ABSTRACT
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.
Competing Interest Statement
The author has filed for related patents.
Footnotes
It has been so modified, with so many changes, that the below is not necessarily an exhaustive list of the changes made since the last version: (1) Added new sections/sub-sections: Headed: Significance. Headed: Does F1F0 ATP hydrolysis (at least partially) turn the hands of the epigenetic clock? (containing a new Figure therein, other Figures renumbered accordingly). Headed: Slightly lower body temperature corresponds with longer lifespan. Headed: Difference in human life expectancy between higher and lower body temperature groups. Headed: Alzheimer's disease increases body temperature, which accelerates/exacerbates its pathology. Headed: Interim summary: Possibly a single drug for many diseases. Headed: Lower specific metabolic rate extends the lifespan of mice. Headed: Humans with lower specific basal metabolic rate have a longer lifespan. Headed: In essence. Headed: A model (containing a new Figure therein, other Figures renumbered accordingly). Headed: Historical odds of making it into clinical trials. Headed: Addressing an anticipated objection: But what about bats? Headed: Addressing an anticipated objection: But what about naked mole rats? Headed: Addressing an anticipated objection: But what about marsupials? Headed: Addressing an anticipated objection: But women are smaller, and yet live longer, than men. Headed: Addressing an anticipated objection: But why do antioxidants only extend life modestly? Headed: Which (if any) of damage to DNA, lipids or proteins constrains maximal lifespan?. Headed: Relative detriment of the different types of molecular damage. Headed: Scaling with adult body mass. Headed: A better plot of DNA repair rate for substitution into Figure 15. Headed: Comparison with senolytics. (2) Some existing section/sub-section headings have been modified. The ordering of some existing sections/sub-sections has been modified. (3) Some new Figures have been added in. And so the figure numbers of existing figures have been changed accordingly. (4) Added + and − symbols to (what is now) Figure 10. (5) Added new (and/or edited some existing) sentences and/or paragraphs in the Abstract, Introduction, Results, Discussion, Methods, and Competing interest sections, i.e. throughout. Much has been changed throughout. (6) In the Methods section: consolidated all the compound synthesis schemes and spectral data, and put them further back in this section. (7) Made varied minor/cosmetic/clarifying improvements/fixes throughout. (8) I've tried to clear up some misunderstandings of the prior version. Most notably, now stressing even more that the tested drugs do NOT inhibit F1F0 ATP synthesis. That they selectively inhibit only F1F0 ATP hydrolysis. This is now stressed at many, many further points throughout.