Rapamycin induced Autophagy Ameliorates Age-Related Neurogenesis Decline and Neurodysfunction

Neural-stem-cell-QBI-brain-physiology-neurogenesis

New research paper that supports previous research (and why many people think rapamycin will reduce risk for Alzheimers). Research on mice and humans suggests that rapamycin (and everolimus even more so) is able to penetrate the blood brain barrier (see links at bottom of this post).

stimulating autophagy by rapamycin not only revitalized the viability of middle-adult neural progenitor cells (NPCs), but also facilitated the neurogenesis in middle-adult subventricular/ subgranular zone (SVZ/SGZ). More importantly, autophagic activation by rapamycin also ameliorated the olfactory sensitivity and cognitional capacities in middle-adult mice.

Preprint of Full Paper Here:

Activation_of_autophagy_ameliorates_age-related_ne.pdf (1.2 MB)

Related Readings:

For more discussion on this see this topic: Rapamycin and the Issue of Getting Through the Blood Brain Barrier

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@ RapAdmin

Great paper! I couldn’t find it beyond paywall, but this link provides the paper broken down by section.

What’s great about this paper is they used Rapamycin in vivo on wild type mice, they confirmed neurogenesis via autophagy/mTOR suppression in the main neurogenic sites in the brain…AND, they actually tested the mice for cognitive enhancement. If a mouse-cognitive study dosen’t actually test the mice for cognitive improvement, I consider it almost worthless.

These mice were given 4mg/kg/day (approx 20mg dose for 60 kg human at 12.3 conversion), every other day, for 4 weeks.

(Rapamycin dosing levels in these studies causes me to pause and wonder if our dosing is moving the needle?)

“We demonstrated that in vivo administration of rapamycin could ameliorate the decline of autophagy in the middle-aged brain and facilitate adult neurogenesis through autophagy activation via the suppression of mTOR. We showed that autophagic activation by rapamycin not only facilitated the endogenous neurogenesis in the middle-aged SVZ and hippocampus, but also improved the olfactory sensitivity and cognitive capability in middle-aged mice. We further confirmed in vitro that rapamycin-triggered autophagy activation via mTOR suppression rejuvenated the viability and pluripotency of middle-aged NPCs. Spilman et al . have reported that rapamycin administration protects hippocampus neurons against injury and improves the learning and memory ability through mTOR inhibition in AD mice [40]. Our results revealed that autophagy was closely correlated with adult neurogenesis. Genetic suppression of Atg7 compromised neurogenesis; conversely, pharmacological activation of autophagy enhanced middle-aged neurogenesis and restored middle-aged brain function. This shed light on the regulation of adult neurogenesis. Genetic or pharmacological activation of autophagy could serve as an attractive therapeutic strategy for age-related brain dysfunction and neurodegenerative diseases where neurogeneis is compromised.”

The conventional dogma is you’re born with a set number of neurons, and you cannot grow more (just loss with age). A growing chorus of work has started to question this thinking. Lifestyle interventions such as exercise can induce neurogenesis.

“The current study compared the effects of short-term and long-term running wheel access on hippocampal neurogenesis and neuroimmune markers in aged (19-23 months) male C57BL/6J mice. Aged mice were given 24-hour access to a running wheel for 14 days (short-term) or 51 days (long-term). Groups of non-running aged and young (5 months) mice served as comparison groups to detect age-related differences and effects of exercise. Long-term, but not short-term, exercise increased hippocampal neurogenesis as assessed by number of doublecortin (DCX) positive cells in the granular cell layer”

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Hopefully spermidine will also come through with similar effects via autophagy enhancement in the brain and at safe achievable doses.

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Found the full preprint of this paper above and added it to the top post - if you want to read it.