For centuries humans have been trying to figure out what causes death and aging. It’s been explained away by spiritual, religious or physical reasons. But why does it happen? In 1956 Denham Harman was the first to propose the Free Radical Theory of Aging (FRTA) and in 1970 he furthered the idea by describing mitochondrial production of reactive oxygen species (ROS) . The free radical theory of aging says that we die because of the accumulation of free radical damage on our cells over time.
A free radical is an atom or molecule with a single unpaired electron in its outer layer. Most free radicals are very reactive and cause oxidative damage. That oxidation can be reduced by antioxidants and other reducing agents. Mitochondria are the cells energy factories that generate adenosine triphosphate (ATP). It’s the energy currency of life. This happens by reacting hydrocarbons from calories or sunlight with oxygen.
The classical free radical theory of aging says that energy generation by the mitochondria damages mitochondrial macromolecules including mitochondrial DNA (mtDNA) which causes aging [9] . After a certain threshold this produces too many reactive oxygen species (ROS) which causes cell death and degradation
Free Radical Theory And Mitochondria Damages
Reactive Oxygen Species (ROS) and Aging: As you age, your ability to handle stress and other stressors is compromised, making you more prone to free radicals. Mutant mtDNA increases with age, especially in tissues with high energy demand like the heart, brain, liver, and kidneys. This supports the theory of mitochondrial aging. In some species like yeast and fruit flies, reducing oxidative stress can extend lifespan. However, blocking the antioxidant system in mice doesn’t typically shorten lifespan. In roundworms, inhibiting the natural antioxidant superoxide dismutase can increase lifespan.
Interestingly, taking a lot of antioxidants and lowering oxidative stress with supplements doesn’t effectively combat disease and may actually increase the chances of getting sick. High-dose antioxidant treatments such as beta-carotene, vitamin A, and vitamin E can increase mortality. Additionally, consuming more fruits and vegetables doesn’t seem to have a significant effect in reducing cancer risk.
While free radicals and ROS are involved in most human diseases and cancers, the extent of their influence remains uncertain. Increasing your body’s own endogenous antioxidant levels may be a better strategy for disease prevention. Oxidative stress and free radicals can increase lifespan in nematodes by inducing a biphasic response to the stress, a process known as mitohormesis or mitochondrial hormesis.
The Role of Hormesis in Boosting Cellular Resilience
Hormesis is a dose-specific response to a toxin or a stressor that makes the organism stronger than it was before… The idea is that you experience a small shock that makes the body want to deal with it better in the future thus becoming more resilient. Sublethal mitochondrial stress with a minute increase in ROS may cause a lot of the beneficial effects found in caloric restriction, intermittent fasting, exercise, and dietary phytonutrients . If you experience no stress and zero exposure to free radicals, then your body is by default weaker because of having no fighting reference from the past.
If you experience too much stress and excessive accumulation of ROS, then you promote disease and sickness because of not having enough time to recover. If you experience just the right dose of stress, then you’ll be able to deal with it, recover from the shock, and thus augment your cells against future stressors. If you block all mitochondrial stress and eliminate free radicals, then your body won’t have the time nor the means to promote mitohormesis. That’s why antioxidants all the time won’t have a positive effect.
Identifying Key Drivers of Oxidative Stress and Mitochondrial Decline
Below is the list of some factors that cause oxidative stress and mitochondrial aging have been demonstrated to occur. Insulin and elevated glucose generate free radicals and induce oxidative stress. The insulin signaling pathway is one of the strongest effectors of accelerated aging. However, this is dose dependent and some level is beneficial for the production of ROS. Chronic stress leads to accelerated aging and ill-being. Excessively produced free radicals due to overproduced stress hormones lower mitochondrial performance and render you more susceptible to illness due to lowered immunity, elevated insulin, and cell damage.
Sleep loss and circadian disruption stimulate all diseases. If your body’s biological clocks are out of sync with its circadian oscillators, then you’ll induce more cellular stress and predispose yourself to all manner of dysfunction. Avoid environmental toxins and pollution. Polluted air, water, heavy metal toxicity, mercury in food, pesticides, glyphosate, GMO crops, toxic personal care products, and house cleaning chemicals—all of them will generate more reactive oxygen species and oxidative stress. The magnitude of these stressors is something our body’s natural resilience can’t handle, thus they don’t have a positive effect in the long run.
Avoid inflammation like wildfire. Inflammation is associated with most diseases, as it directly lowers the body’s immunity. Processing food and overcooking food increases the amount of free radicals and carcinogens in food. There’s a difference between good stressors and too many free radicals. Of course, excessive oxidative stress is still bad for you and accelerates aging. The key is to distinguish it from the positive hormetic stress. The mitochondria are one of the most powerful organelles in your body as they control everything about energy metabolism and cellular homeostasis. Dysfunctional mitochondria will not only accelerate aging but also make you feel more fatigued, exhausted, lethargic, weak, and experience atrophy.
Key Longevity Pathways That Shape Human Aging
As I said before, different humans of the same species can have drastically different lifespans and rates of aging. This is because aging is controlled by many genetic pathways and biological processes. In humans there are several longevity pathways that control the aging process and its mechanisms. I’ll list the ones that are currently recognized to control longevity and lifespan. Then I’ll go through them one by one
- The Growth Hormone/Insulin and Insulin-Like Growth Factor-1 Signaling Pathway
- Controls cell replication, nutrient partitioning, and storage.
- The FOXO/Sirtuin Pathway
- Includes proteins and transcription factors that control energy homeostasis under harsh conditions and stress.
- Hormesis and General Stress Adaptation
- Mediated by FOXO proteins and mitochondrial functioning, enhancing resilience to environmental stressors.
- The mTOR/AMPK Pathway
- Manages the balance between anabolism and catabolism, determining whether the body grows or consumes itself.
These pathways interact with each other and impact longevity in diverse ways, constituting the mechanisms that affect aging and lifespan.
Final Thoughts
As we get into the weeds of human aging it becomes clear that our longevity is determined by many biological mechanisms and genetic pathways. The interaction between these pathways determines how we age and how well interventions will work to extend lifespan. Understanding these processes is key to developing targeted strategies to slow aging and improve life. By looking at the Growth Hormone/Insulin and Insulin-Like Growth Factor-1 Signaling Pathway, the FOXO/Sirtuin Pathway, Hormesis and the mTOR/AMPK Pathway we get to see the cellular activities that underlie aging. Each pathway gives us a different view of how we can strengthen our bodies resilience to stressors and ultimately live longer healthier. This synthesis of knowledge not only gives us a better understanding of aging but also shows us how science can create new roads to longevity.