Protein restriction slows the development and progression of Alzheimer's disease in mice

Babygirija, Reji; Sonsalla, Michelle M.; Han, Jessica H.; James, Isabella; Green, Cara L.; Calubag, Mariah F.; Mill, Jericha; Wade, Gina; Tobon, Anna; Michael, John; Trautman, Michaela M.; Matoska, Ryan; Yeh, Chung-Yang; Grunow, Isaac; Pak, Heidi H.; Rigby, Michael J.; Denu, John M.; Puglielli, Luigi; Simcox, Judith; Lamming, Dudley W.

doi:10.21203/rs.3.rs-3342413/v1

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“…While we were able to observe an age-dependent decrease in Barnes Maze performance, restriction of isoleucine or all amino acids did not improve performance; indeed the trend in both sexes was towards a decrease in performance with the Low Ile diet. This was at odds with our expectations, as we and others have found that PR and restriction of BCAAs improves cognition in a mouse model of AD, and we observed no negative effects of isoleucine restriction on cognition when begun at 6 months of age (Babygirija et al, 2023; Green et al ., 2023; Tournissac et al, 2018). Larger cohorts studied for a longer period will be required to reach definitive answers on the impact of these diets on frailty and memory.…”

Section: Discussioncontrasting

confidence: 99%

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging

Yeh

Chini

Gallagher

et al. 2023

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A growing number of geroprotectors have demonstrated healthspan extension in young animals, but the effectiveness of these therapies when commenced in midlife or later has been under-studied. We and others have shown that much like calorie restriction (CR), restriction of specific nutrients, including total protein, the three branched-chain amino acids leucine, isoleucine, and valine, or isoleucine alone, can promote lifespan and metabolic health. While CR is less efficacious when starting in late life, the effects of interventions restricting amino acids in late life on healthy aging is unknown. Here, we investigate the metabolic, molecular, and physiological effects of consuming diets with a 67% reduction of either all amino acids (Low AA) or of isoleucine alone (Low Ile) in male and female C57BL/6J.Nia mice starting at 20 months of age. We find that both diets reduce adiposity in aged mice; however, these diets decreased lean mass, and did not show significant improvements in frailty or fitness. The glucose tolerance of both male and female mice consuming Low Ile and Low AA diets were improved. We also observed a moderate increase in energy expenditure and respiratory exchange ratio induced by the two dietary interventions. In the hearts of aged female mice, Low Ile reversed age-associated changes in heart rate and stroke volume, returning cardiac function to similar levels as observed in young mice. We found that both Low AA and Low Ile diets promoted a more youthful molecular cardiac profile, preventing age-dependent increases in phosphotidylglycerols. These results demonstrate that Low AA and Low Ile diets can improve aspects of metabolic health in aged mice of both sexes, and has positive effects on cardiac health in aged females, suggesting that these dietary interventions are translationally promising for promoting healthy aging even in older people.

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Section: Discussioncontrasting

confidence: 99%