bioRxiv2021
IF1 protein inhibits F1F0 ATP hydrolysis (and not F1F0 ATP synthesis). Across investigated species more IF1 protein, and less F1F0 ATP hydrolysis, correlates with greater maximal lifespan. Increased IF1 protein, and decreased F1F0 ATP hydrolysis, safely reduces a biomarker of aging in mice. Body temperature decrease, in mice administered with a small molecule drug that selectively inhibits F1F0 ATP hydrolysis (which doesnt inhibit F1F0 ATP synthesis), is evidence that F1F0 ATP hydrolysis is used for metabolic heat generation in vivo. Instrumental to homeothermy, which is a new fundamental discovery. A further discovery is that cancer cells subvert F1F0 ATP hydrolysis to drive their distinctive Warburg metabolism and so selective drug inhibition of F1F0 ATP hydrolysis exerts potent anticancer activity. When the body is in an ambient temperature of 37{degrees}C (or more), no metabolic heat generation is needed for the body to be at 37{degrees}C, and so a large dose of a F1F0 ATP hydrolysis inhibiting anticancer drug may be administered, which may slow aging. So, here might be an entirely new class of anticancer drugs that may (when appropriately used) help, instead of harm, normal cells. Distinct from present anticancer drugs, which greatly harm normal cells, causing horrific side-effects, which kill many and cause many others to abandon cancer treatment. In short, this paper teaches how mammals metabolically generate heat, why different mammal species have different maximal lifespans, and new anticancer drugs, that are predicted to slow aging. SIGNIFICANCEHas nature taught us how to slow aging? Different mammal 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, by its square-cube law, smaller objects have a greater surface-area to volume ratio than larger objects. Meaning smaller mammal species more readily lose their metabolically generated heat. And so, per unit time, 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 around 37{degrees}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), which cause molecular damage. The accumulation of which might be aging. Per unit time, each gram of a smaller mammal species generates more metabolic heat, uses more food, produces more ROS, and ages more. Newly reported herein is a chemical reaction that homeotherms use to generate heat (F1F0 ATP hydrolysis). By the 2nd Law of Thermodynamics, whenever energy converts from one form to another, some of this energy must be dissipated as heat (no energy conversion can be 100% efficient). Ive discovered, in homeotherms, ATP synthase enzyme hydrolyses some of the ATP it synthesizes (i.e., performs F1F0 ATP hydrolysis). Causing futile cycling between ATP synthesis and ATP hydrolysis, conditional upon passing and pumping protons along a concentration gradient respectively. So, cyclically interconverting between potential and chemical energies, which (by the inefficiency of energy conversions) generates heat to maintain body temperature. Across a set of mammal species: per unit time, each gram of smaller (shorter-living) mammal species do more of this heat generating reaction (F1F0 ATP hydrolysis) than each gram of larger (longer-living) mammal species. Because they have less IF1 protein (activity per unit mass), where IF1 protein selectively inhibits F1F0 ATP hydrolysis (doesnt inhibit F1F0 ATP synthesis). Across these mammal species, maximal lifespan is inversely proportional to the use (per unit time per unit mass) of F1F0 ATP hydrolysis. That drives the inverse proportionality between metabolic rate per unit mass and maximal lifespan, which causes the inverse proportionality between heart rate and maximal lifespan, observed across these mammal species. Increased IF1 protein, and decreased F1F0 ATP hydrolysis, safely reduces a biomarker of aging in mice. So, correlational and interventional data. My interpretation of data herein is that different mammal species have different maximal lifespans because of different IF1 protein activity (per unit mass). Where more IF1 protein activity (per unit mass) confers longer lifespan. A small-molecule drug that selectively inhibits F1F0 ATP hydrolysis, which doesnt inhibit F1F0 ATP synthesis, is shown to dose-dependently reduce metabolic heat generation (and metabolic rate thereby) in mice. Higher dose reduces it more. Such a drug is predicted to slow aging. Indeed, its mechanism of action (selectively inhibiting F1F0 ATP hydrolysis) is shown to safely decrease intracellular ROS concentration in mice. Less metabolic heat generation doesnt necessarily mean lower body temperature. Body temperature can be the same with less metabolic heat generation by proportionally greater body insulation, such as wearing more or better clothing, and/or a conducive ambient temperature. A human, in typical clothing, is most comfortable at an ambient temperature around 20.3{degrees}C. But much of the world is hotter, at least for part of the year, especially when close to the equator (43% of the worlds population lives in the tropics). Such a drug might, by dose-dependently reducing metabolic heat generation, increase thermal comfort in hot places, possibly slowing aging. To illustrate: a relatively small drug dose might increase a clothed persons preferred ambient temperature to 23{degrees}C, a higher dose to 27{degrees}C, an even higher dose to 32{degrees}C, and so on. When metabolic heat generation is low, the preferred ambient temperature is close to 37{degrees}C. When the ambient temperature is 37{degrees}C or more, no metabolic heat generation is needed for the body to be at 37{degrees}C. I predict when such a drug is applied topically to a small body part, such as to the face in a cosmetic cream, it will reduce metabolic heat generation at that location, reducing metabolic rate and thereby slow aging there. Wherein heat transfer from the rest of the body, via blood flow, maintains this body part at around 37{degrees}C, because topical use cant reduce body temperature at any ambient temperature. Less F1F0 ATP hydrolysis, enough predicted to slow aging by two-thirds, has been proven safe in mice, at least when localized to a body part. Slowing the aging of even just a small part of the body has cosmetic and - because many diseases of aging are highly localized (for example, to the eyes: e.g., Age-Related Macular Degeneration) - medical applications. Probably the incidence and progression of age-related diseases correlates with age/aging because aging is causal to them, and so a single drug that slows aging might confer therapeutic benefit for many, varied diseases of aging. Such diseases must be beaten to avert the otherwise coming demographic/economic crisis in which too much of the population suffers, and is debilitated by, at least one of them. A drug to slow aging is a desperate want and has been since the dawn of mankind. 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pharmacology and toxicology↗