Are Hormetins the new Fountain of Youth in Aging?

Although aging is inevitable—most likely due to the accumulation of damage at the cellular level, rather than from any one specific program—the actual rate of aging can be an adaptive feature in nature. So although we will all die, there is a certain amount of plasticity in how fast we age and therefore how early or late we die. This plasticity is likely to be controlled by relatively simple mechanisms. Aging research focusing on this plasticity has shown some encouraging results.

Hormetins—sometimes referred to as adaptogens—are a mild stress-induced action that has long-term and broad beneficial effects. Following the dictum that what does not kill you make you stronger, hormetins kick start the body to respond to the mild stress and this response has broader and longer-lasting benefits. Benefits that translate to living longer.

Mild Stress can be induced through four main methods. The easiest and most common is physical activity like exercise, heat, gravity and irradiation. There are emerging interest in psychological methods like meditation, brain exercises, juggling and balancing. However, out of all these methods, hormetins—a unit of a hormesis—are best defined by a supplement. Pop a pill and let your body do the work.

Nutritional stress includes caloric restriction, and anti-oxidants, polyphenols—found more commonly in as fruit and vegetables, tea, red wine, coffee, chocolate, olives, and extra virgin olive oil—flavonoids—plants especially parsley, onions, berries, tea, bananas, all citrus fruits, red wine, and dark chocolate—and lastly micronutrients—that include some vitamins and trace amounts of  iron, cobalt, chromium, copper, iodine, manganese, selenium, zinc and molybdenum..

The trick is to ensure that the trauma is mild enough not to be counterproductive.  With nutrients this is easier to achieve since most of these nutritional supplements are water-soluble and therefore in cases of ineffectiveness you are at worst producing expensive urine.

The problem with nutrients is that everyone is trying to make a buck. Not just snake-oil salesman but also academicians and researchers getting into the “business” of selling immortality and anti-aging pills. In table 2 are a number of nutrients on the far right and far left, that are promoted as beneficial to living longer. On the far right, from Rhodioia  down to Glucosamine, these are said to contribute to the mechanism to their left (shaded smaller cirlces), from Stress Resilience to Tumor Suppression.

We can see that although there are many potential mechanisms, in this review there are nine mechanisms they all contribute to the two main and connected mechanisms through their anti-oxidant benefits and by mimicking caloric restriction (large shaded circles to the left).

Hormesis represents a gyroscope in maintaining a balance between an individual and the environment. Even if a slight elevation of a certain toxic chemical, event or condition in the environment occurs, the body chemistry changes to prepare for it. But this balancing act is not without limitation. The capacity for the body to make biological/chemical adjustments is limited, but there is plasticity in this system of person–environment interaction. Nadine Saul with the Humboldt-University of Berlin and his colleagues have argued that the process of hormesis is a balance that has both positive and negative outcomes. It emerged that for every longevity improvement, there is a reduction in the capacity of the organism for growth, mobility, stress resistance, or reproduction. Saul argues (correctly it seems) that longevity comes at a price, and although hormesis seems to promote longevity, other hormetic costs may ensue, some of which are unknown and unpredictable.

The mechanism of hormesis remains an enigma, although we continue to learn more about how the body develops resilience in response to changes in the environment. In 1962, Italian geneticist Ferruccio Ritossa discovered that heat shock proteins are produced when cells are exposed to a variety of stresses. Initially identified with fruit flies that were exposed to a burst of heat resulting in the production of new proteins that help cells survive. The epigenes responsible for this are called “vitagenes” and maintain balance within cells under stressful conditions. As with the heat shock proteins, these act as chaperones, as minders, in assisting the establishment of “proper protein behavior.” Despite these terms, we do not know how this function is carried out.

Similarly, we now acknowledge that caloric restriction itself might be effective because of its hermetic qualities—a shock to the body—rather than through diet. This might be the case since there are  multiple ways of producing the same effect without adhering to a diet of calorie reduction. The underlying mechanism—rather than the reduction of calories—becomes important. And the underlying mechanism is a shock. If we accept this mechanism, then we should ask “why?”   Why does a shock cause the body to build resilience?

The answer is both simple and radical. A shock causes the body to build resilience because the body is designed to do exactly that. Our body interacts with the environment in order to survive. And to accomplish this adaptation there must be plasticity, some wiggle room, in our capacity. And our biology is a constellation of different entities that depend on each other. How it does this adaptation is more enigmatic, but we now know that there are plasmids and bacteria that help address the needs of our body. These might even recombine with our own DNA to make these adaptations more permanent.

Just as Thales of Miletus (624-546 BCE) the ancient Greek philosopher created science by arguing that we should stop referring to natural phenomena as the “will of god,” in our world we should move away from looking at end of life diseases as “caused by aging” and become more appreciative of the balance we maintain with our natural world. By discarding the new mythology of aging—immortality gurus—we can then focus on plasticity in older age. The fountain of youth might be a fountain for living-well in older ages.

© USA Copyrighted 2017 Mario D. Garrett 

References

Garrett, M. (2017). Immortality: With a Lifetime Guarantee. Createspace. USA.

Lenart, P., & Bienertová-Vašků, J. (2017). Keeping up with the Red Queen: the pace of aging as an adaptation. Biogerontology, 18(4), 693-709.

Rattan, S. I. (2017). Hormetins as Drugs for Healthy Aging. In Anti-aging Drugs (pp. 170-180). Royal Society of Chemistry.

Hope Versus Depression

In Hesiod’s telling of the Greek myth of Pandora—the first woman on earth—Pandora is said to have opened a large jar from which all evils escaped into the world, leaving behind hope. Hope was the only thing that remained for us humans. Hope is not tangible, but a state of positive expectation. Hope is an illusion—a trick of the mind—that motivates us to anticipate rewards, rewards that are themselves purely cerebral encouragement. Hope is a house of cards built on the anticipation and yearning for illusory and ephemeral rewards. When Pandora left us with hope she left us with a whole bunch of tricks of psychology. Perhaps for those with depression, even hope escaped out of “Pandora’s box.”  In reality we struggle and suffer and gain momentary pleasure and transient satisfaction until we are released from this ongoing strife by death. This is how we view the life of animals, but not how we view our own lives.  This trick of psychology—Pandora’s Box—releases us from acknowledging our natural daily grind of survival. We have something that we do not ascribe to animals. Humans have feelings, emotions and hope.

In order to understand why we have emotions, we must grasp that humans have a very large brain. Our brain is the most complex entity in the universe and it is this complexity that provides us with a clue of what it does. It represents the world—as we know it—as a model. A virtual reality machine designed to understand our environment and predict the world. It is our passport for survival as individuals and as a species. Emotions are our transient indicators of how well we are approaching this virtual ideal.  Emotions nudge us to change towards specific expectations. Our brain is a perfectly balanced tool to help us improve. However, having such a complex thinking organ comes with one huge disadvantage: It also has the capacity for self-reflection. And self-reflection might be the Achilles Heel in our survival strategy.

In order for the brain to deal with this seemingly inconvenient critical contemplation, it has developed ways of dealing with self-reflection and the obvious daily struggle to survive and our eventual death. Our brain has generated hope as an illusion of a utopia, a heaven—whether on earth or in the afterlife. For the long term we have hope that everything has a meaning, a purpose.  We have a narrative, a story that we make our own. For this hope to be realistic we need to think of ourselves as unique and at the center of our reality. A selfish existence—solipsism—necessary in order for us to have hope. Without a selfish investment in the outcome we would have no interest in hope. Hope is selfish and central to being human.

In 2017 Claudia Bloese wrote that, “…almost all major philosophers acknowledge that hope plays an important role in regard to human motivation, religious belief or politics.” Hope can either be seen as a way to motivate humans to do better, or an excuse to be lazy and hope for the best. In psychology, starting with Charles Snyder’s hope theory, there are two components to hope: the belief that there is a possibility of happiness in achieving goals, and a path to achieving these goals. A kind of behavioristic stepladder, with each successive step-up being promoted by positive reinforcement. But this interpretation changed with Ernst Bloch‘s three-volume work The Principle of Hope (1954-1959). Bloch transforms the aim not of happiness but of an ideal state. Bloch argued that we aim to achieve our goals not because we become happier but because we will achieve our utopia. This is an important admission. For Bloch, a German Marxist, hope is not about being optimistic—some kind of behaviorist ploy of gaining pleasure for every rewarding behavior—hope is an ambition to attain an ideal state. In this interpretation of hope, there is only one other alternative, if not heaven then hell.

The psychology of hope has converged with the utopian and dystopian view of mankind. And Bloch’s proposition fits in with traditional religious beliefs about utopia. Bloch argues that the utopian package entails no death, no disease, no injustices and where everyone is equal. Richard Rorty, the American pragmatist philosopher shares such an interpretation as well. Rorty further acknowledges that hopelessness is always based on the absence of a narrative of (political) progress. This lack of (positive) narrative defines depression.

This is the triad of depression: lack of self worth, negative evaluation of situations and lacking optimism for the future. The opposite of hope, depression is defined by the feeling that “there is nothing to live for.” Depression is having a narrative arc that does not anticipate positive changes. Both hope and depression project into the future. The difference comes in that in order for hope to be real our psychology needs to get rid of the looming prospect of death that has a long shadow in our future. Hope cannot exist with the acknowledgment that we will stop existing. Death is the antithesis of hope. How do we “cure” this final nothingness in our narrative arc?

One of the wrinkles in this concept of hope however is the fact that we all die. What’s the point of everything if at the end of this journey we find that it was just a transient passage. Hosting a party at an airport lounge. There is something rotten in the center of hope, this forbidden fruit for the depressed. In the 1900s William James, the early psychologist called this fear of death the  “worm at the core” of our being. This tension between the belief that we behave as though we are at the center of a consistent universe, with the knowledge of the certainty of our death. To psychologists that now follow Terror Management Theory, this tension constitutes a fundamental quandary for humankind, affecting us radically as nothing else does.

Our psychology came up with a more subtle solution than simply to completely ignore our mortality. We have learned to trick ourselves that perhaps even if we die, we don’t really die. A small part of us remains (soul), or this is only temporary (reincarnation), or we remain living in other dimensions (legacy), or everyone else is already dead (zombies) or this is all a dream anyway (intellectualization.) All together these sophisticated tricks embrace hope and are a formidable barrier to accepting death.

This tension is alleviated by some sophisticated thinking strategies. And these tricks are exactly what are needed to dispel that loss of hope, that depression. But does the science support this view?

In a review of the effectiveness of therapies for depression Andrew Butler and his colleagues reported that Cognitive Behavior Therapies (CBT) was better than antidepressants for depression and was found to be effective for many other mental disorders.  Which is good news since a recent study by the Canadian Marta Maslej and her colleagues reported that medication for depression increases the risk of dying early from all causes, by some 33%. So if we look at the mechanisms of CBT we find some surprising insights. In a classic book on cognitive therapy in 1979, Aaron Beck and his colleagues go on to say that the difference is due to the “…gross changes in his cognitive organization…” (p.21) These cognitive deficits involve:

1.  Arbitrary inference: making preconceived conclusion

2.  Selective abstraction: focusing on select negative aspects

3.  Overgeneralization: applying the lessons from an isolated incident to broader contexts

4.  Magnification and minimization: highlighting the negative and diminishing the positive

5.   Personalization: relating external event to self

6.   Absolutistic dichotomous thinking: categorizing events into two extreme classes (perfect vs. broken)

But if the function of our mind is to develop a view of the world, a world that might be dangerous, then these aspects of cognition are what we do best for our survival. In a world that can and does ultimately kill you, you have to make everything personal.  We select quickly what is good or bad and enhance the ability to protect ourselves and ensure that future events are anticipated, especially if they are likely to be dangerous. The fact that this makes us feel miserable is a separate issue. This cognitive organization is designed for survival, focused exclusively on what could harm you and that ultimately there is no hope as we are all mortal. This acceptance of mortality is perhaps the reason for the salience of death and suicide ideation, attempts and engagement.

Aaron Beck and his colleagues go on to report that: “A way of understanding the thinking disorder in depression is to conceptualize it in terms of “primitive” vs. “mature” modes of organizing reality.”(p.14).  Within our line of thought, if we see depression as a natural state without the tricks of hope, then we can interpret this excellent description of “primitive…gross changes in [his] cognitive organization.” Rather than a mature embrace of this bag of tricks, those with depression are stuck without their own bag of tricks. This is where CBT comes in. Resulting in a narrative arc that our life holds great benefits and pleasure and success and accomplishment, CBT is a way of accepting this bag of tricks that accompany hope. To paraphrase Dan Gilbert, we manufacture happiness. The conclusion is that we accept and promote certain beliefs that round the edges off our ultimate fate—we delude our impending death by having these celebratory moments like bread crumbs on the path to nirvana.

Understanding how we maintain this delusion—of hope—for so long is the linchpin of human psychology. As we get older we lose this shine of hope. We face our mortality up close and personal. As a result, depression increases with older age. From the very first step we take, we strive for independence. Our brain gains mastery in predicting the environment we live in and gaining a sense of self-mastery, even hubris. We control others when we have a positive disposition, when we have a positive story line. Out brain understands this advantage. Our positive narrative arc attracts others and our brain gains better mastery of the environment.   The mastery of our brain is perhaps the only understood at older age, when some of the social façade starts to disintegrate. The question is whether it is better to be happy and live in a delusion of hope or to be depressed and be right. Hesiod’s story of Pandora might have revealed a deeper truth.

© USA Copyrighted 2017 Mario D. Garrett 

References

Bloeser, Claudia and Stahl, Titus, "Hope", The Stanford Encyclopedia of Philosophy (Spring 2017 Edition), Edward N. Zalta (ed.). Accessed online: https://plato.stanford.edu/archives/spr2017/entries/hope/

Beck, A. T. (Ed.). (1979). Cognitive therapy of depression. Guilford press.

Butler, A. C., Chapman, J. E., Forman, E. M., & Beck, A. T. (2006). The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clinical psychology review, 26(1), 17-31.

Crona, L., Mossberg, A., & Brådvik, L. (2013). Suicidal Career in Severe Depression among Long-Term Survivors: In a Followup after 37–53 Years Suicide Attempts Appeared to End Long before Depression. Depression research and treatment, 2013.

Gilbert, D. (2009). Stumbling on happiness. Vintage Canada.

O'donnell, I., Farmer, R., & Catal, J. (1996). Explaining suicide: the views of survivors of serious suicide attempts. The British Journal of Psychiatry, 168(6), 780-786.

Maslej, M. M., Bolker, B. M., Russell, M. J., Eaton, K., Durisko, Z., Hollon, S. D., ... & Andrews, P. W. (2017). The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis. Psychotherapy and Psychosomatics, 86(5), 268-282.

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