Research shows that aging and age related diseases (ARDs) do have common molecular and cellular mechanisms of action as a common underpinning process. This integrated view of aging and ARDs suggests that precise boundaries between the two do not exist, and we are able to exercise control and influence over the rate and trajectory of this underpinning process.
It is becoming apparent that each ARD is the result of its own particular combination of alterations within a limited set of basic mechanisms shared with the aging process. This leads to the likelihood that ARDs are the result of an accelerated aging process. The obvious question then is can we influence this aging process such that is can be decelerated, and are there markers capable of measuring and assessing this. And the answer is yes!
We know that aging is the predominant risk factor for most diseases and conditions that limit health span. It is regarded as a physiological condition, which favors the onset of many diseases. But what if ARDs are the result of the acceleration of the aging process. To show what I mean here are some examples of common molecular and cellular mechanisms of action for a few age related diseases.
It is acknowledged that correlation does not necessarily equal causation. But what if aging is a disease in itself? If so what could the root cause be, apart from chronological age? The fact that we may not all succumb to ARDs at a similar chronological age, would seem to indicate there are some other factors involved.
It does seem to be that people who are able to reach an extremely high chronological age (such as centenarians), do so by being able to evade or delay ARDs that would otherwise lead to a shorter health-span or shorter life-span. It would seem that the biological age of many centenarians may actually be less than their chronological age.
So what are some of these likely factors that influence our biological age? I have created this diagram to show these factors, without diving deeply into the science.
Some questions follow which relate to this concept.
Can Aging and Disease Be Predicted Based on the Triggers and Regulators of Aging?
Given that there is a relationship between (a) environmental conditions (epigenetics) we subject ourselves to (nutrition, movement, love & support, mental state, sleep, stress, toxins, poor quality water & air, pathogens, etc), (b) our longevity genes, and (c) our cellular functioning (biological age), then certain broad predictions can be made.
Our body has evolved to handle both positive and negative influences. As you would expect, the positive influences support the processes involved in our physiology, immune system and survival. However we have also evolved to thrive and to benefit from some influences, or stressors, which you likely may regard as negative. Such stressors also benefit us in a positive way, by activating our genes associated with longevity without causing damage. I am referring here to the principle of hormesis.
“Hormesis has been defined as an adaptive response of cells and/or organisms to a moderate, usually intermittent stress. The agents which bring about the process of hormesis are called hormetins. Hormetins have been broadly classified into physical, psychological, and biological/nutritional. Physical factors such as moderate exercise, irradiation, thermal shock, and cold stress are grouped under physical hormetins. Factors which lead to social and mental well-being of an individual are classified as psychological hormetins. These include mental engagement such as intense brain activity and focused attention such as meditation.” [1]
“The beneficial effects of mild stress (or hormetic effects) on aging and longevity have been studied for several years. Mild stress appears to slightly increase longevity, delay behavioral aging, and increase resistance to some stresses.” [2]
It is well known that negative lifestyle habits not focused on optimizing health can lead to chronic diseases. Many of these diseases are also seen in older people. So there is a correlation, and a degree of predictability. However positive lifestyle habits, and those within the principle of hormesis, can change that predictability at any stage of life. Today we have a way of measuring biological age, by measuring our own methylation process, which is a key biochemical process essential for optimal functioning of our body. This can measure epigenetic marks on our DNA. So to a large extent aging and disease can be predicted by measuring methylation, which in theory is the result of the functioning of our innate regulators of aging.
What is mTOR and How is it Linked to Epigenetics?
The mTOR (mammalian target of rapamycin) gene is a regulator of cell growth and proliferation, and provides the instructions for making the protein mTOR. It is able to sense the presence or absence of nutrients essential for the growth, division and survival of our cells, and can switch on or off catabolism (breaking down) and anabolism (building up).
The science of epigenetics explains how our lifestyle and environment (both internal and external) influence our genes. For example, a decrease in calories or nutrition will inhibit mTOR activity, while an increase will encourage it. That can either be good or bad, depending on our unique situation. There may be times when we want to increase mTOR to grow muscle and improve cognition. However there may be other times when we want to have low levels of mTOR to increase longevity, encourage autophagy, decrease cancer risk, and reduce inflammation. If our lifestyle and environment is always at its highest level (with a constant increase in mTOR), then we may be unknowingly doing damage to our own longevity and health. Again this brings to mind the abovementioned principle of hormesis.
So there is a direct link between mTOR and epigenetics.
To What Extent Can We Extend Our Life by Controlling the Diseases of Aging?
There is no doubt that by being able to control or delay the diseases of aging, we should be able to extend our life. Of course we can’t do much if our life is shortened as a result of fatal accidents or life threatening infectious diseases which we were unable to overcome. However based on the concepts of what I have been bringing to light in this article, there is much that can be done to control the diseases of aging. Even in the face of acute conditions of illness and infection, if our physiology is optimally functioning, then such conditions may be able to be overcome without any impact on our lifespan.
My interpretation of extending life, is the extension of our chronological aging through the reduction or reversal of our biological aging. In effect that means we are optimizing the functioning of our physiology by focusing on keeping it in the best working state we can. In other words if at the chronological age of 70 we can manage to be at a biological age of 55 or less, then logically we have mitigated the risk of age-related diseases by delaying their onset, thereby enjoying a longer health span and longer lifespan. To control or reduce our biological age we have at our disposal many epigenetic options as well as supplements known to have a beneficial effect. It is also likely that pharmaceutical drugs will be identified or come available to support the process. The answer is in knowing what has the ability to reduce or increase our biological age.
What is the Role of Sirtuins?
To answer that, let’s first look at an overview of DNA. Our entire set of DNA (our genome) contains all of the information (blueprints) needed for our development, function, unique characteristics, and our biological responses in support of our life experiences, illnesses, and aging. We also have an epigenome, which is all the chemical compounds to tell the genome what to do. The epigenome is the control center that informs our genome (our entire set of DNA throughout our cells) which genes should be turned on or off.
So we can conclude it is our epigenome that has the most impact over our lives, as opposed to our DNA. Anything that may interfere with the functioning of the epigenome has the potential to disrupt or impede the biological processes that support our life and health, including aging.
The DNA in the nucleus of each of our cells needs to be packaged carefully to be able to fit inside such a small space. It is wrapped in strands around a scaffold of proteins into a structure called chromatin, which is itself then folded into other structures that form chromosomes. The cell influences how the chromatin is compacted to fit inside its nucleus, in order to facilitate access to the genes for their expression. To provide access to the genes or instructions to carry out protein generation and other biological activities, the DNA needs to be unpacked or unfolded. Sirtuins play a role in influencing this overall process.
One of the major risks we all face by simply living our life is damage to our DNA, which occurs almost every time cellular DNA is copied; when we are exposed to environmental conditions that damage our DNA; or as a direct result of our lifestyle habits. Fortunately our body has evolved ways of detecting and repairing DNA damage, including a call to action from sirtuins. However if for some reason our DNA is not correctly repaired then cells may lose their identity, which does occur and is part of our normal aging process.
Most genes, including sirtuins, contain the encoded information needed to make functional molecules. In mammals sirtuins are a family of seven genes, which encode the information to make their respective proteins / enzymes Sir1 through Sir7 within most of our cells. “These critical epigenetic regulators [sirtuins] sit at the very top of cellular control systems, controlling our reproduction and our DNA repair ……. [and] …. have evolved to control our health, our fitness, and our very survival.” [3] Their contribution in allowing development of age-related diseases is believed to occur when sirtuin activity declines. If that is the case, it is obviously beneficial to do everything we can to enable them to function optimally.
Dr. David Sinclair, tenured Professor of Genetics at Harvard Medical School and an expert researcher in the field of longevity, writes in his book on Lifespan [3] “we mammals have seven sirtuin genes that have evolved a variety of functions. Three of them, SIRT1, SIRT6 and SIRT7, are critical to the control of the epigenome and DNA repair. The others, SIRT3, SIRT$ and SIRT5, reside in mitochondria, where they control energy metabolism, while SIRT2 buzzes around the cytoplasm, where it controls cell division and healthy egg production” [3]. SIRT1 has been linked to the increase in longevity associated with caloric restriction.
What is AMPK?
This gene encodes the protein adenosine 5′ monophosphate-activated protein kinase (AMPK). It is a regulator of our cellular energy metabolism through its ability to balance our energy production and energy consumption. Insufficient cellular energy stimulates AMPK activity. Like many other things it is believed to diminish as we age. It is believed there is a link between AMPK and SIRT1, indicating that to some extent they may regulate each other.
In traditional Chinese medicine one of the naturally occurring substances found in some plant medications, used as an antimicrobial/fungal agent and as a treatment for type 2 diabetes, is berberine. Studies have shown that berberine activates AMPK in the liver, skeletal muscle, and adipose tissue.
[1] The Science of Hormesis in Health and Longevity, 2019.
[2] Hormesis, aging and longevity, Biochimica et Biophysica Acta (BBA) – General Subjects, October 2009, Éric Le Bourg
[3] Lifespan: Why We Age―and Why We Don’t Have To, by David A. Sinclair PhD, and Matthew D. LaPlante.