Can Boosting NAD+ Prevent Muscle Loss with Age?

According to a new scientific review, sarcopenia — age-related muscle loss — can potentially be mitigated by replenishing NAD+.

Key Points:

The muscles of sarcopenia patients exhibit lower than normal NAD+ levels.
NAD+ precursor supplementation improves muscle mitochondria and muscle stem cells in middle-aged adults while increasing strength in older adults.
Individuals with conditions that negatively affect NAD+ metabolism, such as obesity, may benefit the most from NAD+ supplementation.

Without sufficient resistance exercise, our muscles tend to lose size and strength with aging. However, for 60-75% of older adults, resistance exercise isn’t enough to combat sarcopenia. While the reasons for this are unclear, it could potentially be related to depleted NAD+ levels. It follows that, for some individuals, replenishing NAD+ levels could help to prevent sarcopenia.

In a review published in Ageing Research Reviews, Xu & Xiao from the Shanghai University of Sport in China concluded:

“NAD⁺ deficiency is one of the core mechanisms of skeletal muscle aging. NAD⁺ boosting strategies may reshape skeletal muscle homeostasis…”

This conclusion is based primarily on animal studies, but the effects of increasing NAD+ in healthy adults have also been tested, which will be summarized here.

Low Muscle NAD+ and Sarcopenia

Sarcopenia is characterized by reduced muscle mass and strength, which leads to poor mobility and adverse outcomes such as increased falls and shortened lifespan. Furthermore, muscle aging and sarcopenia are associated with cognitive dysfunction, cardiovascular disease, and metabolic syndrome — including high blood pressure, high blood sugar, and fat around the waist.

For these reasons, preventing, slowing, or reversing sarcopenia is crucial in promoting longevity, overall health, and quality of life. While many factors contribute to the advent of sarcopenia, low NAD+ levels have been observed in sarcopenia patients. Furthermore, these low NAD+ levels were associated with indicators of sarcopenia, such as low muscle mass and strength, as well as reduced gait — pattern of walking — speed.

(Migliavacca et al., 2019 | *Nature Communications*) **Low Muscle NAD+ and Sarcopenia.** b: Individuals with sarcopenia (blue) have lower muscle NAD+ levels than otherwise healthy individuals (orange). c: Low muscle NAD+ is correlated with low muscle mass (ALM index), reduced grip strength, and slower gait speed, which are indicators of sarcopenia.

Preventing Muscle Aging by Restoring NAD+

While limiting caloric intake and partaking in regular exercise contribute to maintaining NAD+ levels with age, it may be difficult to follow these interventions consistently over a lifetime. Therefore, using NAD+ precursors to raise NAD+ levels can be used to supplement these lifestyle habits. Based on the human studies described below, replenishing NAD+ levels can restore the function of muscle mitochondria and muscle stem cells, as well as increase muscle strength to counteract sarcopenia.

Mitochondria

Several underlying factors contribute to muscle aging, including dysfunctional mitochondria. Importantly, NAD+ plays a major role in maintaining the health of mitochondria. This was demonstrated in a study of middle-aged adults (33 to 41 years old) given 1 g of the NAD+ precursor nicotinamide riboside (NR) for 5 months, which increased the production of new muscle mitochondria, as shown by an elevated number of mitochondria.

However, it seems that longer-term treatment with NR may be required to see benefits, as other NR studies ranging from 1 to 12 weeks did not show mitochondrial improvements in human muscle. Furthermore, it is unclear whether increasing the number of mitochondria in muscle with an NAD+ precursor leads to increased muscle size and strength in disease-free individuals.

Muscle Stem Cells

Another underlying driver of muscle aging is dysfunctional stem cells. Our muscle stem cells, known as satellite cells, help regenerate injured muscle, contributing to increased muscle size in response to resistance exercise. When these stem cells become dysfunctional, as with aging, the muscle regeneration process is hindered, thus promoting sarcopenia.

In the same study that showed 5 months of NR treatment increased mitochondria production, it was shown that NR restored muscle stem cell function. Such improvements may have been mediated by longevity-associated enzymes called sirtuins, which use NAD+ as fuel. However, whether rejuvenating muscle stem cells with NAD+ precursors increases muscle strength and size in healthy humans remains unclear.

(Lapatto et al., 2023 | *Science Advances*) **NR Improves Muscle Mitochondria and Stem Cells.** Regardless of being lean (black) or overweight (red), middle-aged adults treated with NR have more muscle mitochondria (left), suggesting increased mitochondria production, and a higher MYMK to MYOD gene ratio (right), suggesting improved stem cell function.

Strength

In disease-free individuals, few studies have shown that NAD+ precursor supplementation can increase strength. One study showed that 250 mg of the NAD+ precursor nicotinamide mononucleotide (NMM) improved left-hand grip strength after 12 weeks of treatment. Additionally, another study showed that 500 mg of NR for 10 days increased the isometric muscle strength (contraction without movement) in older but not younger men. However, concentric strength (with movement) was not improved by NR in this study.

Can Supplementing with NAD+ Precursors Prevent Muscle Aging?

Based on the clinical evidence and assuming that NMN and NR have similar effects, supplementing with either NAD+ precursor could potentially counteract muscle aging by improving mitochondrial health, rejuvenating muscle stem cells, and slightly increasing muscle strength in middle-aged and older individuals.

Still, NAD+-boosting precursors may be more beneficial for individuals with preexisting conditions such as insulin resistance, obesity, mitochondrial disease, and antioxidant deficiencies, as shown by clinical studies. The authors say,

“In clinical studies, NAD⁺ precursors appear to show significant benefits primarily in the skeletal muscle of NAD⁺-deficient individuals, and it is important to determine the criteria for NAD⁺ deficiency during ageing and the clinically optimal dosages and bioavailabilities of different NAD⁺ boosters in skeletal muscle.”

Therefore, in the future, clinicians may be able to assess the NAD+ levels of patients to determine if they are NAD+-deficient and recommend NAD+ precursor supplementation accordingly. Alternatively, home NAD+ test kits are available but can be rather expensive ranging in the hundreds of dollars.