PGC-1α is one of the most important genes for mitochondrial health. As the master regulator of mitochondrial biogenesis, it is responsible for creating new mitochondria and for improving the quality of existing ones.
- Tire easily?
- Have a slow metabolism?
- Generally lack energy?
- Have dysregulated circadian rhythms?
- Suffer from chronic inflammation?
While these can have a number of contributors, mitochondrial dysfunction, something that steadily worsens with age, is one of major culprits. It should be kept in mind that “metabolism”, more than just something that burns off last night’s cheesecake, is a broad term that affects virtually every aspect of your health.
Upregulating PGC-1α is possible through lifestyle interventions.
Cold exposure, among a growing list of other health benefits, has been strongly linked with more PGC-1α (Pilegaard, 2016). Endurance exercise also induces its expression and, as a key player in lactate metabolism, it prevents lactate levels from rising too quickly (Liang, 2016).
- Upregulates energy production genes, optimizing the performance of existing mitochondria
- Reduces the accumulation of free radicals by distributing the workload among more mitochondria. This hypothesis has been tested in transgenic mice (Kang, 2012).
- May have benefits for neurodegenerative disorders like Alzheimer’s and Parkinson’s (Austin et. al, 2012).
- Reduces oxidative damage, thereby potentially alleviating or staving a wide variety of diseases and disorders associated with mitochondrial damage.
As a widely cited paper states, “PGC-1 alpha is intimately involved in disorders such as obesity, diabetes, and cardiomyopathy. In particular, its regulatory function in lipid metabolism makes it an inviting target for pharmacological intervention in the treatment of obesity and Type 2 diabetes.”
Dietary interventions, like ketosis (arising from the restriction of carbohydrates for a period of time) and caloric restriction, have a positive effect on PGC-1α (Newman, 2014; Ramhotra 2010).
Antioxidants are a long running fad in the health and fitness community. While there are obvious benefits to taking in appropriate amounts of vitamin C and E (like warding off scurvy), there is very little evidence to suggest elevated antioxidant consumption is beneficial. As we’ve noted, PGC-1a directly addresses the problem by creating new mitochondria, which spreads the workload.
Nrf2 regulates antioxidant proteins produced in response to injury and inflammation. It is gaining interest as a potential therapeutic target for Parkinson’s (Buler, 2011). PXR is known as the “master” xenobiotic receptor. This means that foreign substances, like pharmaceuticals and toxins, are sensed by PXR before proteins are made to metabolize them. The proper expression of both of these genes is modulated in part by PGC-1α (Buler, 2011).
The amino acid carnitine is a popular supplement because it accelerates the metabolism of fatty acids, which has potential benefits to weight loss and to cognitive health (Song, 2010). PGC-1α fosters the production of carnitine in the body.
Levels of PGC-1α, like telomere length and Klotho production, decline with age. While healthy living and (maybe) some supplements can help, genetic factors, and above all, the inexorability of the aging process, make it unavoidable that they will eventually dwindle. Gene therapy, once again, is a long term solution.
For these reasons and more PGC-1α gene therapy is being investigated by Integrated Health Systems as a way to reap these benefits continuously and make up for the slack, unimpeded by lifestyle change or, more importantly, the aging process.
Buler, Marcin, et al. "Energy sensing factors PGC-1α and SIRT1 modulate PXR expression and function." Biochemical pharmacology 82.12 (2011): 2008-2015.
Newman, John C., and Eric Verdin. "Ketone bodies as signaling metabolites." Trends in Endocrinology & Metabolism 25.1 (2014): 42-52.
Kang, Chounghun, and Li Li Ji. "Role of PGC-1α signaling in skeletal muscle health and disease." Annals of the New York Academy of Sciences 1271.1 (2012): 110.
Lira, Vitor A., et al. "PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity." American Journal of Physiology-Endocrinology and Metabolism 299.2 (2010): E145-E161.
Pilegaard H, Saltin B, Neufer PD (February 2003). "Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle". J. Physiol. 546 (Pt 3): 851–8. doi:10.1113/jphysiol.2002.034850. PMC 2342594. PMID 12563009.
Ranhotra, Harmit S. "Long-term caloric restriction up-regulates PPAR gamma co-activator 1 alpha (PGC-1a) expression in mice." Indian journal of biochemistry & biophysics 47 (2010): 272-277.
Song, Shulan, et al. "Peroxisome proliferator activated receptor α (PPARα) and PPAR gamma coactivator (PGC-1α) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements." Molecular and cellular endocrinology 325.1-2 (2010): 54-63.