If research results continue to be repeated and are turned into clinical trials, the drug Rapamycin already approved for some uses could be marshaled — sooner than we expect — to prevent Alzheimer’s disease in humans and improve health to the end of life.
A few weeks after a report that rapamycin, a drug that extends lifespan in mice and that is currently used in transplant patients, curbed the effects of Alzheimer’s disease in mice, a second group is announcing similar results in an entirely different mouse model of early Alzheimer’s.
Both reports are from The University of Texas Health Science Center at San Antonio, where the rapamycin studies are conducted in the Sam and Ann Barshop Institute for Longevity and Aging Studies and in basic science departments.
The second report, released April 1 by the journal PLoS ONE, published by the Public Library of Science, , showed that administration of rapamycin improved learning and memory in a strain of mice engineered to develop Alzheimer’s. The improvements in learning and memory were detected in a water maze activity test that is designed to measure learning and spatial memory. The improvements in learning and memory correlated with lower damage in brain tissue.
Rapamycin is the first pharmacologic intervention shown to extend life in an animal model of aging.
“The fact that we are seeing identical results in two vastly different mouse models of Alzheimer’s disease,” Dr. Galvan added, in reference to the recent study by Caccamo et al, “provides robust evidence that rapamycin treatment is effective and is acting by changing a basic pathogenic process of Alzheimer’s that is common to both mouse models. This suggests that it may be an effective treatment for Alzheimer’s in humans, who also have very diverse genetic makeup and life histories.”
Target of rapamycin (TOR) signaling stimulates cell growth by regulating protein synthesis in response to a variety of stimuli in a wide range of species and is inhibited by rapamycin, a naturally occurring antifungal compound produced by bacteria and discovered on Easter Island or in the local vernacular, Rapa Nui (rapamycin’s namesake). Recently, rapamycin was shown to extend life span for mice, even when administered late in life, suggesting that inhibiting the mammalian TOR pathway may improve health span for people.
The target of rapamycin (TOR) pathway is key for this regulation thus, it is a good therapeutic target for life-span extension, but administration of TOR inhibitors may impart negative side effects, particularly if they are administered early in life at a time when growth is important for fitness. This notion is in accordance with evolutionary theories of aging which propose growth is essential for early life fitness that enables reproduction but may subsequently lead to age-related decline in health due to diminished selective pressure.
Interestingly, rapamycin extended life span even when chronic administration began in mice as old as 600 days (equivalent to 60 years in people). Thus, rapamycin or other mammalian TOR (mTOR) inhibitors may be efficacious for treating age-related illnesses in people without early or prolonged intervention; rapamycin may also be used as an aging prophylactic, assuming that chronic intervention is not toxic.
Could there be potential adverse side effects? This is a critical question to answer if mTOR inhibitors will be used to treat age-related diseases (especially if they are to be used prophylactically). One concern is that mTOR inhibitors may suppress the immune system. Rapamycin and other mTOR inhibitors have been used to prevent rejection of transplanted organs, since they are powerful immunosuppressants by reducing T-cell proliferation (Tsang et al., 2007). As a result, there is a history of using mTOR inhibitors in humans. At this time, organ transplant patients tolerate rapamycin at the doses given with minimal negative side effects. One of these side effects includes impaired glucose tolerance in kidney transplant patients. mTOR inhibitors may also prove valuable for treating autoimmune disease, since it is important for the survival of monocyte-derived dendritic cells and since rapamycin decreases MHC class II molecules on murine bone marrow-derived dendritic cells. Even though these immunosuppressant activities may have medical advantages, they may also have undesirable outcomes for people without the need to suppress their immune system, thus, limiting wide-spread prophylactic treatment.
These recently published results show that rapamycin-fed mice exhibit an extended life span when compared with control mice. The rapamycin-fed cohort exhibited the same spectrum of age-related diseases as the control cohort; thus, rapamycin seems to have a broad impact on ameliorating the aging process as opposed to resolving specific life-threatening illness endemic to these genetically heterogeneous mice used by the NIA-ITP study. This life-extending property was realized even when rapamycin treatment was initiated late in life. On the basis of these results, rapamycin is a strong candidate for attenuating the aging process, even when first administered to individuals at advanced age. This could be a boon for extending health span. Still major questions must be addressed to understand just how mTOR inhibition ameliorates aging. Since mTOR has many functions, it might be desirable to target downstream proteins with a more specific action. Also it will be important to fully realize negative side effects to determine if rapamycin or other mTOR inhibitors should be administered as an aging prophylactic or as a treatment for specific age-related illnesses.
2. Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC) at the University of Birmingham have discovered that a gene called DAF-16 is strongly involved in determining the rate of ageing and average lifespan of the laboratory worm Caenorhabditis elegans (C. elegans) and its close evolutionary cousins. DAF-16 is found in many other animals, including humans. It is possible that this knowledge could open up new avenues for altering ageing, immunity and resistance to stresses in humans.