Why Do We Age?

??In this Nexus:

? Is aging a disease?

?? The Hallmarks of aging

?? How to beat aging?

?? Book recommendation

For many years it was thought that aging is a natural process and there is not much to be done about it. However, with recent scientific and medical advancements in the past few decades, scientists are more loudly and I would say bravely speaking about stoping and reversing aging. There are even suggestions in the scientific society that we should consider aging as any other disease. And if aging is a disease, does that mean it can be cured? Well, the biggest issue here is the complexity of the aging process, which I will try to explain in this Nexus.

Is Aging a Disease?

So is aging a disease? Disease is typically defined as a pathological condition of a body part, an organ, or system resulting from various causes, like infection, genetic defect, or environmental stress, and characterized by an identifiable group of signs or symptoms. Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death (1). So if you look at the description of a disease, aging could be a slow but aggressive one, targeting multiple body systems and having clear signs and symptoms.

What we understand as a disease usually targets an organ or a system, with the effects to other body systems as a secondary outcome. In the meantime, aging affects the whole body, so in a way, it can be compared to a terminal stage of cancer, which has spread beyond the organ of origin and affected different body systems. I believe that the debate that is currently ongoing on this matter will still continue for at least a couple of decades, until we know even more about aging complexity and possible ways to slow, stop or reverse aging.

What Does Science Say?

The Hallmarks of Aging

The "hallmarks of aging" refer to a set of cellular and molecular processes that contribute to aging and the associated decline in biological function. The hallmarks of aging were first published back in 2013 in the scientific journal Cell (by Cell Press ), which included nine hallmarks (1). It was updated by the same scientific group in 2023, including the addition of three new hallmarks (2). This shows how our understanding about the complexity of aging is expanding, thus, allowing breakthrough advancements in the field.

Aging is driven by hallmarks fulfilling the following three premises:

1. Their age-associated manifestation (meaning they appear as we age)
2. The acceleration of aging by experimentally accentuating them (meaning by triggering them in experimental conditions we see the aging speed up)
3. The opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them (meaning we can "cure" them)

The twelve hallmarks of aging are shown below:

So lets dig deeper into each hallmark (2):

1. Genomic Instability: Aging cells exhibit increased DNA damage due to environmental factors and normal metabolic processes. This damage can lead to mutations and genomic instability, contributing to the aging process and the development of age-related diseases.
2. Telomere Attrition: Telomeres are the protective caps at the ends of chromosomes and they shorten with each cell division. Shortened telomeres trigger cell senescence or apoptosis, contributing to aging. Telomere length has now become one of the key measurement in defining cellular aging and predicting lifespan.
3. Epigenetic Alterations: Changes in epigenetic markers (chemical modifications that affect gene expression without altering the DNA sequence) occur with aging. These alterations can affect gene expression patterns, influencing aging and longevity.
4. Loss of Proteostasis: Proteostasis involves the balance of protein synthesis, folding, and degradation. Aging disrupts proteostasis, leading to the accumulation of misfolded and aggregated proteins, which can impair cellular function.
5. Deregulated Nutrient Sensing: Aging affects the pathways that sense and respond to nutrients, such as insulin and IGF-1 (insulin growth factor-1) signaling pathways. These changes can disrupt metabolic homeostasis and influence lifespan.
6. Mitochondrial Dysfunction: Mitochondria, the energy-producing organelles of cells, become less efficient with age. This dysfunction contributes to reduced energy production and increased oxidative stress, which contributes to the cell damage.
7. Cellular Senescence: Senescent cells accumulate with age and secrete inflammatory factors that can harm surrounding tissues. They are resistant to apoptosis and can contribute to aging and age-related diseases.
8. Stem Cell Exhaustion: Stem cells have the ability to renew themselves and differentiate into various cell types. With age, the regenerative capacity of stem cells declines, impairing tissue repair and regeneration.
9. Altered Intercellular Communication: Aging is associated with changes in the communication between cells, including increased inflammatory responses and changes in the hormonal environment. These alterations can contribute to systemic aging and the development of age-related diseases.
10. Disabled Macroautophagy: Or simply autophagy, is a cellular degradation and recycling process. It plays a crucial role in removing damaged organelles, misfolded proteins, and pathogens, thereby maintaining cellular homeostasis. The impaired cellular cleaning, leads to accumulation of damaged cells and increased disease risk, negatively affecting longevity.
11. Chronic Inflammation: Chronic inflammation is a prolonged inflammatory response that can damage tissues and organs. Chronic inflammation is harmful and can be triggered by various factors, including persistent infections, autoimmune diseases, exposure to environmental toxins, and lifestyle factors. It is associated with a wide range of age-related diseases, including arthritis, diabetes, heart disease, Alzheimer's disease, and cancer.
12. Dysbiosis: Dysbiosis refers to an imbalance of microbiota in the gut. A healthy microbiome is essential for digestion, synthesis of vitamins, immune function, and protection against pathogens. Dysbiosis has been linked to a variety of age-related conditions and it can contribute to aging by promoting chronic inflammation, altering metabolic processes, and impairing immune function.

These hallmarks interconnect and influence each other, contributing to the complex biological process of aging. In the recent year, understanding these hallmarks has been crucial in developing new strategies aimed at delaying aging and improving healthspan.

How to Beat Aging?

While you (currently) can't beat aging (yet) completely, you can at least give aging a good punch in the face! Addressing the hallmarks of aging to slow down the aging process involves a combination of lifestyle interventions, dietary adjustments, and potential pharmacological approaches. Here's what you can do for each of the hallmarks:

Genomic Instability:

• Avoid DNA-damaging agents like UV radiation and tobacco smoke to protect your DNA.
• Consume antioxidant rich food or take supplements to decrease oxidative stress that harms DNA.

Telomere Attrition:

• Reduce stress (just hate this one, easy to say...), exercise regularly, and maintain a healthy diet to help preserve telomere length.
• Consider food supplements (like omega-3 fatty acids, vitamin D, NAD+, NMN), that may support longer telomeres.

Epigenetic Alterations:

• Consume healthy food rich in beneficial compounds like green tea, blueberries, and curcumin to support healthy epigenetic regulation.
• Engage in regular exercise to induce positive epigenetic changes, enhancing health and longevity.

Loss of Proteostasis:

• Utilize heat exposure (e.g., sauna) to increase heat shock proteins, aiding in protein folding.
• Promote autophagy by practicing fasting or caloric restriction.

Deregulated Nutrient Sensing:

• Practice caloric restriction to potentially extend lifespan, ensuring you're not malnourished.
• Try intermittent fasting or time-restricted eating to beneficially modulate nutrient sensing pathways.

Mitochondrial Dysfunction:

• Engage in regular physical activity to boost mitochondrial function and biogenesis.
• Incorporate nutrients like coenzyme Q10, creatine, and alpha-lipoic acid to support mitochondrial health.

Cellular Senescence:

• Explore senolytic drugs, which target and remove senescent cells, promising in research.
• Regular exercise can lessen the accumulation of senescent cells in your body.

Stem Cell Exhaustion:

• Exercise can improve stem cell functionality across various tissues.
• A diet high in polyphenols may enhance stem cell function and support regeneration.

Altered Intercellular Communication:

• Adopt an anti-inflammatory diet, such as the Mediterranean diet, to lower systemic inflammation and aid cellular communication.
• Regular exercise can adjust inflammatory responses and hormonal balance, improving communication between cells.

Enhancing Macroautophagy:

• Intermittent fasting and caloric restriction can boost autophagy, aiding in the removal of cellular waste.
• Regular exercise and consuming polyphenol-rich foods like berries, nuts, and green tea can stimulate autophagy pathways.

Reducing Chronic Inflammation:

• Follow an anti-inflammatory diet with omega-3s and antioxidants to combat inflammation.
• Moderate exercise and stress management practices like meditation can reduce inflammation.
• Avoid processed foods, sugar, and trans fats, known to trigger inflammatory responses.

Correcting Dysbiosis:

• Integrate probiotics and prebiotics into your diet to balance your gut microbiome.
• Eat a diverse range of high-fiber foods to support a healthy microbiome.
• Don't self-medicate with antibiotics to prevent disruption of gut bacteria.

Have you calculated how many times I have mentioned healthy diet and regular exercise? Well, a lot. Most of these things are easy to do and you don't have to spend a fortune on food supplements or some kind of posh procedures to significantly increase your chances of longer lifespan and healthspan. You just need will, which not always comes easily, so you will have to work on it.

While more and more scientific data emerge on food supplements and anti-aging drugs, we still lack properly designed longitudinal clinical trials to confirm these findings. However, it seems clear from the complexity of the aging process and the hallmarks of aging presented above, that there won't be a single pill to address them all at once.

Book Recommendation

Another Nexus - another recommendation from me. I won't pretend I am reading books. I don't. I read loads of scientific articles, but not books. It is just not my thing somehow. But I listen to audiobooks whenever I can use my time more productively, e.g. while I am waiting in the dark until my son falls asleep or while I am driving alone in the car or on a plane. And this book is definitely a must-read (or in my case a must-listen) to any longevity beginner or a fan.

The longevity guru himself David A. Sinclair A.O., Ph.D. about his research and journey to what we know about aging to date. As the author writes:

Aging is a disease, and that disease is treatable.

I listened to it on the Everand app, recorded by the author himself with his comments. Enjoy!

I hope you found this Nexus useful and interesting! In just two weeks, I'll dive into another topic of longevity and healthspan. Don't miss out and subscribe now to stay in the loop. I'd love to hear your insights and experiences. Share your thoughts and join the conversation!