Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice

Abstract

Aging is, by far, the greatest risk factor for most neurodegenerative diseases. In non-diseased conditions, normal aging can also be associated with declines in cognitive function that significantly affect quality of life in the elderly. It was recently shown that inhibition of mTOR activity in mice by chronic rapamycin treatment extends lifespan, possibly by delaying aging {Harrison, 2009 #4}{Miller, 2011 #168}. To explore the effect of chronic rapamycin treatment on normal brain aging we determined cognitive and non-cognitive components of behavior throughout lifespan in male and female C57BL/6 mice that were fed control- or rapamycin-supplemented chow. Our studies show that rapamycin enhances cognitive function in young adult mice and blocks age-associated cognitive decline in older animals. In addition, mice fed with rapamycin-supplemented chow showed decreased anxiety and depressive-like behavior at all ages tested. Levels of three major monoamines (norepinephrine, dopamine and 5-hydroxytryptamine) and their metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid) were significantly augmented in midbrain of rapamycin-treated mice compared to controls. Our results suggest that chronic, partial inhibition of mTOR by oral rapamycin enhances learning and memory in young adults, maintains memory in old C57BL/6J mice, and has concomitant anxiolytic and antidepressant-like effects, possibly by stimulating major monoamine pathways in brain.

A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs

“…If such an effect can be confirmed in a future larger scale trial, one possible explanation could be the anti-inflammatory effects of rapamycin reducing pain associated with arthritis. Rapamycin is also known to improve cognitive function in middle-aged mice (Halloran et al 2012;Majumder et al 2012), and it is possible that rapamycin could alter cognitive function in dogs in a way that induces these behavioral changes. It will be of particular interest to determine whether similar effects are observed in future longer term studies and to directly assess cognitive function and inflammatory state in dogs receiving rapamycin.…”

“…Treatment with rapamycin increases lifespan in evolutionarily divergent organisms including yeast, nematodes, fruit flies, and mice (Johnson et al 2013;Johnson et al 2015). In addition to increasing lifespan, treatment with rapamycin has also been shown to improve a variety of age-associated conditions in mice, including reducing cancer incidence (Anisimov et al 2011), improving cognitive function (Halloran et al 2012;Majumder et al 2012), reversing cardiac (Dai et al 2014;Flynn et al 2013;Neff et al 2013) and immune (Chen et al 2009) declines, restoring stem cell function (Chen et al 2009;Yilmaz et al 2012), and improving muscle function (Bitto et al 2016;Fischer et al 2015) in aged animals. Of particular note, initiating treatment with rapamycin late in mid-life appears to increase longevity to an extent comparable to treatment beginning early in life (Harrison et al 2009), and one recent study reported increases in life expectancy from 20 to 60% following single transient treatments with rapamycin from 20 to 23 months of life in mice (Bitto et al 2016).…”

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

“…Rapamycin 4.7, 14, and 42 ppm in food also slows age-dependent pathology of the liver, heart, and tendons (Wilkinson et al 2012). A recent study demonstrated that chronic 2.24-mg/kg rapamycin inhibits age-associated cognitive decline (Halloran et al 2012). Furthermore, rapamycin treatment was associated with anxiolytic and anti-depressive effects (Halloran et al 2012).…”

“…A recent study demonstrated that chronic 2.24-mg/kg rapamycin inhibits age-associated cognitive decline (Halloran et al 2012). Furthermore, rapamycin treatment was associated with anxiolytic and anti-depressive effects (Halloran et al 2012).…”

Comparison of rapamycin schedules in mice on high-fat diet

“…[62][63][64][65][66][67][68][69][70] In the organism, suppression of geroconversion prevents age-related diseases in mammals [70][71][72][73][74][75][76][77][78] and pathological conditions in invertebrates, 79,80 extending healthy lifespan.…”