Mitochondrial determinants of mammalian longevity

Area of Science:

• Gerontology
• Metabolic Research
• Evolutionary Biology

Background:

• Current aging theories, including the rate-of-living theory, face challenges due to numerous contributing factors.
• The rate-of-living theory posits a constant product of maximum lifespan (MLS) and mass-specific basal metabolic rate (msBMR), termed lifetime energy expenditure (LEE).
• Existing data show inconsistencies, with some studies finding no inverse msBMR-MLS relationship within orders and significant variation in LEE values across species.

Purpose of the Study:

• To address the limitations of the rate-of-living theory.
• To introduce and validate a new metric, mitochondrial lifetime energy output (mtLEO), as a more accurate predictor of maximum lifespan.
• To investigate the relationship between mtLEO, mitochondrial metabolic rate (mtMR), and amino acid variables (AAVs) in mtDNA-encoded proteins.

Main Methods:

• Proposed mtLEO = MLS × mtMR as a replacement for LEE.
• Analyzed the distribution and correlation of mtLEO values across species.
• Investigated the correlation between mtLEO and four specific amino acid variables (Ser, Thr, Cys content and hydrophobicity) of mtDNA-encoded membrane proteins.

Main Results:

• mtLEO values exhibited a narrower distribution compared to LEE values.
• mtLEO showed a strong correlation with the four identified amino acid variables (AAVs).
• The mtLEO metric, along with AAVs, resolved inconsistencies in the rate-of-living theory and significantly improved the correlation with maximum lifespan.

Conclusions:

• Mitochondrial lifetime energy output (mtLEO) offers a more robust framework for understanding the determinants of maximum lifespan than traditional lifetime energy expenditure (LEE).
• Mitochondrial metabolic rate (mtMR) and specific amino acid characteristics of mtDNA-encoded proteins are key factors influencing lifespan.
• This revised approach enhances the predictive power of metabolic theories of aging.