Can We Slow Aging in Patients? Autophagy, Mitophagy, Genetics & Epigenetics
CHRIS D. MELETIS, ND
Aging – or more specifically, how to slow it down – is a topic that has fascinated scientists, doctors, and the general population for thousands of years. Yet despite our advancements in medicine and science, we still don’t know for sure about healthy aging or precisely what it takes to tip the scales into unhealthy aging.
Several years ago, I was a keynote speaker at an event in New York. My lecture was at 7 am. I flew in from Oregon and arrived at the hotel around 11 pm the night before the lecture. I started the lecture with a question: “How many cells in the human body must be tired before perceiving being tired? When do we hit a threshold of cells impacted in the adrenals or brain before proclaiming that we are tired?” I confessed that I did not know the answer, and I would be pleased if someone might share the answer with the group.
When nobody offered a proposed number of cells, I asked another question: “How many cells in my finger must hurt before I consciously recognize the pain? Have we not all had a paper cut or a microscopic splinter that triggers a more exquisite level of discomfort than a larger affliction?” These questions had a purpose. We know much about the human body; our knowledge of physiology and interventional medicine has grown astronomically. Yet we must stay humble and recognize that there is much more to know.
There are some fundamental principles of healthy aging that we do know. We must eat healthily, avoid preserved food, sugar, and refined carbs, and eat as many fruits and vegetables as possible to slow aging. A recent study in PLOS Medicine found that people who changed their diet to a healthier, Mediterranean-style eating plan extended their life by 8 to 13 years, depending on their age.1 I like to say, “Live food for living people, dead food for dying people.” We also need to avoid toxins as much as possible by eating organic foods, avoiding the Environmental Working Group’s Dirty Dozen foods, and avoiding pesticides and herbicides in our yards. Eliminating indoor air pollution in our homes and offices is also a fundamental strategy for healthy aging.
These foundational practices are essential. This article is far too short to cover all the causes of accelerated aging and interventions for healthy aging. Consequently, I will focus on several important aspects of aging, including mitochondria, sirtuins, autophagy, mitophagy, and the role of nicotinamide adenine dinucleotide (NAD+). I’ll also discuss the importance of testing for genetic polymorphisms that can affect aging and things we can do to alter genetics and epigenetics in our patients’ favor.
Theories of Aging
Scientists have proposed several theories about why we age. Vladimir Dilman, a Russian researcher, proposed the neuroendocrine theory of aging.2 This theory states that dysregulation of homeostasis is the cause of aging. An essential part of the neuroendocrine theory is the hypothalamus-pituitary-adrenal axis. In this theory, dysregulation of the hypothalamus is to blame for undesirable age-related changes in human health, such as reproductive decline.2 Ward Dean, MD, was instrumental in bringing Dilman’s theory to physicians and the general public.
Another theory is the free radical theory proposed by Denham Harman.3 Harman’s theory particularly supports the use of NAD+, which we will explore later in this article. Also relevant to aging is the cellular garbage theory created by Vadim Gladyshev.4 It is Gladyshev’s theory that we will explore next.
Aging, Autophagy, and Mitophagy
Autophagy is the process of the body cleaning out components that are not needed or damaged. A significant form of autophagy is the removal of damaged mitochondria, also known as mitophagy. Autophagy is an important aspect of the cellular garbage theory of aging, which states that the buildup of biological garbage that can’t be entirely removed from the body leads to cell senescence.4 Impaired autophagy can lead to the inability to remove damaged and unneeded cellular components and is a hallmark of aging.5 Compromised autophagy plays a role in age-related disorders such as Alzheimer’s and Parkinson’s diseases.5 Conversely, stimulating autophagy may slow the onset of aging and age-related diseases.6 The activation of autophagy suppresses important markers of aging such as inflammation.7 Autophagy blocks inflammation via regulation of immune mediators, innate immune signaling pathways, and inflammasomes.7
Impaired mitophagy also plays a role in aging. Mitochondria produce reactive oxygen species (ROS), otherwise known as free radicals. Postmitotic cells such as neurons and cardiac myocytes, which are responsible for essential functions of the brain and heart, tend to exhibit particularly prominent evidence of cellular aging.8 Changes in these cells are involved in the overall aging process, and mitochondria in these postmitotic cells undergo some of the most significant age-related alterations of all cellular organelles.8 Lysosomes are cellular organelles that break down unneeded or damaged cell parts and are responsible for mitochondrial turnover. Lysosomes experience significant age-related changes.8 While mitochondria become enlarged or structurally disorganized with aging, lysosomes progressively build up an aging pigment known as lipofuscin.8
Damaged, aged mitochondria that haven’t gone through autophagy undergo further oxidative damage, leading to reduced energy production and increased production of ROS.8 This corresponds to Harman’s free radical theory of aging. The lipofuscin that accumulates in lysosomes also interferes with their ability to recycle the damaged mitochondria.8 Over time, damaged, enlarged, and dysfunctional mitochondria replace normal ones.8 Therefore, it’s critical for both autophagy and mitophagy to continue functioning optimally. That is where NAD+ and nicotinamide riboside come into play.
NAD+ in Autophagy and Mitophagy
NAD+ is a critical cofactor in cellular bioenergetics and adaptive stress response. In his 1930 Nobel Prize lecture, Dr. Hans von Euler-Chelpin stated that NAD+ “is one of the most widespread and biologically important activators within the plant and animal world.”5 Many metabolic pathways such as glycolysis, fatty acid β-oxidation, and the citric acid cycle require NAD+ as a cofactor. The reduced form of NAD+ (NADH) is a primary donor in the generation of ATP via anaerobic glycolysis and mitochondrial oxidative phosphorylation.5
Reduced levels of NAD+ occur in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, as well as in cardiovascular disease and muscle atrophy.5 During aging, various tissues show low levels of NAD+.5 Replenishing cellular NAD+ could slow aspects of aging and inhibit age-related diseases.
NAD+ may retard aging via the regulation of both autophagy and mitophagy. Studies in human cell and animal models indicate NAD+ has a novel role in autophagy and mitophagy.9 In these models, NAD+ plays an important role in mitochondrial maintenance, and the action of enzymes governs DNA repair.5 The role NAD+ plays in autophagy and mitophagy also relies on the presence of sirtuin-1 (SIRT1).5 The NAD+/SIRT1 signaling pathway promotes autophagy, which is necessary for SIRT1’s ability to prolong lifespan.10
Utilizing NAD+ precursors, especially nicotinamide riboside (NR), is ideal for promoting optimal autophagy and mitophagy. Human research in aged subjects indicates supplementation with 1 gram per day of NR for 21 days increases the skeletal muscle NAD+ metabolome and suppresses inflammatory cytokines.11 Another randomized, double-blind, placebo-controlled, crossover clinical trial showed that NR supplementation led to increased levels of NAD+ in healthy middle-aged and older subjects.12 Other human research in overweight and obese human subjects indicates NR supplementation can elevate markers of increased NAD+ synthesis, increase fat-free mass, elevate the sleeping metabolic rate, and significantly increase acetylcarnitine concentrations in skeletal muscle.13 Acetylcarnitine is linked to metabolic flexibility and improved metabolic health.13
The Role of Genetics and Epigenetics in Aging
Not all individuals have the same genetic longevity and wellness potential as others. As far as the rate of aging is concerned, there are considerable differences among individuals and even among tissues within a body. Centenarians have genetic differences and specific protein signatures that predict longer survival.14 A comparison study of centenarians, their offspring, and a control group found distinct serum protein signatures of extreme longevity.14 Centenarians also acquired markers of aging much later in life compared to people who did not have longevity in their family. Centenarians also continued to age but at a much slower pace than shorter-lived people.14
Ordering genetics testing for patients can identify if specific attention is necessary. A particularly important genetic mutation to look for is the methylenetetrahydrofolate reductase (MTHFR) gene mutation linked to age-related diseases, including Alzheimer’s and atherosclerosis.15,16 Any mutation in the MTHFR enzyme can cause suboptimal methylation. In addition, MTHFR is involved in the metabolism of folate, so people who have this gene mutation are unable to make use of this important vitamin. Supplementing with an active form of folate (5-MTHF) circumvents the need for MTHFR.17
Much can depend on genetics, but many people don’t manifest their full genetic potential due to epigenetic factors such as stress, diet, lifestyle, environmental toxins, and pollution. These epigenetic factors can alter DNA methylation, which are the biochemical markers of an individual’s age.18 Consequently, some researchers proposed that aging itself has its basis in epigenetic changes (including methylation alterations) over time.18
I like to say that genetics loads the gun, but lifestyle pulls the trigger. In a recent randomized controlled clinical trial conducted among 43 healthy adult males aged 50-72, the men were put on an 8-week treatment regimen that included eating a healthy diet, getting enough sleep, exercising, using relaxation techniques, and taking probiotic and phytonutrient supplements.18 The study found that lifestyle and diet changes reversed epigenetic aging in the men compared to the control group, as demonstrated by their methylation rates.18
In the end, it’s all about the total burden on the human body. When our trillions of cells get exposed to factors including poor diet, lack of sleep, and excessive stress, they become vulnerable to dysfunction. Altered methylation, shortened telomeres, free radical damage, and diminished ATP production are required to sustain homeostasis and reduce aging. We should not ignore mental health as another factor involved in aging. It’s easy to get bogged down in the world’s problems when we’re going through challenging experiences, yet many centenarians say their secret to healthy aging is to have an attitude of gratitude. Although our patients can’t change hardwired genetics, they can impact susceptibility and probability of many risks by taking charge of both their mental and physical health to the extent that they are able.[REFS]
- Fadnes LT, Økland JM, Haaland ØA, Johansson KA. Estimating impact of food choices on life expectancy: A modeling study [published correction appears in PLoS Med. 2022 Mar 25;19(3):e1003962]. PLoS Med. 2022;19(2):e1003889.
- Sergiev PV, Dontsova OA, Berezkin GV. Theories of aging: an ever-evolving field. Acta Naturae. 2015;7(1):9-18.
- Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11(3):298-300.
- Gladyshev VN. On the cause of aging and control of lifespan: heterogeneity leads to inevitable damage accumulation, causing aging; control of damage composition and rate of accumulation define lifespan. Bioessays. 2012;34(11):925-929.
- Fang EF, Lautrup S, Hou Y, et al. NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med. 2017;23(10):899-916.
- Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell. 2011;146(5):682-695.
- Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 2013;13(10):722-737.
- Brunk UT, Terman A. The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem. 2002;269(8):1996-2002.
- Fang EF, Scheibye-Knudsen M, Brace LE, et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 2014;157(4):882-896.
- Lee IH, Cao L, Mostoslavsky R, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A. 2008;105(9):3374-3379.
- Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep. 2019;28(7):1717-1728.e6.
- Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286.
- Remie CME, Roumans KHM, Moonen MPB, et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. Am J Clin Nutr. 2020;112(2):413-426.
- Sebastiani P, Federico A, Morris M, et al. Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans. Aging Cell. 2021;20(2):e13290.
- Rai V. Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Alzheimer Disease Risk: a Meta-Analysis. Mol Neurobiol. 2017;54(2):1173-1186.
- Peng X, Zhou Y, Wu X, et al. Association of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of carotid atherosclerosis: a cross-sectional analysis of 730 Chinese Han adults in Chongqing. BMC Cardiovasc Disord. 2020;20(1):222.
- Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488.
- Fitzgerald KN, Hodges R, Hanes D, et al. Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial. Aging (Albany NY). 2021;13(7):9419-9432.
Chris D. Meletis, ND, is an educator, international author, and lecturer. He has authored 18 books and more than 200 scientific articles in prominent journals and magazines. Dr Meletis served as Dean of Naturopathic Medicine and CMO for 7 years at NUNM. He was recently awarded the NUNM Hall of Fame award by OANP, as well as the 2003 Physician of the Year by the AANP. Dr Meletis spearheaded the creation of 16 free natural medicine healthcare clinics in Portland, OR. Dr Meletis serves as an educational consultant for Fairhaven Health, Berkeley Life, TruGen3, US BioTek, and TruNiagen. He has practiced in Beaverton, OR, since 1992.