science/article/pii/S0092867413007551).
Alternatively, increasing levels of the NAD-metabolizing enzyme CD38 has been proposed to be involved in the age-associated loss of NAD+. Increasing NAD+ levels could therefore alleviate aspects of potential aging from persistent PARP1 and/or CD38 activation.
NAD+ precursors are effective anti-aging molecules
Several studies have recently validated NAD+ precursors as a potentially effective therapy for premature aging diseases and normal aging through stimulation of DNA repair pathways.
Further, inhibition of CD38 appears to reinstate NAD+ levels leading to healthier aging in mice. Along these lines, the molecule P7C3 activates NAMPT, the rate-limiting enzyme that converts nicotinamide to nicotinamide riboside, and this activation can be neuroprotective.
Loss of NAD+ leads to attenuation of NAD-dependent enzymes
Conversely, loss of NAD+ leads to attenuation of NAD-dependent enzymes. Here, the sirtuin family is particularly important: multiple sirtuins appear to be central in regulating the rate of aging in a variety of species and most mammalian sirtuins stimulate DNA repair.
The effect of NAD+ on genome stability could, therefore, be responsible for the life- and healthspan effects mediated by sirtuins. Alterations of the NAD+:NADH ratio lead to shunting of pyruvate to lactate and loss of the small metabolite acetyl-CoA.
Ketones generated through a ketogenic diet can act as acetyl-CoA donors and could be efficacious as a premature aging therapy and attenuate the consequences of normal brain aging. In addition to the role of b-hydroxy-butyrate as a fuel source, this metabolite can also alter the epigenetic landscape through inhibition of histone deacetylases and attenuates features of age-associated neurodegeneration.
Other interventions in the genomic instability cascade
Besides NAD+ precursors, there are also other therapeutic opportunities throughout the cascade of genome instability. Another point of intervention is through metabolic changes. The energetic deficiency that occurs with DNA damage leads to compensatory activation of the AMPK energy sensor.
Interestingly, decreasing caloric intake activates AMPK and extends the lifespan from yeast to primates. Pharmacological activation of AMPK by the AMPK activator (like AICAR) ameliorates age-related pathology result from DNA damage.
DNA damage leads to altered mitochondrial function
DNA damage also leads to altered mitochondrial function, which is another hallmark of aging. The damage inhibits mitochondrial degradation via mitophagy and leads to the accumulation of damaged mitochondria.
Accordingly, stimulation of autophagy via mTOR inhibition reduces mitochondrial membrane potential and attenuates mitochondrial dysfunction in premature aging. Therefore, autophagic stimulation, via for example the mTOR inhibitor rapamycin, may be efficacious in ameliorating this as well.
If homeostasis of the cells cannot be remediated post-DNA damage, ultimately cells can enter senescence. Here, senescent cells can be specifically targeted and driven to apoptosis via senolytics. For example, ABT263, fisetin, dasatinib, quercetin, etc. may remove the accumulation of senescent cells caused by genomic instability.
Genomic instability a fundamental cause of DNA damage and aging
Genomic instability is one of the fundamental causes of damage during aging and to some extent, very hard to avoid. Luckily, although we can not avoid DNA damage, we can attenuate the consequences of it through multiple potential therapeutic strategies, including NAD+ precursors, AMPK activators, mTOR inhibitors, and senolytics.