The sedentary (r)evolution: Have we lost our metabolic flexibility?

Area of Science:

• Evolutionary biology
• Human metabolism
• Nutritional science

Background:

• Human metabolism evolved for survival during environmental fluctuations and food scarcity.
• Modern lifestyles feature constant energy-dense food availability, stress, and inactivity.
• This shift has led to widespread metabolic disorders like metabolic syndrome and type 2 diabetes.

Purpose of the Study:

• To argue that metabolic disease is primarily caused by a deficit in metabolic flexibility.
• To hypothesize that modern energetic inflexibility can be reversed by restoring ancestral metabolic programs.
• To identify neglected metabolic programs and draw conclusions for disease prevention.

Main Methods:

• Comparative analysis of primal hunter-gatherer metabolic programs versus modern sedentary lifestyles.
• Hypothesizing the reversal of modern metabolic inflexibility through re-cultivating suppressed metabolic pathways.
• Simplified model contrasting ancestral and current metabolic adaptations.

Main Results:

• Metabolic flexibility was crucial for human survival against environmental changes and food scarcity.
• Modern lifestyles promote metabolic inflexibility, leading to chronic fat accumulation and disease.
• Suppressed metabolic programs, including ketone body and fat oxidation, are key to restoring flexibility.

Conclusions:

• The current epidemic of metabolic diseases is largely due to a deficit in metabolic flexibility.
• Re-cultivating ancestral metabolic programs, particularly fat and ketone oxidation, can reverse modern energetic inflexibility.
• Understanding and restoring these neglected programs is vital for preventing chronic metabolic diseases.