Overview of Aging

All about damage and its accumulation

In my last blog on longevity, I built a case for investors to seek out and fund longevity companies and why it makes sense to be a stakeholder in this burgeoning industry. In this and several of my forthcoming blog posts, I want to tease out the science of aging from a mechanistic point of view with a survey of what kinds of technologies are being developed, and what are the most sought-after scientific developments that make this field of medicine a foreseeable reality.

Let’s begin with the definition of aging. The most accepted definition is this: Aging is a chronic health condition that results from the lifelong accumulation of damage. The types of damage associated with aging are extensively studied and are most frequently defined as HALLMARKS of AGING, as introduced in the most highly-cited gerontology paper of the past decade. The image below is adapted from the paper I have put in as a reference.

Cell. 2013 Jun 6; 153(6): 1194–1217.

Other authors have classified aging differently, but the differences are relatively secondary to the central concept of making such a classification at all, which leads to the conclusion that aging must be attacked by a divide-and-conquer approach. So instead of going into a debate of how many hallmarks exist or the comprehensiveness of one method of classification or the other, I would like to divide age-related damage in a way that makes it simple to understand. This might not be a completely new classification or a complete deviation from what exists, but it hopefully makes it simpler and the grouping of the damage in a hierarchical manner helps the visualization and research on targeted designing medications easier to grasp.

Every cell in the body is a network of interacting molecules, and there is a fine equilibrium in their functional states — which, initially, is very robust to perturbation from external insults like infections, but becomes increasingly fragile with age due to the accumulation of changes that we will call “damage”. This extends to the tissues, organs and also to the level of organ systems and the whole body. In a nutshell, the damage could be at the:

• Sub-cellular level — genetic damage (mutations, epi-mutations, methylation patterns, telomere attrition etc), changes in macromolecular structure (protein glycosylation, aggregation etc), sub-cellular organelles (mitochondrial leakage, mitochondrial deletions, lysosomal inactivation etc) and functional pathways (autophagy, protein degradation, nutrient sensing etc.)
• Cellular level — damage affecting cellular behavior, especially cell death and cell division
• Intercellular level — Extracellular matrix alterations (stiffening, changes in the stem cell niche etc.), alterations in intercellular communications (hormones, circulating waste products, redox state)
• Organ and organ system level — changes in the extracellular and cellular composition and cell number, that affect systemic (whole-body) function such as the plasma proteome or metabolome.

Two aspects are particularly important to note here:

1. In the living organism, all systems are interconnected and work in a continuum. Compromise in any one system’s structure, function, and composition can impact other components in the network; systems operate both upstream and downstream of each other in homeostatic feedback loops, and this homeostasis becomes ever more fragile with age. Often the changes in multiple systems have additive deleterious effects that can progress with time.
2. Worse, even if an upstream causative change is countered, it is possible that the secondary damage that it already caused can persist. This emphasizes the need for combination therapies in the anti-aging field.

Now that we have understood the types of damage that cause the phenomenon of aging, let’s all wear the hats of futurists and imagine what the world would look like if we had the medicine to stop us from aging; but for now, let’s consciously avoid the question of lifespan extension and death. (I am not minimizing the necessity to address those questions but would like to address the concepts and the misconceptions associated with them in a separate blog post and will do so very respectfully taking into account all the sensitivities.) The first step in imagining a future with drug(s) that can mitigate all the damage is to look at some of the outstanding questions:

1. Is this a single medicine, as most folklore makes it out to be, or is it a set of medicines?
2. Should it be preventive or curative?
3. Periodic (life-long) vs. single-dose?
4. What age group should be targeted?
5. Damage accumulation begins as soon as the balance between the regenerative capacity of the body and the damage accumulation loses its fine tuning. Since this is an interplay between genes and the environment, the initiation point and the rate of damage accumulation varies between and within different ethnicities, sexes, individuals, and their lifestyles to name a few. What measurements (biomarkers) should become the industry standard to detect that inflection point and begin the treatment?
6. How different should these medications be for people before they hit the inflection point vs. people who are at the inflection point and people in their 60s and 70s that have accumulated significant damage and resulting chronic diseases?
7. How should the dosing be decided?
8. What parallel scientific advances need to be made to make this a reality? This incorporates several interrelated questions, such as targeted delivery to the exact compartment where these drugs are needed, or how long the drugs remain active.

We can carry on and run wild with the questions but I choose to stop here and transfer the futuristic questioning hat to you all….!!

I don’t have definite answers to any of the above questions, but while I am wearing the hat of a futurist, all I do is hypothesize. In my opinion, there will be a set of drugs that need to be taken lifelong beginning at a very young age in a highly personalized fashion (maybe like vitamins but far more effective?). It is only natural to assume so, as we have seen above the multitude of damage types that accumulate in specific compartments with age and it is difficult to imagine a “panacea” that can fix all of them at once. In the population groups that have already accumulated the damage, dosing needs to be done based on a robust set of measurements. Typical characteristics that these medicines should have are:

1. Completely safe, as there could be accumulated side effects with lifelong consumption that could be an initiator of several types of damage
2. There should be minimal to zero drug-drug interactions

These medicines are still some way from becoming reality. However, once they become available, they will transform the medical system.

Some of the changes that will occur as these medicines arrive include:

1. Preventative healthcare will become the norm
2. Testing and drug administration will become personalized
3. Health insurance will change dramatically because of the populace’s changed risk profile
4. The medical industry will become truly a health service, rather than a sickness service.

We might in the future end up in a world where Alzheimer’s, age-related cancers, cardiovascular diseases, and the long list of other age-related health conditions all become a thing of the past and we will be able to work and pursue our passions without physical limitations or age-associated diseases. A future to die for(!!! sorry) — to live for — to invest in — to be a part of — is being created!!!

My aim in future posts is to introduce each of these types of damage from a series of perspectives: what they mean, the diseases that result from their accumulation, the impact of fixing them (including both a global healthspan extension perspective and a disease-specific perspective), and ultimately the investment angle.