Mitochondria and Aging: Why Mitochondrial Health is a Hallmark of Longevity and How to Improve It

If you remember anything about 7th-grade biology class, you probably recall that the mitochondria are the “powerhouses of the cell.” And this is true—appearing in almost every cell, these energy-producing powerhouses are undoubtedly essential to power our lives.

These oval-shaped organelles—a small “organ” inside of a cell—produce energy in the form of ATP (adenosine triphosphate), allowing us to do everything from tying our shoes to running marathons to simply sitting and turning food into fuel. Although these tiny organelles are vital to our health, many people experience a decline in mitochondrial quality, especially with advancing age or various health conditions. Fortunately, like most things in life, there are things you can do to improve your mitochondrial function—and, with it, your healthspan.

Mitochondria and Aging 

First described in a June 2013 paper published in Cell, the nine hallmarks of aging are fundamental characteristics that define why our bodies and cells age. One of these hallmarks is mitochondrial dysfunction.

Although mitochondria produce vital energy in the form of ATP, these organelles also create free radicals and reactive oxygen species (ROS). We all produce ROS when mitochondria turn food into energy—a process called respiration that mainly occurs within the electron transport chain (ETC) in the mitochondria’s innermost membrane. 

People with healthy mitochondria can effectively neutralize those excess reactive compounds without causing damage. However, individuals with dysfunctional mitochondria can experience a buildup of these damaging molecules, leading to oxidative stress.

With age, mitochondrial function declines, leading to reduced energy production and cellular turnover combined with increased free radical damage. This buildup of ROS in the mitochondria is also linked to several other hallmarks of aging, including genomic instability, epigenetic alterations, and cellular senescence. For example, dysfunctional mitochondria can induce cellular senescence—a state where cells stop dividing but remain in the body, causing inflammatory reactions to nearby cells.

Healthy people also have mechanisms in place to maintain mitochondrial quality, including mitophagy—a more specific form of autophagy that selectively removes damaged mitochondria. As we age, mitophagy becomes less efficient, and dysfunctional mitochondria can accumulate, leading to a decline in mitochondrial function. Plus, mitochondrial biogenesis—the process of creating new mitochondria—also drops off with age.

Therefore, while mitochondrial dysfunction is a hallmark of aging, mitochondrial health could be considered a hallmark of longevity. 

How to Support Mitochondrial Health

Several lifestyle habits and supplemental compounds can allow the mitochondria to produce ATP from food more efficiently, support new mitochondrial growth, or strengthen mitochondrial membranes and antioxidant capacity.

1. Exercise

Similar to just about every health condition out there, exercise can benefit mitochondrial quality. Physical activity—predominantly aerobic or cardio exercises like running, swimming, or cycling—can enhance mitochondrial function and stimulate the production of new mitochondria.

Exercise also helps to improve oxygen utilization and energy production within the mitochondria. Research shows that exercise activates several mechanisms that regulate mitochondrial biogenesis. It also triggers mitophagy by stimulating mitochondrial turnover.

Aerobic activity primarily stimulates mitochondrial biogenesis in skeletal muscle, increasing the number of mitochondria within muscle cells and enhancing their capacity for energy production. But it’s not just aerobic exercise that is beneficial for mitochondrial health—strength or resistance training can also positively affect mitochondrial quality within existing muscle cells and improve mitochondrial respiration.

2. Sleep

Getting enough quality sleep plays a crucial role in maintaining optimal mitochondrial function. Although it doesn’t seem like much is happening when you’re sleeping, your body is actually undergoing vital restorative processes. During deep sleep especially, cells and mitochondria perform repair and maintenance activities, including mitophagy to remove damaged mitochondria and create healthy, new ones.

We also need high-quality sleep—typically 7.5 to 9 hours for adults—to support our antioxidant defense systems, which help to clear free radicals produced during mitochondrial respiration. To promote good sleep, power down electronics at least an hour before bed, avoid drinking alcohol or eating close to bed, and keep your bedroom dark, cool, and quiet. Sleep supplements containing L-theanine, magnesium, GABA, or 5-HTP can also help if you have trouble falling or staying asleep.

3. Time-Restricted Eating

Time-restricted eating typically involves forgoing food and caloric beverages for 14 to 16 hours per day, limiting the eating window to 8 to 10 hours. Another term for time-restricted eating is intermittent fasting, which could be as extreme as a 4-hour eating period followed by 20 hours of fasting (although this is not always recommended). 

When we fast, the body can utilize different energy sources than its typical preferred fuel of glucose. After about 12 hours of fasting, the body will start to use molecules called ketone bodies for fuel, which has been linked to improved metabolic markers. Another benefit of fasting is that it activates mitophagy (as well as autophagy—the clearing of damaged or dysfunctional cells and cell parts) and stimulates mitochondrial biogenesis.

4. NAD+ Precursors

Nicotinamide adenine dinucleotide, or NAD+, is a compound that is fundamental to our lives. As a coenzyme, NAD+ helps other enzymes to function correctly and carry out reactions. NAD+ cannot easily cross over membrane barriers to enter cells, so NAD+ precursors are commonly used, including nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). 

Mitochondrial health and NAD+ levels go hand in hand, as the mitochondria need NAD+ to transform food into cellular energy efficiently. With a decline in NAD+, a drop in mitochondrial quality will follow suit. As mitochondrial energy metabolism is highly dependent on NAD+, supplementing with NAD+ precursors like NMN or NR can help to support these processes.

5. Sirtuin Activators

Sirtuins are a family of proteins nicknamed “longevity genes.” Involved in mitochondrial repair and biogenesis, sirtuins are essential for health and longevity. Three of the seven sirtuin proteins (SIRT3, SIRT4, and SIRT5) are found exclusively within the mitochondria, acting as metabolic sensors to modulate mitochondrial activities in response to nutrient levels. However, all of the sirtuins are important for mitochondrial health—for example, SIRT1 is a vital regulator of mitophagy and mitochondrial biogenesis.

Many compounds are thought to activate or boost sirtuin activity, therefore supporting mitochondrial health: 

• Trans-resveratrol: Found in grapes and red wine, this bioavailable form of resveratrol activates sirtuins—especially SIRT1—to support mitochondrial biogenesis.

• Fisetin: Acting as an antioxidant, fisetin activates sirtuins, clears mitochondria-induced oxidative stress, and acts as a senolytic that removes senescent cells. 

• Pterostilbene: A potent sirtuin activator that promotes mitochondrial health by reducing oxidative stress and supporting mitochondrial biogenesis.

• Quercetin: A flavonoid compound found in several fruits and vegetables, quercetin has been found to modulate sirtuin activity, improve mitochondrial biogenesis, and protect against mitochondrial damage.

• Curcumin: The active compound in turmeric, curcumin upregulates SIRT1 and supports several aspects of mitochondrial quality. 

• Berberine: Best known for supporting healthy blood sugar levels, berberine also promotes healthy mitochondrial function by promoting SIRT3 activity and mitophagy.

6. Calcium-AKG

Alpha-ketoglutarate (AKG) is a component of energy respiration in the Krebs cycle—a series of reactions that creates ATP from the food we eat. AKG also acts as an antioxidant to fight free radical damage. 

In supplemental form—the only available oral route, as the compound is not found in food—AKG can be attached to a calcium salt (Ca-AKG), which has been studied for its role in supporting metabolic function and longevity. 

AKG helps to stimulate mitophagy and autophagy and activates AMP-activated protein kinase (AMPK)—a pathway that senses and maintains cellular energy balance by supporting the function of our mitochondria.

7. Coenzyme Q10

Coenzyme Q10 (CoQ1o0) is a coenzyme—a “helper” molecule that activates and assists other enzymes with functioning correctly to make energy from food. CoQ10 is essential for the cellular respiration pathways that make ATP and may work particularly well with NADH (the “reduced” form of NAD). 

CoQ10 is also a vital antioxidant that fights free radicals and plays a role in the electron transport chain within mitochondria. Research shows that a form of CoQ10 called ubiquinol-10 enhances mitochondrial activity by boosting levels of SIRT1 and SIRT3.

8. PQQ (Pyrroloquinoline Quinone)

PQQ (pyrroloquinoline quinone) is a vitamin-like compound found in many foods that acts as an antioxidant and benefits mitochondrial health by boosting mitochondrial biogenesis. A study from 2020 found that men who took 20 mg of PQQ per day had improved markers of mitochondrial biogenesis when combined with six weeks of aerobic training. 

PQQ may also support cellular resilience to stress, helping to prevent damage caused by environmental stressors that can harm mitochondrial quality. 

Key Takeaways

Our mitochondria are undeniably essential to health and longevity. Although their quality and efficiency naturally decline with age, there is plenty we can do to support mitochondrial health as we grow older. 

Some key lifestyle habits to support mitochondrial health include exercise (especially aerobic), high-quality sleep, and moderate periods of intermittent fasting. Supplements to consider for mitochondrial health include NAD+ precursors like NMN or NR, sirtuin activators (like trans-resveratrol, quercetin, fisetin, curcumin, and more), calcium-AKG, CoQ10, and PQQ. 

References: 

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