How to Improve Autophagy to Improve Longevity
This blog does not intend to provide diagnosis...
In this article:
- What Is Autophagy?
- Consequences of Impaired Autophagy
- Aging and Inflammaging
- How to Support Autophagy
- Autophagy and Spermidine
- Dietary Supplements to Enhance Autophagy
Autophagy is the cell's quality control process to dispose of cellular garbage, debris, microorganisms, and unwanted compounds. During this cleaning process, accumulated waste products are delivered to a compartment in cells known as lysosomes so that they can be destroyed and potentially reused.
The science and importance of autophagy is a relatively new discovery. In 2016, Yoshinori Ohsumi won the 2016 Nobel Prize in Physiology or Medicine for his discoveries of the mechanisms for autophagy.
Enhanced autophagy has been found in exceptionally healthy centenarian humans and appears to be a key target for living a healthier, longer life. Genetics plays a role in autophagy, but diet, lifestyle, and dietary supplements can considerably influence the expression of autophagy genes as well.
Before highlighting how to enhance autophagy specifically, it is important to point out again that impaired autophagy can have several consequences. For example, an increase in oxidative damage, loss of control in protein building and breakdown, decreased mitochondrial function, a decline in immune function, and other issues associated with an increased rate of cellular aging. These effects hit every tissue of the body, especially the brain, since it is the most metabolically active tissue. Age-related decline in autophagy is also responsible for sarcopenia—the progressive loss of muscle mass and strength associated with aging.1
One of the keys to helping your body's ability to deal with cellular debris is to prevent its formation and accumulation in the first place. Accelerated human aging is characterized by a state of chronic, low-grade inflammation. This process is referred to as inflammaging, and that inflammation also leads to reduced autophagy.2
A few triggers of inflammaging include poor blood sugar control and a lack of vital dietary factors that fight inflammation. Inflammation fighting foods include omega-3 fatty acids, polyphenol-rich fruit, and carotenoid-rich vegetables.3 With inflammaging, mitochondrial function is reduced primarily because of damage and stress caused by free radicals and pro-oxidants. The mitochondria are the compartment in cells that create the energy currency of our body – adenosine triphosphate (ATP). And a decrease in mitochondrial function is another factor that leads to reduced autophagy.
Typically, as people age, there is a decline in mitochondrial numbers and function. This leads to decreased energy (ATP) production, leading to the leakage of inflammatory compounds from mitochondria and a more significant formation of cellular garbage within the cell itself. Hence, the term "garb-aging" is used to describe the effects of excess accumulation of cellular garbage, reduced autophagy, or both.2
To prevent garb-aging and preserve autophagy, you must reduce the formation of excessive cellular garbage and support mitochondrial function.5 Here are some of the critical steps to help these goals:
- Exercise, body movement, and diaphragmatic breathing are the key factors that keep autophagy functioning properly in clearing cellular debris and fighting gab-aging.
- Eating a health-promoting diet rich in colorful fruit and vegetables, nuts and seeds, and adequate in protein.
- Avoiding sugar and over-consumption of carbohydrates and calories.
- Intermittent fasting—one popular method is a daily 16-hour fast with an 8-hour eating window.
- Regularly include in your diet superfoods like spirulina and other super greens, raw cacao, berries, green tea (particularly matcha), etc.
- Spice it up! Use spices and herbs liberally in the diet to take advantage of their benefits in reducing garb-aging and protecting mitochondria.
- Take essential foundational dietary supplements to support good health:
- A high-quality multiple vitamin and mineral supplement.
- Vitamin D3 - 2,000-5,000 IU daily is recommended to keep your blood levels in the optimal range.
- A high-quality fish oil product to provide 1,000 mg EPA+DHA daily.
- A polyphenol-based antioxidant like resveratrol, grape seed extract, quercetin, or curcumin. These supplements are somewhat interchangeable, and all have been shown to enhance both mitochondrial function and autophagy.6
- For additional support for reducing garb-aging and promoting mitochondrial health consider:
- N-Acetylcysteine (NAC) or L-glutathione. At 500 mg twice daily, either boosts glutathione levels, supports detoxification reactions, and protects mitochondria.
- Ubiquinol—100 to 200 mg daily. Ubiquinol is the best-absorbed form of coenzyme Q10 (CoQ10). Generally, CoQ10 levels decline with aging. Low levels are also seen in many health conditions, especially in people taking statins or dealing with cardiovascular diseases such as angina, high blood pressure, mitral valve prolapse, and congestive heart failure. Taking CoQ10 is an insurance policy to help mitochondria function optimally.
There are over 40 different genes that are involved in autophagy processes. Still, the overexpression of an essential autophagy gene (ATG5) is a primary determinant of autophagy processes associated with a longer life expectancy in humans.
The expression of ATG5 is reduced in response to oxidative and free radical damage and reduced mitochondrial function. Hence, the recommendations above are essential to enhancing autophagy for those reasons.
One of the vital dietary factors linked to enhanced autophagy is spermidine.7 As its name suggests, spermidine was first discovered as crystals seen under a microscope in a sample of human semen in 1678 by the famous Dutch scientist Anton Van Leeuwenhoek, commonly known as "the Father of Microbiology." Not surprisingly, spermidine is very important to sperm function, but it also plays a significant role in cells throughout the body.
Spermidine can bind to and activate critical molecules involved in cell growth, genetic expression, and protein synthesis. Spermidine also plays a significant role in regulating the immune response and the antioxidant system.
Spermidine helps fight cellular aging via several mechanisms. It exerts significant antioxidant activity, especially in protecting membrane lipids and nucleic acids. But it is spermidine's role as an enhancer of autophagy and mitochondrial function that produces substantial anti-aging effects.7
In addition to dietary sources, spermidine can be manufactured from the amino acid ornithine in the human body. Still, tissue concentrations decline with age, primarily due to a decline in the activities of spermidine-synthesizing enzymes. A higher spermidine intake is linked to a lower overall mortality rate, including reduced mortality from cancer and cardiovascular disease.8-10 Spermidine also shows promise in protecting against the effects of aging on the brain, improving liver function and overall metabolism, and protecting against intervertebral disk degeneration.
Spermidine is found in many foods. Wheat germ, whole grains, legumes, soy foods, and mushrooms provide the highest content. Aged cheeses and fermented foods, as well as chicken or beef liver, are also good sources.
The dietary intake of spermidine varies considerably based on the intake of polyamine-rich foods. The estimated daily spermidine intake for adults in the United States and Europe is approximately 12.5 mg per day. Three tablespoons of wheat germ provide around 5 mg of spermidine, or about 40% of the typical daily intake.
There have been several clinical trials with wheat germ or wheat germ extracts in elderly patients with declining memory and cognitive function.10-13 For example, one double-blind study focused on the effect of wheat germ intake on 85 subjects between 60 and 96 years old from 6 nursing homes.13 One group received a grain roll (roll A) with wheat germ, with each roll A providing 3.3 mg of spermidine. The second group received rolls baked with wheat bran instead of wheat germ (roll B) that provided 1.9 mg of spermidine per role. In addition to memory tests, blood samples were taken to measure spermidine levels in the blood. Results demonstrated a clear link between the intake of spermidine, blood levels of spermidine, and improved cognitive performance and memory. Based on the results and blood measurements, the minimum daily dosage of spermidine required to show improvement was 3.3 mg (roughly two tablespoons of wheat germ).
Vitamin D3, fish oils rich in omega-3 fatty acids, and plant-based antioxidants such as resveratrol, grape seed extract, curcumin, NAC, and CoQ10 all enhance autophagy. Below is more information on resveratrol and nicotinamide mononucleotide, as these two dietary supplements have gained significant popularity as autophagy enhancers and work very well together.
Resveratrol is a polyphenol compound found in low dosages in grapes (only in the skin), red wine, peanuts, and blueberries. Most resveratrol supplements use Japanese knotweed (Polygonum cuspidatum) as the source.
Resveratrol has many unique health benefits as an essential regulator of cellular defense mechanisms.14-16 It works well within a comprehensive anti-aging strategy. Resveratrol enhances autophagy and activates an enzyme known as sirtuin 1 that plays an essential role in regulating cellular life spans; it also boosts brain function and promotes improved blood sugar control by enhancing insulin action.
Several clinical studies have shown that the tremendous anti-aging effects of resveratrol produced in animal studies translate to humans as well.16,17 In particular, resveratrol lowers markers of brain inflammation associated with aging and poor mental function in older adults. As a result, resveratrol improved mood, mental cognition, and scores on measures of activities of daily living in older adults. In other words, it helped them act and feel younger. Improved autophagy is likely one of the key reasons. And it does so safely and without side effects.
Nicotinamide mononucleotide is a unique form of vitamin B3 that exerts beneficial effects in increasing the levels of nicotinamide adenine dinucleotide (NAD+), an essential compound in energy production and many cellular processes.18,19 Since NAD+ levels drop with aging even with adequate intake of other forms of vitamin B3, restoring depleted NAD+ levels with nicotinamide mononucleotide is also emerging as part of an anti-aging as well as a cellular health-promoting strategy. Low levels of NAD+ in our cells and throughout the body can lead to: 20,21
- A decline in metabolism, leading to weight gain and poor blood sugar control
- Reduced blood vessel health
- Age-related muscle loss (sarcopenia)
- Aging-related memory loss and mental decline
- Aging-related loss of sight and hearing
Many of these issues may be the result of impaired autophagy.
- Kitada M, Koya D. Autophagy in metabolic disease and ageing. Nat Rev Endocrinol. 2021;17(11):647-661.
- Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and 'Garb-aging'. Trends Endocrinol Metab. 2017;28(3):199-212.
- Di Giosia P, Stamerra CA, Giorgini P, Jamialahamdi T, Butler AE, Sahebkar A. The role of nutrition in inflammaging. Ageing Res Rev. 2022;77:101596.
- Abdullah A, Mohd Murshid N, Makpol S. Antioxidant Modulation of mTOR and Sirtuin Pathways in Age-Related Neurodegenerative Diseases. Mol Neurobiol. 2020;57(12):5193-5207.
- McCarty MF. Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy. Int J Mol Sci. 2022;23(4):2054.
- Brimson JM, Prasanth MI, Malar DS, et al. Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases. Pharmaceuticals (Basel). 2021;14(10):982.
- Madeo F, Bauer MA, Carmona-Gutierrez D, Kroemer G. Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans? Autophagy. 2019;15(1):165-168.
- Kiechl S, Pechlaner R, Willeit P, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018;108(2):371-380.
- Eisenberg T, Abdellatif M, Schroeder S, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22(12):1428-1438.
- Wirth M, Schwarz C, Benson G, et al. Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)-study protocol for a randomized controlled trial. Alzheimers Res Ther. 2019;11(1):36.
- Wirth M, Benson G, Schwarz C, et al. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex. 2018;109:181-188.
- Schroeder S, Hofer SJ, Zimmermann A, et al. Dietary spermidine improves cognitive function. Cell Rep. 2021;35(2):108985.
- Pekar T, Bruckner K, Pauschenwein-Frantsich S, et al. The positive effect of spermidine in older adults suffering from dementia : First results of a 3-month trial. Wien Klin Wochenschr. 2021;133(9-10):484-491.
- Farkhondeh T, Folgado SL, Pourbagher-Shahri AM, Ashrafizadeh M, Samarghandian S. The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway. Biomed Pharmacother. 2020 Jul;127:110234.
- Truong VL, Jun M, Jeong WS. Role of resveratrol in regulation of cellular defense systems against oxidative stress. Biofactors. 2018 Jan;44(1):36-49.
- Koushki M, Dashatan NA, Meshkani R. Effect of Resveratrol Supplementation on Inflammatory Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin Ther. 2018 Jul;40(7):1180-1192.e5.
- Marx W, Kelly JT, Marshall S, et al. Effect of resveratrol supplementation on cognitive performance and mood in adults: a systematic literature review and meta-analysis of randomized controlled trials. Nutr Rev. 2018 Jun 1;76(6):432-443.
- Shade C. The Science Behind NMN-A Stable, Reliable NAD+Activator and Anti-Aging Molecule. Integr Med (Encinitas). 2020;19(1):12-14
- Hong W, Mo F, Zhang Z, Huang M, Wei X. Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism. Front Cell Dev Biol. 2020 Apr 28;8:246.
- Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021 Feb;22(2):119-141.
- Gilmour BC, Gudmundsrud R, Frank J, et al. Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing. Mech Ageing Dev. 2020 Mar;186:111208