Rapamycin by decreasing activity of mTOR can preserve normal cognitive function through the pathways related to prevention of AD. Those pathways have been looked at in detail in previous sections and include preservation of cerebral microcirculation and increasing autophagy which can prevent accumulation of amyloid-B.
Here we look at pathways related to decreasing activity of mTOR; but independent from AD pathways.
As usual the two leading papers are by Galvan group (88) 2012 and the Oddo group (89) 2012.
In this paper by Galvan group (88) they used standard non-transgenic lab mice called C57 Black 6. The treated mice were fed oral rapamycin in the standard low dose used by Harrison in 2009 anti-aging studies (9).
Results showed this dose only inhibits mTORC1 in brain but not mTORC2.
8 month old mice was fed rapamycin for 4 months and then evaluated at 12 months. Rapamycin fed mice had better spacial learning and memory than control mice fed standard diet.
They then test effect of rapamycin on older mice. They tested 12 month old mice and 25 month old mice, both had been fed rapamycin for 10 months. They also tested a 25 month old mice in which rapamycin was started at 18 months of age.
All three groups of mice fed rapamycin had better preserved cognitive function than regular chow fed mice.
They also tested a 8 month old mice and 14 month old mice that had been treated wth rapamycin. The mice showed reduced anxiety.
They also tested 4 month old, 8 month old and 12 month old mice that had been treated with rapamycin for 2 months. All groups treated with rapamycin demonstrated reduced depressive like behavior.
Studies showed the treated mice had increased levels of monoamines in midbrain after being fed rapamycin. The monoamines were epinephrine, norepinephrone, dopamine and 5-hydroxytrptamine.
They state: "In summary, the results of the present study demonstrate that chronic feeding with encapsulated rapamycin enhances memory in young C57BL/6 mice and delays cognitive decline associated with aging. Moreover, our results show that long-term feeding with rapamycin has concomitant anxiolytic and antidepressant like effects."
Very important note in discussion was that there was an approximate 30% reduction in TOR activity in brain. They state 30% reduction in TOR activity can improve learning and memory in old animals. mTOR levels too high or too low are bad.
"It has been suggested that there was little selective pressure to evolve effective mechanisms of neuroprotection in old age. It is therefore conceivable that brain mTOR levels that are adequate during the reproductive years may be detrimental as mammals age."
In other words, mTOR is like a rheostat, set at the proper level for the growing animals; but too high for the older animal.
The Oddo group 2012 paper is entitled, "Life-long rapamycin administration ameliorates age-dependent cognitive deficits by reducing Il-1B and enhancing NMDA signaling. (89)
The study used the common lab mouse same as used in above study. Mice were tested for spacial learning and memory. Untreated mice did well at age 2 and 6 months; but showed decreases in learning and memory at 15 months and 18 months.
Mice were fed rapamycin in same low dose used in Harrison study. Mice fed rapamycin for 16 months, starting at age 2 months, had preserved learning and memory. Mice fed rapamycin for 3 months, starting at 15 months had no improvement. The results showed rapamycin prevents age-dependent cognitive deficits. They conclude:
"Short-term rapamycin administration to 15-month-old mice, an age at which mice already have spatial learning deficits, has no impact on learning. In contrast, life-long rapamycin administration ameliorates age-dependent spatial learning."
What was of great interest was the mechanism:
Rapamycin decreases mTOR signaling in brains of mice treated for 16 months and for 3 months. However, the cytokine IL-1B was only reduced in 2-->18 rapamycin mouse and not reduced in the 15-->18 rapamycin mouse in which rapamycin was begun at 15 months. IL-1B is a proinflammatory cytokine. The conclusion was "high levels of IL-1B impair hippocampal-dependent learning and memory. "
NMDA is one of main signaling molecules in the brain. NMDA has receptors designated NR1and NR2 and there is subunit NR2B receptor which is important for learning and memory. Rapamycin increases phosphorylation of NR2B receptor and this facilitates NMDA signaling of this receptor.
"The NMDA receptors play a key role in synaptic plasticity and long-term potentiation, which is believed to be the cellular mechanism underlying learning and memory."
They state: "Taken together, these data suggests that rapamycin ameliorates age-dependent cognitive deficits by decreasing hippocampal IL-1B levels and by facilitating NR2B surface expression and overall NMDA signaling."
Discussion: All these substances, like mTOR and Il-1B have a window of proper level. [They all follow the Goldilocks rule: too much, too little, and just right ]
"Overall these data ...show that a small decrease in mTOR signaling in aged mice has beneficial effects on learning and memory, suggests that there may be a window of mTOR activity that is necessary for learning and memory, wheras complete blockage of mTOR or hyperactive mTOR are detrimental to learning and memory."
Discussion of IL-1B:
"It is very well established that the production of pro-inflammatory cytokines increases in the brain as a function of age while the levels of anti-inflammatory cytokines decreases."
"IL-1B levels increase as a function of age in the hippocampus and its involvement in memory has been clearly established."
"Specifically, there is growing appreciation for a dual role of IL-1B in learning and memory; whereas IL-1B is required for memory, a chronic increase in IL-1B has a negative effects on learning and memory."
"The data presented here are consistent with these reports as we have shown that the improvement in behavior is strictly linked to reduction of central IL-1B levels. Indeed, we show that rapamycin improved learning and memory only in Rapa 2--18 mice, which have significantly lower IL-1B levels compared to the other two groups. In contrast Rapa 15-18 mice, in which IL-1B levels were not decreased, performed the same as the control mice."
Conclusion: "Data presented here suggests that rapamycin-mediated changes in IL-1B and NMDA signaling contribute to the learning and memory improvements in the Rapa 2-18 mice.
The results were that rapamycin administered in young mice and continued until age 18 months reduced IL-1B signaling and this reduction in IL-1B brain levels enhanced NMDA signaling which then ameliorated age-related cognitive deficits.
This study looked at genetic variation in the IL-1B converting enzyme, which regulates IL-1B and is associated with lower production levels of IL-1B. (90) They found lower levels of IL-1B were associated with better performance in cognitive function in elderly persons, suggestion that low levels of IL-1B are protective against age-associated learning and memory deficits.
In this study 2 month old mice were maintined on diet of long-term intermittent fasting diet, consisting of alternate day feeding for 6-8 months. (91) They found the caloric restriction mice had enhance learning.
In the hippocampus of CR mice they found increase in expression of NMDA receptor subunit NR2B.
This was similar to above rapamycin mouse study with enhanced function of NMDA signaling through NR2B subunit and improved memory.
In this study 50 healthy overweight elderly adults, mean age 60.5 years and mean BMI 28 [overweight BMI 25-30], were studied. The study group had 30% caloric restriction for 3 months. (92)
They found a significant increase in verbal memory scores after caloric restriction. The increase in verbal memory sores was correlated with a decrease in fasting levels of insulin.
Note: Both caloric restriction and decrease in fasting levels of insulin are correlated with decrease activity of mTOR.
Rapamycin fed mice were protected against cognitive decline in older age group. (88,89).
The cognitive protection was associated with rapamycin decreasing activity of mTOR; which caused decrease in pro-inflammatory cytokine IL-1B. The preserved cognitive function was associated with NR2B receptor subunits of the NMDA receptor in hippocampus. (89)
Elderly persons with genetic mutation which caused decreased levels of IL-1B had improved cognitive function. (90)
Mice treated with intermittent long-term caloric restriction had improved memory. This was associated with mechanism dependent on NR2B subunits of NMDA receptor in hippocampus. (91).
60 year old overweight adults on 30% caloric restriction for 3 months had lower fasting insulin levels and improved memory performance. (92) Caloric restriction and decreased fasting insulin levels would cause lower activity of mTOR.
Looking at these 5 studies in total would suggest that in elderly humans @ 60 years of age, decrease of activity of mTOR with rapamycin would decrease proinflammatory cytokine levels of IL-1B land improve cognitive function through improved NMDA signaling through NR2B receptor.
Elderly humans not infrequently suffer from depression. The Galvan study (88) suggests rapamycin treatment and reduction activity of mTOR might increase monoamine levels in midbrain and decrease depression as noted in older mice.