By: Bryan Oronsky, Ahad Javansalehi
“Who wants to live forever?”
-Freddie Mercury
Introduction
A common phrase that adults use with hyperactive children is “act your age!”. However, for hypoactive middle-aged and older adults, the best advice is “don’t act your age”. Many of these older adults, beset by chronic conditions like type 2 diabetes, atherosclerotic cardiovascular disease, osteoarthritis, osteoporosis, joint inflexibility, and sarcopenia (muscle loss) that are rare in childhood would do well to sit less and move more.
Aging and inactivity, which tend to go hand-in-hand, contribute to “inflammaging”, a hybrid term of inflammation and aging. This term describes a state of chronic, low-grade inflammation, which progresses insidiously with age and contributes to deterioration of the mind and body. As referred to herein, inflammation is defined as a protective response that involves increased levels of cytokines and reactive oxygen species (ROS) or free radicals. The former are small proteins, which activate the immune system in response to tissue damage from trauma, microbial invasion, toxins, and a variety of irritant particles, including crystals, minerals, and protein aggregates. The latter, ROS, are short-lived, kamikaze-like, unstable molecules which ricochet wildly and damage the cell. Paradoxically, however, ROS also turn on an adaptive detoxification response and act as indirect antioxidants, when exposure to them is moderate and short lived, rather than excessive and chronic, so the situation is not black and white.
Like ROS, inflammation is a trade-off between acutely beneficial and chronically harmful. Acute or short-term inflammation is helpful and necessary to eliminate invading microorganisms and debris. On the other hand, when inflammation persists and turns chronic, it is more harmful than helpful. These harmful effects are related to the “scorched earth”, shoot-first, ask-questions-later tactics of inflamed immune cells, which release a toxic mix of protein-degrading enzymes and reactive chemical species to get rid of the invader, whatever the cost to the surrounding normal tissues. The longer that inflammation goes on the greater the collateral damage to tissues, cells, DNA, and proteins, which drives a vicious circle of more inflammation and more damage that eventually leads to irreversible organ dysfunction and disease.²
Two expressions come to mind. These are “let sleeping dogs lie” and “break glass only in case of emergency” because inflammation is a response of last resort; in other words, it is not to be trifled with or activated on a whim. Like a guard dog that escapes its leash to violently confront trespassers, inflammation may, in its overprotective zeal, accidentally bite- and severely damage or maim – the hand of its master, if not quickly brought to heel. It is a fine line between too little inflammation so that infection persists, and too much of it and for too long of a time so that tissue damage results.
Besides infection, other so-called “sterile” or non-infectious triggers or signals that activate an inflammatory response include cholesterol, uric acid, obesity, misfolded proteins like beta-amyloid, free radicals, stress, mechanical trauma, senescent cells, and cell death. What all these triggers share in common is that exposure to them tends to increase and accumulate with age, which leads to inflammaging. The onset and continuation of inflammation depends on a series of proteins called the inflammasome, which assemble in response to the above triggers. The most studied and well-characterized inflammasome is that of nucleotide-binding domain (NOD)-like receptor protein 3 or NLRP3, for short. The main outputs of NLRP3 inflammasome activation are secretion of the inflammatory cytokines, IL-1β and IL-18, and the initiation of a form of cell death called pyroptosis.
Figure 1. Activation of the inflammasome
It is common to attribute ill health to “bad genes”, and while genetic predisposition certainly factors in and plays a role, lifestyle and dietary factors may play an even more important one. In so-called Blue Zones around the world, where a measurably higher proportion of long-lived individuals reside, commonalties include a high level of physical activity, family solidarity, social interaction, and plant-based diets or caloric restriction. In Okinawa, one of the five blue zones, (the others are Loma Linda, CA, USA, Nicoya, Costa Rica, Sardinia, Italy, and Ikaria, Greece), the residents practice hara hachi bu, which is to eat until 80% satiety.³
The emphasis of this article is on anti-inflammaging interventions with the proven (or hypothesized) potential to increase not only lifespan, but perhaps, more importantly healthspan, that is, the duration of health and independence before chronic disease and disability set in and take over. These interventions include diet, exercise, metformin, statins and angiotensin receptor blockers, rapamycin, indirect antioxidants, and senolytic drugs.
Indirect antioxidants or “hormentins”: Antioxidants neutralize free radicals, which randomly oxidize and damage cells. The main source of free radicals is the mitochondria, the “Tesla-like” battery packs that take up residence in every cell and give them energy. A common misconception is that antioxidant supplements decrease inflammation and extend healthspan. In fact, the opposite is true. In several clinical trials high doses of antioxidant supplements like vitamin E, beta carotene or vitamin A, and vitamin C that directly quench or scavenge free radicals (hence the commonly used term, “free radical scavengers”) increase mortality and decrease exercise performance.4 This unexpected result is most likely related to interference with Nrf2 activation, as shown in Figure 2. Nrf2 is a gene, which turns on many antioxidant and detoxifying enzymes. By contrast, indirect oxidants activate Nrf2. Indirect oxidants include sulforaphane in broccoli, resveratrol in wine, curcumin in the curry spice turmeric, quercetin in berries, and ECGC found in tea.
Figure 2. Direct and indirect antioxidants
Direct antioxidants (in red) decrease ROS and a protective antioxidant response. Indirect antioxidants (in green) activate antioxidant defenses such as Nrf2
Diet: The intrinsic appeal of plant-based diets is that they are rich in indirect antioxidants, which activate Nrf2. A prototypical example is the Mediterranean diet, which consists mainly of vegetables, fruit, whole grain, legumes, and nuts. Other Nrf2-activating patterns of eating include the ketogenic diet, which replaces carbohydrates with fats and proteins, calorie restriction, and intermittent fasting. Also, a Western diet is associated with gut inflammation and aging. Meanwhile, diets rich in nondigestible fiber or prebiotics may reduce the risk of inflammaging.
Metformin: The most prescribed treatment for Type 2 diabetes, metformin, which comes from a herbal medicine, Galega officinalis, that was used in medieval Europe, blocks activation of the NLRP3 inflammasome. Metformin also turns on AMP-activated protein kinase (AMPK), a protein, which blocks the production of glucose in the liver, a process known as gluconeogenesis. Metformin is also associated with anti-aging effects in lower order organisms such as the nematode, C. elegans, and mice, however whether this benefit extends to humans is unknown. Anti-aging studies in humans are ongoing.5,6
Exercise: Longer life expectancy correlates with exercise, in general, the more the better. Furthermore, elite athletes, for example, Olympic wrestlers, marathoners, and Tour de France cyclists usually live considerably longer than the general population. Mechanisms include activation of Nrf2, AMPK, and inhibition of the NLRP3 inflammasome.7
Direct inflammasome inhibitors: The most clinically advanced of the direct inflammasome inhibitors is RRx-001, in a Phase 3 trial for the treatment of cancer.8 Its anti-inflammatory properties make it potentially well suited for the treatment of age-related conditions like Parkinson’s Disease and ALS/MND, where it is under evaluation.
Heat stress: In response to heat exposure, as in a sauna, increased production of heat shock proteins (HSPs) occurs. These stress proteins may contribute to anti-aging effects through removal of misfolded proteins, which accumulate during aging, and which are toxic to cells.9
Statins and angiotensin receptor blockers (ARBs): These are drugs used to treat high cholesterol and high blood pressure respectively. In a study of 130 middle aged males, treatment with a low dose of the statin, fluvastatin, and/or the ARB, valsartan, either separately or in combination substantially increased the expression of several longevity genes.10
Senolytic drugs: Senescent cells also known as zombie cells accumulate during aging and disease, where they activate the inflammasome. Senolytics are drugs, which selectively kill or eliminate senescent cells. They are associated with anti-aging effects in experimental animals. Examples of potential senolytics include rapamycin and dasatinib, already approved for the treatment of organ rejection and pulmonary hypertension, respectively, which should accelerate their use in the general population.11
Conclusion
From Gilgamesh, the Babylonian who sought immortality as far back as 2100 BC,12 and the Spanish Conquistador, Ponce de Leon, who, according to legend, trekked through Florida in search of the Fountain of Youth only, ironically, to meet death from an Indian arrow, and, more recently, to Silicon Valley-backed anti-aging biotechs, the quest to live forever is as old as recorded history—and as urgently pursued as ever. A counterpoint to the desire for immortality is the parable of Tithonus, the ancient Greek, who was cursed with eternal life but not eternal youth so that, with each passing year, he grew ever older and more decrepit. This parable underlies the difference between lifespan/agespan and healthspan, an important distinction, since the former refers to number of years lived, the latter to number of years lived disease-free, which is probably most important and relevant to human mortality.
The common denominator between all the anti-inflammaging interventions discussed in this article is that they activate mild-to-moderate stress responses. To put it another way, a little bit of stress goes a long way, emphasis on “a little bit” since low amounts or “doses” of stress are beneficial, but excessive amounts are not. In response to heat and cold, exercise, oxidative stress, caloric restriction, low oxygen, chemical toxins, pollution, radiation, heavy metals, trauma, and even emotional and psychological stresses, as well as many others the organism takes the hit, adjusts, repairs, and comes back better and stronger, especially if the “doses” are low enough not to overwhelm and paralyze the compensatory responses. These compensatory responses are known as hormesis (adjective hormetic).13
Hard-wired into all life on Earth is hormetic adaptation, which makes sense considering that over billions of years change was constant and continuous. The seas rose and fell—and rose again. Climactic shifts occurred. An anaerobic atmosphere was replaced with an oxygenated one. Asteroids and comets bombarded the planet. High ultraviolet (UV) radiation reached the surface before the presence of protective ozone in the atmosphere. Metal ions saturated the primitive oceans. Volcanoes erupted and sulfuric clouds choked the atmosphere. Species competed for scarce resources.
“Adapt or die” is a basic principle of evolution.14 To survive and thrive it was – and still is – primordially necessary to acclimate to multiple stressful conditions from which life on Earth emerged; these include oxidation, frigid temperatures, radiation, starvation, pollution, heavy metal exposure, infection, and trauma. In modern life the absence of these “old” known stresses, to which human physiology adapted as a protection mechanism, is a “new” stress, which decreases resilience and contributes to inflammaging.
So, in summary, for a long and healthy life, the take home messages are these: 1) don’t get too comfortable (i.e., deprive to stay alive) and 2) use it or lose it. Deliberate exposure to moderate and intermittent levels of stress (moderate and intermittent levels being the key words here) activates or dials up hormetic protective responses. However, with age resilience to stress decreases. As shown below in Figure 3, the more that these protective responses are activated or “worked out” the less they deteriorate over time and the better equipped an individual, especially an older individual, is to mount a defense against inflammaging and stave off age-related diseases either now or in the future.
Figure 3. Use it or lose it, the downward spiral of aging from inflammaging
Author Bios
Dr. Bryan Oronsky serves as EpicentRx Chief Development Officer and combines firsthand clinical experience as a physician with 17 years of pharmaceutical development experience.
Ahad Javansalehi is a three-time Olympic wrestler who continued his career as a USA National Team Assistant Coach, Cornell RTC Head Wrestling Coach and currently as CARTC Head Wrestling Coach at Stanford. Mr. Javansalehi holds a Master’s in physical education and sports science.
References
1. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15(9):505-522. doi:10.1038/s41569-018-0064-2
2. Oronsky B, Caroen S, Reid T. What Exactly Is Inflammation (and What Is It Not?). Int J Mol Sci. 2022;23(23):14905. Published 2022 Nov 28. doi:10.3390/ijms232314905
3. Buettner D, Skemp S. Blue Zones: Lessons From the World’s Longest Lived. Am J Lifestyle Med. 2016;10(5):318-321. Published 2016 Jul 7. doi:10.1177/1559827616637066
4. Li S, Fasipe B, Laher I. Potential harms of supplementation with high doses of antioxidants in athletes. J Exerc Sci Fit. 2022;20(4):269-275. doi:10.1016/j.jesf.2022.06.001
5. Hur KY, Lee MS. New mechanisms of metformin action: Focusing on mitochondria and the gut. J Diabetes Investig. 2015;6(6):600-609. doi:10.1111/jdi.12328
6. Valencia WM, Palacio A, Tamariz L, Florez H. Metformin and ageing: improving ageing outcomes beyond glycaemic control. Diabetologia. 2017;60(9):1630-1638. doi:10.1007/s00125-017-4349-5
7. Garatachea N, Pareja-Galeano H, Sanchis-Gomar F, et al. Exercise attenuates the major hallmarks of aging. Rejuvenation Res. 2015;18(1):57-89. doi:10.1089/rej.2014.1623
8. Oronsky B, Reid TR, Larson C, et al. REPLATINUM Phase III randomized study: RRx-001 + platinum doublet versus platinum doublet in third-line small cell lung cancer. Future Oncol. 2019;15(30):3427-3433. doi:10.2217/fon-2019-0317
9. Murshid A, Eguchi T, Calderwood SK. Stress proteins in aging and life span. Int J Hyperthermia. 2013;29(5):442-447. doi:10.3109/02656736.2013.798873
10. Janić M, Lunder M, Novaković S, Škerl P, Šabovič M. Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”. Int J Mol Sci. 2019;20(8):1844. Published 2019 Apr 14. doi:10.3390/ijms20081844
11. Blagosklonny MV. Anti-aging: senolytics or gerostatics (unconventional view). Oncotarget. 2021;12(18):1821-1835. Published 2021 Aug 31. doi:10.18632/oncotarget.28049
12. Faria MA. Longevity and compression of morbidity from a neuroscience perspective: Do we have a duty to die by a certain age?. Surg Neurol Int. 2015;6:49. Published 2015 Mar 30. doi:10.4103/2152-7806.154273
13. Zimmermann A, Bauer MA, Kroemer G, Madeo F, Carmona-Gutierrez D. When less is more: hormesis against stress and disease. Microb Cell. 2014;1(5):150-153. Published 2014 May 5. doi:10.15698/mic2014.05.148
14. Bell G, Collins S. Adaptation, extinction and global change. Evol Appl. 2008;1(1):3-16. doi:10.1111/j.1752-4571.2007.00011.x