Targets, mechanism and optimal delivery of therapeutic ketosis for functional longevity and amelioration of Alzheimer's disease
An overall goal of this Program Project is to elucidate the very novel discovery that the continuous, isocaloric ketogenic diet increases memory, cognitive and muscle function as well as longevity in mice1. We were led into this discovery through Shc-depleted mice that resist neurodegenerative stress in models of AD3,4, MS5, and ALS6, and are 'genetically ketogenic'6, and we tested consequences of increased dietary fat at expense of carbohydrate, and observe dose-dependent effects (higher fat, better) on function in aging and longevity1.
There is potential for impact on mechanistic understanding of aging and the potential for translation to humans, we focus exclusively on the mechanism by which therapeutic ketosis increases functions and longevity in mice.
A companion paper by Newman et al in the very same Sept. 5th 2017 issue of Cell Metabolism2 showed that the intermittent ketogenic diet preserves many late-life functions and some midlife mortality, this supports the novel idea that therapeutic ketosis does not need to be continuous to achieve a functional benefit in aging. Thus both continuous and intermittent ketosis extend the preservation of function in healthy aging mice, and continuous ketosis extends median longevity1,2. Also there is a recent epidemiological study across 15 countries, 7 continents, and 135,000 people suggests that increasing dietary fat protects from age-related mortality8. Thus there is support now in mice and a recent human study that increased dietary fat preserves functions in late age and reduces mortality.
In order for these findings to have maximal significance and impact both for understanding the mechanistic biology of aging, and also for preserving health, function and longevity in the US, we pose these questions.
1. What is the mechanism by which therapeutic ketosis extends functional longevity? (Projects 1, 2, 3, 4). What does therapeutic ketosis for aging mean functionally (Project 4), what are its targets (Projects 2, 3, 4), and how does it work to extend longevity in mice (Project 4)?
2. what are the genes that therapeutic ketosis engages to cause increased functional longevity (Projects 1, 2, 3) and can these serve as biomarkers not only of dietary compliance (Project 4) but more importantly the functional longevity effect (Projects 1, 2, 4). Furthermore, are these aging-relevant (Projects 1& 2) and function-relevant (Projects 1& 4), and KD-reversible (Projects 1 & 2) gene biomarkers known to be altered in published studies of AD brain and blood? Also, because for maximum translation and impact it may be difficult for the US population to adopt a continuous KD, are there keto- therapeutic strategies like intermittent KD (iKD) and ketone supplements (KS) that preserve function and longevity to at or nearly the same extent as continuous isocaloric KD? (Project 4).