F1F0 ATP Hydrolysis is a Determinant of Metabolic Rate, a Correlate of Lifespan, and a Weakness of Cancer

Body temperature decrease, in mice administered with a drug that selectively inhibits F1F0 ATP hydrolysis (which doesn’t inhibit F1F0 ATP synthesis), is evidence that F1F0 ATP hydrolysis is used for metabolic heat generation in vivo. It being pivotal to homeothermy, which is a new discovery. This drug, capable of dose-dependently lowering body temperature, might slow aging and extend lifespan (combating all age-related diseases thereby). Because slightly lower body temperature corresponds with a much longer lifespan in mice and humans. Alzheimer’s, a disease of aging, can cause a higher body temperature (that accelerates its progression), which this drug might counteract. Across twelve investigated species, less F1F0 ATP hydrolysis correlates with greater maximal lifespan. A case for causality is made. Selective drug inhibition of F1F0 ATP hydrolysis exerts potent anti-cancer activity in vitro. Teaching F1F0 ATP hydrolysis as a new cancer drug target. SIGNIFICANCE Different species age at different rates, conferring different maximal lifespans. For example, the maximal lifespan of a mouse is 4 years, while that of a bowhead whale is 211 years. So, aging is modifiable. But how? A clue might be body size: smaller mammal species tend to age faster than larger ones. In geometry, smaller objects have a greater surface-area-to volume ratio than larger objects. Meaning smaller mammal species lose more of their metabolically generated heat. And so, each gram of a smaller mammal species needs to generate more metabolic heat than each gram of a larger mammal species. To keep their body temperature at 37°C. The chemical reactions that the body uses to obtain energy from food (e.g., to keep the body warm) produce harmful by-products: Reactive Oxygen Species (ROS). That cause molecular damage. The accumulation of which might be aging. Each gram of a smaller mammal species generates more metabolic heat, uses more food, produces more ROS, and ages faster. Herein reported is a chemical reaction (F1F0 ATP hydrolysis) that mammal species use to generate heat. Showing that each gram of smaller (shorter-living) mammal species use it more than each gram of larger (longer-living) mammal species. A drug that selectively inhibits it (which doesn’t inhibit F1F0 ATP synthesis) is shown to decrease metabolic heat generation in mice. Higher doses decrease it more. The human body (in typical clothing) is most comfortable at an ambient temperature of around 20.3°C. But much of the world is hotter than that (for at least part of the year). Conceivably, this drug can, by decreasing metabolic heat production (in a dose-dependent manner), increase the ambient temperature that someone is comfortable at, increasing comfort in hot climates/seasons/rooms. If this drug is applied to only part of the body (e.g., in a face cream), heat transfer from the remainder of the body (via blood flow) is expected to maintain this part at 37°C, no matter the ambient temperature. In the literature, lower body temperature extends the lifespan of mice (0.34°C lower increases lifespan by 20%) and corresponds with a longer human lifespan and healthspan. Moreover, calorie restriction, which slows aging and increases the lifespan of model organisms, reduces body temperature. This drug can (dose-dependently; if the ambient temperature is permissively low) reduce body temperature. This drug is predicted to slow aging (whether reducing body temperature or not). Indeed, in mice, its mechanism of action (selectively inhibiting F1F0 ATP hydrolysis) is shown to safely decrease intracellular ROS concentration. This drug is shown to have anticancer activity in vitro. Thence (prospectively) here is an anticancer drug that helps, rather than harms, normal cells.