Organ reserve, excess metabolic capacity, and aging

Abstract

"Organ reserve" refers to the ability of an organ to successfully return to its original physiological state following repeated episodes of stress. Clinical evidence shows that organ reserve correlates with the ability of older adults to cope with an added workload or stress, suggesting a role in the process of aging. Although organ reserve is well documented clinically, it is not clearly defined at the molecular level. Interestingly, several metabolic pathways exhibit excess metabolic capacities (e.g., bioenergetics pathway, antioxidants system, plasticity). These pathways comprise molecular components that have an excess of quantity and/or activity than that required for basic physiological demand in vivo (e.g., mitochondrial complex IV or glycolytic enzymes). We propose that the excess in mtDNA copy number and tandem DNA repeats of telomeres are additional examples of intrinsically embedded structural components that could comprise excess capacity. These excess capacities may grant intermediary metabolism the ability to instantly cope with, or manage, added workload or stress. Therefore, excess metabolic capacities could be viewed as an innate mechanism of adaptability that substantiates organ reserve and contributes to the cellular defense systems. If metabolic excess capacities or organ reserves are impaired or exhausted, the ability of the cell to cope with stress is reduced. Under these circumstances cell senescence, transformation, or death occurs. In this review, we discuss excess metabolic and structural capacities as integrated metabolic pathways in relation to organ reserve and cellular aging.

Keywords: Complex IV; Excess metabolic capacity; Mitochondria; Organ reserve; Telomeres; mtDNA.

Scheme 1. mtDNA excess capacity

1) A hypothetical case of a mitochondrion with one copy of mtDNA (i.e., 37 genes). When one or more of the 37 genes is mutated (e.g., due to conditions that mutate DNA) a loss of function occurs and the mitochondrion is impaired. Thus, the lack of a backup to the 37 genes increases the risk of compromising the mitochondrial function, energy metabolism, and the cell. 2) A hypothetical case of a mitochondrion with three copies of mtDNA, (i.e., each of the 37 genes is represented three times in three mtDNA copies). The risk of a mutation that compromise the function of this mitochondrion is much lower when the mitochondrion is exposed to the same conditions as in (1). The backup of three copies for each of the 37 gene sets represents excess structural capacity of mtDNA.

Scheme 2. Telomeres excess capacity

1) A model of a hypothetical cell with a single chromosome that has single copy of a telomere (red bar). When the cell is exposed to conditions that compromise the integrity of the telomere (oxidative damage or after one cycle of cell division) the telomere becomes dysfunctional or shorter, thus compromising the chromosome stability risking the cell normal function through senescence or transformation. 2) A model of a hypothetical cell with a single chromosome that has three copies of telomere repeats. The risk of cell senescence or transformation is much lower when the cell is exposed to the same conditions as in (1). The backup of three telomere repeats represents the excess structural capacity of telomeres.

Scheme 3. The proposed change to excess metabolic capacity, metabolic function, and organ reserve with age

Excess metabolic capacities could contribute to organ reserve and the aging process. Excess metabolic capacity and organ reserve also provide the opportunity of integrating many of the factors that were shown to contribute to the aging process. Reduction in excess metabolic and structural capacities could result in an increase in cell entropy and oxidation; resulting in cell senescence, transformation, or death, thus compromising organ reserve. The proposed relations of age, excess capacities, and organ reserve are schematically depicted. A hypothetical plot of the age-related molecular modifications and metabolic dysfunctions are also presented (^____) line. Excess metabolic capacities presented in this scheme include enzymes (e.g., Na/K ATPase), mtNDA copy numbers, and repeats in telomeres. The line (^…..) indicate the age-related decline in excess capacity. Telomeres erosion or dysfunction are presented with a decrease in the length of the blue lines.