Keeping the beat against time: Mitochondrial fitness in the aging heart

Figures

• 

  FIGURE 1. Cardiac Aging. At the time of birth, the postnatal human heart exhibits a brief period of cell growth through proliferation. However, this proliferative capacity is lost shortly after birth and heart growth proceeds by an increase in cardiomyocyte (CM) size throughout adolescence (ages 12–24). During adulthood (ages 25–64), a decline in heart function occurs due to the emergence of pathological age-related stresses, such as imbalances in force distribution per myocyte as a result of natural CM dropout, altered metabolism, decreased ATP generation, and accumulation of reactive oxygen species. These stresses consequently lead to mitochondrial dysfunction, increased CM death, inflammation, fibrosis, and the overall functional decline of the heart late in life.

• 

  FIGURE 2. Mitochondrial Dysfunction in Aging. There are various intracellular pathways that become altered over time, especially with regard to mitochondrial function. Between the stages of young and late adulthood, mitochondria within the cardiomyocytes experience a decreased level of biogenesis due to decreased expression of PGC-1 and downregulation of NAD+-dependent sirtuins. A metabolic shift occurs in old hearts, resulting in greater glucose and less fatty acids utilization for energy production. Mitochondrial quality control by mitophagy induction is also compromised. Cell death levels increase in the form of apoptosis and necrosis, which utilize mitochondrial outer membrane permeabilization (MOMP) through the Bcl-2 family and mitochondrial permeability transition pore (MPTP), respectively. Excess ROS is generated through increase electron transport chain (ETC) leak, resulting in increased levels of mitochondrial DNA (mtDNA) damage, imbalance of CM redox states, damage to lipids/proteins within the mitochondria, and the inability of antioxidants to clear ROS from the microenvironment. Together, these stressors lead to a decrease in mitochondrial function and lower levels of ATP…

• 

  FIGURE 3. Behavioral and Medicinal Interventions against Cardiac Aging. Currently, various studies have implemented many approaches to reduce the negative effects associated with the aging heart. Diets such as caloric restriction (CR), intermittent fasting (IF), and increasing antioxidant rich foods or supplements have been investigated with regard to heart health. However, the latter was shown to be ineffective at mitigating the effects of aging. On the other hand, CR and IF are both effective at reducing many of the negative consequences of aging. Exercise has been demonstrated to enhance cardiac function in both mouse and human models, however it only produces beneficial effects when it is initiated during middle age and may impose an increased oxidative stress burden. In addition to these lifestyle changes, medicinal intervention utilizing sirtuin stimulators SRT1720, resveratrol, and polyamine spermidine have exerted positive effects against cardiac stress.