AKG, the antiaging agent already on the market, could also protect our hearts from failing, a new study on mice shows.
Alpha-ketoglutarate (AKG) plays many metabolic roles [1], but it is its role as an established biomarker of heart failure (HF) that’s of interest here. [2]. Several clinical studies have determined that higher levels of plasma AKG in patients with acute or congestive HF [3] associate with HF severity [4] and this study indicates that AKG can boost myocardial mitophagy by rescuing mitochondrial function and morphology and reduce ROS toxification and cellular death.
Longevity.Technology: AKG is a known anti-aging agent that has already been shown to increase lifespan and healthspan in mammalian models. These antiaging benefits could work for us too. Used as a dietary supplement, AKG already successfully tackles osteoporosis. What of heart failure? Well, studies on the metabolic changes in HF are trending, but not many focus on the effect of AKG on HF.
A team of researchers from the Southern Medical University in Guangzhou, China, addressed this issue by studying the impact of AKG supplementation on the cardiac muscle in a mouse model of induced HF.
The HF model displayed a pathologically enlarged heart with its cardiomyocytes around 91% larger than in its control counterpart [5]. Treatment with AKG attenuated this hypertrophy – as measured with cardiac hypertrophy markers. Cardiomyocytes’ size was reduced by an average of 49%.
Improved cardiac insufficiency and reduced fibrosis
Cardiac function is measured by the blood pumped through the left ventricle (LV) [6]. The model of HF had a LV 51% larger than normal [5].
The evaluation of blood flow dynamics: fractional shortening (FS) – the measuring of ventricular diameter during systole – and ejection fraction (EF) – the percentage of blood pumped out after each contraction – revealed lower levels of these two factors in the HF mouse model than in its control counterpart. This suggests a LV morphological reshaping and cardiac dysfunction under pressure overload-induced cardiac hypertrophy. AKG administration triggered an increase of FS and EF, and a decrease of LV mass, suggestive of a cardioprotective effect of AKG from cardiac dysfunction under pressure overload [5].
Ventricular fibrosis is a marker of ventricular remodelling and a sign of cardiac insufficiency [7]. The HF model presented an increased amount of fibrosis in the cardiac muscle tissue, mitigated by AKG administration through its action on the transforming growth factor-ß1 (TGF-ß1), one of the main proteins involved in fibrogenesis [5].
Improved detoxification of myocardial cells and reduced apoptosis
Oxidative stress – a cell’s toxification by an imbalance between the production and accumulation of oxygen reactive species (ROS) – is a hallmark of heart failure. ROS are mainly produced by mitochondria, the ‘powerhouse’ of our cells. A dysfunction of these organelles leads to an excess production of ROS and eventually cell death [8]. Mitophagy – the removal of dysfunctional mitochondria from the heart – rescues oxidative damage and prevents the progression of HF [9].
In this study, induced myocardial hypertrophy revealed the presence of dysmorphic mitochondria, characterized by their vacuolated, swelled and incomplete structure. AKG supplementation reversed the swelling and enhanced the clearance of damaged mitochondria, as demonstrated by the increase of mitophagy-associated markers [5].
The study also showed that compared to control mice, the HF mouse model had higher levels of ROS and an increase in myocardial cell death. These were reduced once administration with AKG [5].
Thus, under heart failure conditions, AKG can boost myocardial mitophagy by rescuing mitochondrial function and morphology and reduce ROS toxification and cellular death.
Translation to humans and benefits?
This was another “works on mice” study, however, the work of AKG in humans is already underway at the Centre for Healthy Longevity of the National University of Singapore.
More data is needed on the benefits of AKG on heart disease as heart failure is a multifactorial syndrome. The exact mechanism of cardioprotective action of AKG remains to be clarified, and the release source of plasma AKG, since AKG is produced in various tissues of the body and not just the heart, also needs to be identified. Then remains the question of metabolite availability in the elderly, as AKG decreases with aging [10].
However, should additional research answer these points, AKG might be on the way to becoming the supplement with the ability to reduce the number of deaths caused by the world’s greatest killer – heart disease.
[1] https://www.sciencedirect.com/science/article/pii/S156816372030372X
[2] https://link.springer.com/article/10.1007/s11306-007-0063-5
[3] https://www.sciencedirect.com/science/article/pii/S221317791730481X
[4] https://www.sciencedirect.com/science/article/pii/S0925443914002300
[5] https://www.sciencedirect.com/science/article/pii/S2213231721002470
[6] https://www.ncbi.nlm.nih.gov/books/NBK541098/
[7] https://www.sciencedirect.com/science/article/pii/S2213231718310620
[8] https://www.sciencedirect.com/science/article/abs/pii/S0098299719300962
[9] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.117.312317
[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC69
