Highlights

  • Sinclair’s Information Theory of Aging posits that aging is caused by a loss of (epi)genetic information. 
  • We can push back against cellular aging by targeting two key cellular pathways: the sirtuin pathway and the mTOR pathway. 
  • We can target these pathways by fasting or with supplements that boost NAD+ levels, such as NMN. 

The modern conception of medicine often separates age-related conditions like heart disease, Alzheimer’s, and type 2 diabetes. However, a perspective popularized by Harvard geneticist Dr. David Sinclair suggests that we are failing to see the big picture. In a compelling discussion with Stanford neuroscientist Dr. Andrew Huberman, Dr. Sinclair argues that aging itself is the disease, and by treating its root cause, we can prevent a host of chronic conditions.

The Information Theory of Aging: A Scratched CD

Dr. Sinclair’s central theory of aging is not about the accumulation of genetic mutations, but about the loss of information. He distinguishes between two types of information in our cells:

  • Genetic Information (Digital): The DNA sequence itself (the ATCG letters), which is like the music recorded on a compact disc. This remains largely intact.

  • Epigenetic Information (Control System): The system that dictates which genes are switched on or off in a specific cell at a specific time. This is the “reader” that plays the right “songs” (genes) for a liver cell versus a nerve cell.

Aging, in this model, is equivalent to scratching a CD. The DNA is still there, but the cell’s machinery can no longer read the instructions correctly. Genes that should be silent (like those for embryonic development) turn on, and genes that should be active (like those for youthful function) turn off. This loss of cellular identity is the fundamental driver of aging and its associated diseases.

The Scratches: What Damages the Epigenome?

The “scratches” on the cellular “CD” are caused by various forms of stress and damage:

  • DNA Damage: Cuts and breaks in the DNA, caused by things like X-rays, cosmic rays, or ultraviolet radiation, accelerate the unwinding and disorganization of the DNA structure, leading to epigenetic chaos.

  • Massive Cell Damage or Stress: Severe physical stress, such as pinched nerves, can also accelerate the aging process.

In animal models, Sinclair’s team has artificially accelerated this process, creating an “old mouse” with a bent spine and gray hair, demonstrating that aging is a controllable process in the forward direction.

Actionable Protocols: Pushing Back Against Entropy

If aging is a loss of information, the goal is to activate the body’s natural defense mechanisms that protect and repair the epigenome. Dr. Sinclair highlights two important pathways that govern longevity:

Intermittent Fasting and Caloric Restriction

The evidence from animal studies is clear: animals that don’t eat all the time live significantly longer and healthier lives. One of the key mechanisms is that low levels of insulin and insulin-like growth factor (IGF-1) turn on the sirtuin longevity genes.

  • Daily Fasting: Sinclair mentions that he likes to skip a meal a day, extending the overnight fast. This keeps the longevity genes active. Notably, while Sinclair prefers skipping breakfast, skipping dinner has the same effect while also improving sleep, which is another crucial factor in promoting longevity.

  • Extended Fasting: Fasting for two or three days triggers an even deeper cleanse called chaperone-mediated autophagy, which helps the body get rid of old and misfolded proteins.

The Role of Supplements: NMN and NAD+

Sirtuin enzymes require a molecule called NAD+ (nicotinamide adenine dinucleotide) to function. As we age, our NAD+ levels naturally decline, which is why sirtuins become less effective. Dr. Sinclair personally takes a precursor to NAD+ called NMN (nicotinamide mononucleotide). The body uses NMN to make NAD+. He notes that taking NMN can double NAD+ levels in the blood within about two weeks, fueling the sirtuin defense system.

Iron Load and Inflammation

Another key factor in aging is the accumulation of senescent cells (which Sinclair calls “zombie cells”). Senescent cells appear throughout the body in response to cellular stressors and support chronic inflammation. Excess iron can accelerate the increase of these senescent cells.

  • Iron Management: Dr. Sinclair suggests that having slightly low iron and ferritin levels is common in very healthy, long-lived individuals. It is an example of how personalized medicine is necessary, as a doctor treating the “average” human might recommend iron supplementation that is counterproductive for longevity.

  • C-Reactive Protein (CRP): He highlights high-sensitivity CRP (hs-CRP) as a critical marker for inflammation and a strong predictor of cardiovascular risk and overall mortality. Keeping CRP levels low through diet (less food, more vegetables) and exercise is a key behavioral goal.

Exercise and Hormones

Exercise is also a powerful tool for modulating the epigenome, as it has been shown to raise NAD+ levels and activate sirtuin genes. Furthermore, maintaining muscle mass is crucial for maintaining youthful hormone levels, such as testosterone and estrogen, which are essential for long-term health and performance.

Be Informed: Understand Biases 

The overall message is that we are not slaves to our genes. While DNA provides the blueprint, the epigenome—the control system—is highly adaptable. By introducing periods of mild adversity through lifestyle choices like fasting and exercise, we activate our ancient survival circuits, slow the ticking of the biological clock, and fundamentally reset the body’s system for a longer, healthier life.

While, in general, biological aging research supports fasting and exercise as two of the most powerful promoters of longevity, it’s important to take into account the inherent biases held by any one individual. Dr. Sinclair’s research surrounds the investigation of the Information Theory of Aging, and this is why he believes that epigenetic dysregulation is the root cause of aging. While he may be correct, other researchers in the field may disagree, and the research is ongoing. 

Dr. Sinclair is on the scientific advisory board for Metro Biotech, a biotechnology company that is currently investigating NMN as a new drug. While the amalgamation of scientific research suggests that boosting NAD+ counteracts cellular aging and age-related diseases, especially in animal models, there is not yet a consensus on which method is best for doing so. Multiple NAD+ precursors, including nicotinamide, niacin, and NR (nicotinamide riboside), elevate NAD+ levels. Moreover, low stress levels, good sleep, a balanced diet, and exercise help maintain NAD+ levels.