Aging: Lifespan versus Healthspan

At MotoGene, we are driven by the bold vision of redefining how society copes with aging. We recognize the profound burden that chronic diseases like heart failure and cancer place on individuals, particularly the elderly.

Our approach is firmly grounded in evidence-based science, leveraging clinical research and nutritional innovations.

By addressing the root causes of age-related symptoms, we aim to empower individuals to reclaim their health, resilience, vitality, and quality of life, a concept that has also been termed “healthy aging”.

1. Genomic Instability

Arguably one of the most important factors impacting healthspan, genomic instability has been considered as the primary hallmark and driver of aging. Genomic instability refers to various forms of DNA damage such as DNA mutations. DNA damage can take place in either the cell nucleus or in the organelle called mitochondria. It can happen due to normal metabolic processes within our cells, spontaneous errors during DNA replication, or environmental stressors such as radiations, genotoxic drugs, smoking and infections.

To maintain healthspan, our body deploys robust repair systems to reverse the DNA damage. One main player of these systems is a DNA repair enzyme called PARP1. PARP1 ensures DNA in the cell nucleus is intact by acting as a key sensor of DNA damage and directs many DNA repair proteins to correct the damage. 

Yet, it is worth noting that PARP1 activity can decline with age. Failure to promptly rectify DNA damage leads to accumulating mutation loads, which drive cellular senescence, inflammation and age-related diseases.

2. Mitochondrial Dysfunction

With some notable exception, each cell in our body contains many copies of mitochondria to generate energy to carry out important cellular functions. Another critical issue facing human healthspan is that mitochondrial functions tend to decline with age. This is because mitochondrial DNA undergoes mutations due to errors of the DNA replication mechanism.

Unfortunately, mitochondrial DNA mutations appear to be amplified through a process known as ‘clonal expansion’. Additional factors such as reactive oxygen species (ROS) or ‘free radicals’ and smoking, can exacerbate such phenomenon.

Mitochondrial DNA mutations are gradual. They accumulate over time, eventually reaching excessive levels and leading to defective mitochondria, poor energy production, inflammation, and predisposition to age-related diseases such as neurodegeneration.

3. Chronic Inflammation

It is relatively easy to conceptualize how inflammation is essential for maintaining healthspan. For example, our immune cells rely on acute inflammation to combat infections and repair cellular injuries. However, as we age, chronic inflammation (also known as ‘inflammaging’) becomes prevalent. This persistent, low-grade inflammatory state can be triggered by various factors, including poor diets, infections, injuries, mitochondrial dysfunction, and more.

Chronic inflammation is an inherently complex topic because it involves dysfunctions at both molecular and cellular levels. For instance, it may originate from DNA damage caused by reactive oxygen species but often manifests as abnormal immune cell behavior or senescent cells in specific areas of the body. Depending on the organs affected, chronic inflammation can lead to a spectrum of age-related diseases such as cardiovascular disease, cancer, diabetes, and neurodegenerative disorders.

The consequences of chronic inflammation extend beyond impairing the body's ability to respond effectively to new challenges, such as infections. It also significantly hinders our ability to perform daily tasks, thereby reducing quality of life.

NAD⁺: 

The Essential Link to Healthy Aging

At MotoGene, we recognize that the three hallmarks of aging described are deeply interconnected rather than independent processes. Through rigorous research into these key contributors to aging, we focus on identifying actionable nutritional interventions that may help slow or counteract their effects.

Our dedicated research has pinpointed a crucial cellular metabolite — NAD⁺ (Nicotinamide Adenine Dinucleotide) — as a key target in promoting healthy aging.

1. Genomic Integrity

NAD⁺ plays a crucial role in maintaining genomic stability and other cellular functions by serving as a substrate for various enzymes, particularly PARP1. When DNA damage occurs, PARP1 is rapidly activated and consumes NAD+ to synthesize poly(ADP-ribose) chains on target proteins. This process acts as a signal to recruit other DNA repair proteins to the site of DNA damage.

When DNA damage is repairable, PARP1 activation promotes cell survival by engaging the DNA repair machinery. However, in cases of severe DNA damage, excessive PARP1 activation can lead to a drastic depletion of cellular NAD⁺ pools, ultimately resulting in cell death. Thus, NAD⁺ availability in cells not only influences DNA repair but also regulates other cellular processes, including cell death, inflammation and senescence.

2. Mitochondrial Efficiency

NAD⁺ is a key regulator of mitochondrial function and metabolic health. It participates in redox (or ‘reduction’ and ‘oxidation’) reactions by cycling between its oxidized (NAD⁺) and reduced (NADH) forms, driving essential metabolic processes such as glycolysis, the TCA cycle, oxidative phosphorylation, and lipid oxidation. As a vital coenzyme, NAD⁺ depletion greatly impairs metabolic efficiency and diminishes cellular energy production.

Because the NAD⁺/NADH ratio is crucial for maintaining a healthy cellular redox environment, low NAD+ levels (or excess NADH) can contribute to oxidative stress, mitochondrial dysfunction, and inflammation, ultimately reducing healthspan

Beyond redox functions, NAD⁺ regulates key metabolic enzymes, including sirtuins. Sirtuin enzymes use NAD⁺ as a substrate to chemically modify mitochondrial and nuclear proteins (meaning that it removes acetyl and other acyl groups from lysine residues of the target proteins). This can alter many aspects of cells, including gene expression and mitochondrial biogenesis. Therefore, NAD⁺ availability in cells can have a significant impact on mitochondrial function and is directly linked to cellular health.

3. Balanced Inflammation

Although the mechanisms involved are intertwined and complex, NAD⁺ can exert a notable influence on the inflammatory state in our body, thereby affecting overall health.

To introduce one of the many mechanisms, NAD⁺ is utilized by sirtuin enzymes to modulate various cellular activities across different compartments, including regulating gene expression in the nucleus and metabolic processes in the mitochondria. These effects can be diverse, ranging from tuning signaling pathways that control how our immune cells secrete proinflammatory molecules (a phenomenon also known as the ‘senescence-associated secretory phenotype or ‘SASP’) to activating antioxidant defenses against oxidative stress generated by mitochondria.

Another mechanism worth mentioning is that NAD⁺ influences inflammation through the extracellular NAD⁺ consuming enzyme CD38. Reduced NAD⁺ levels, due to CD38 activity, can exacerbate ‘inflammaging.’ For instance, when CD38 is expressed on immune cells such as M1 macrophages, it can deplete NAD⁺ to the extent that perturbs mitochondrial and triggers localized tissue inflammation.

Thus, depending on the context, NAD⁺ influences different enzymes and cells to exert anti-inflammatory effects, thereby modulating the incidence of chronic inflammation and therefore healthspan.

NAD⁺ Levels in Our Body Plummet as We ​Age

Discussing the three key hallmarks of aging underscores the importance of maintaining adequate NAD⁺ for healthspan. Nevertheless, the relationship between NAD⁺ levels in the human body and aging warrants deeper exploration.

It has been observed that NAD⁺ levels tend to decline with age, although the extent of this decline vary across different individuals, potentially due to factors like genetics, lifestyle, circadian rhythm, and physiological conditions. Here, we cite a few examples to illustrate this notion.

BLOOD

Studies on blood show that plasma NAD⁺ (extracellular NAD⁺) levels decrease sharply with age, whereas whole blood NAD⁺ levels appear to significantly decline later in life. Intriguingly, women tend to have lower whole blood NAD⁺ levels compared to men, suggesting sex-specific differences in NAD⁺ metabolism.

SKIN

Human skin samples consistently display a marked decline in NAD⁺ (intracellular NAD⁺) levels with age, with some reports indicating a reduction of at least 50% over aging adults.

BRAIN

Research indicates that the brain experiences a decline in NAD⁺ (intracellular NAD⁺) with age, although the degree of reduction can vary. Some studies have reported a 10-25% decline in brain NAD⁺ levels from young adulthood to old age. Some studies, however, suggest otherwise.

While changes in NAD⁺ levels in other organs are still being uncovered, most human clinical studies so far point to a trend of age-related NAD⁺ reduction. Reduced NAD⁺ levels lower the NAD⁺/NADH redox ratio, shifting our body toward a more reduced state (also known as 'pseudo-hypoxia' state), which is associated with a wide range of age-related pathologies.Consequently, strategies to replenish NAD⁺ holds immense potential to ameliorate the multiple key hallmarks of aging.