Lowering the genetic expression of mTOR gene extends lifespan of mice by 20%

By lowering the expression of a single gene, researchers at the National Institutes of Health have extended the average lifespan of a group of mice by about 20 percent — the equivalent of raising the average human lifespan by 16 years, from 79 to 95. The research team targeted a gene called mTOR, which is involved in metabolism and energy balance, and may be connected with the increased lifespan associated with caloric restriction.

A detailed study of these mice revealed that gene-influenced lifespan extension did not affect every tissue and organ the same way. For example, the mice retained better memory and balance as they aged, but their bones deteriorated more quickly than normal.

Cell Reports – Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression

Highlights
* In mammals, decreased mTOR expression produces a profound increase in lifespan
* Reduced mTOR expression results in lower rates of spontaneous tumor formation
* Age-related benefits of reduced mTOR expression are tissue specific

Summary

We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic (mTORΔ/Δ) alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While mTORΔ/Δ mice are smaller than wild-type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, mTORΔ/Δ mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as mTORΔ/Δ mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.

Results

* Reduced mTOR Expression Increases Survival
* No Alterations in Glucose Homeostasis or Metabolism in the mTORΔ/Δ Mice
* Biomarkers of Aging Are Reduced in the mTORΔ/Δ Mice
* mTORΔ/Δ Mice Have Selective Improvement in Tissue and Organ Aging

The Work

The researchers engineered mice that produce about 25 percent of the normal amount of the mTOR protein, or about the minimum needed for survival. The engineered mTOR mice were a bit smaller than average, but they otherwise appeared normal.

The median lifespan for the mTOR mice was 28.0 months for males and 31.5 months for females, compared to 22.9 months and 26.5 months for normal males and females, respectively. The mTOR mice also had a longer maximal lifespan; seven of the eight longest-lived mice in this study were mTOR mice. This lifespan increase is one of the largest observed in mice so far.

While the genetically modified mTOR mice aged better overall, they showed only selective improvement in specific organs. They generally outperformed normal mice of equivalent age in maze and balance tests, indicating better retention of memory and coordination. Older mTOR mice also retained more muscle strength and posture. However, mTOR mice had a greater loss in bone volume as they aged, and they were more susceptible to infections at old age, suggesting a loss of immune function.

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