Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice
- University of Washington, United States
- Fred Hutchinson Cancer Research Center, United States
- University of Missouri, United States
Figures
Figure 1 with 4 supplements
Rapamycin injection at 8 mg/kg/day for 3 months extends life expectancy of male mice.
(A) Body weight of male mice measured weekly after starting rapamycin and vehicle treatment. Data are indicated as mean ± s.e.m. *p<0.05. **p<0.01. (B) Survival of control and rapamycin-treated male …
Figure 1—figure supplement 1
Rapamycin serum level does not differ between female and male mice.
Blood levels of rapamycin in mice 24 hr after finishing daily i.p. injections for 3 months. p=0.359. Females, N = 16. Males, N = 16. Data are indicated as mean ± s.e.m.
Figure 1—figure supplement 2
Food intake of male mice receiving 8 mg/kg/day i.p. rapamycin or vehicle injections.
Food intake measured weekly by weighing the food given to each cage and the food remaining on the wire rack in each cage.
Figure 1—figure supplement 3
Survival plots of male mice treated with 8 mg/kg/day i.p. rapamycin for 90 days starting around 600 days of age.
Gray box approximately indicates treatment period. Note: although the curves start at age=0 to represent all of life, we have no data on animals that may have died in this cohort prior to receipt …
Figure 1—figure supplement 4
Inclusion of non-age-related deaths does not alter survival outcomes.
Lifespan curve of male mice injected with either vehicle or 8 mg/kg/day rapamycin including deaths during the treatment period from non-age-related causes. N=20 vehicle injected, N=20 rapamycin.
Figure 2 with 2 supplements
Rapamycin injection at 8 mg/kg/day for 3 months does not increase life expectancy of female mice.
(A) Body weight of female mice measured weekly after starting rapamycin and vehicle treatment. Data are indicated as mean ± s.e.m. *p<0.05, **p<0.01 (B) Survival of control and rapamycin-treated …
Figure 2—figure supplement 1
Survival plots of female mice treated with 8 mg/kg/day i.p. rapamycin for 90 days starting around 600 days of age.
Note: although the curves start at age=0 to represent all of life, we have no data on animals that may have died in this cohort prior to receipt from NIA (dashed lines). Gray box approximately …
Figure 2—figure supplement 2
Food intake of female mice receiving 8 mg/kg/day i.p. rapamycin or vehicle injections.
Food intake measured weekly by weighing the food given to each cage and the food remaining on the wire rack in each cage.
Figure 3 with 2 supplements
Rapamycin injection at 8 mg/kg/day for 3 months alters cancer incidence of female mice.
(A) Hematoxylin and eosin (H&E) sections of multisystemic aggressive lymphoma (top) and atypical plasmacytoid lymphoma (bottom) from rapamycin-treated female mice. Arrows indicate a bizarre mitotic …
Figure 3—figure supplement 1
Morphologies of aggressive hematopoietic tumors observed in rapamycin injected females.
H&E sections of 3 representative hematopoietic tumor types observed in rapamycin treated female mice. Lower magnification (A, C, E. Original magnification 4x) represents an uncommon site of invasion …
Figure 3—figure supplement 2
Cancer incidence of male mice with rapamycin injection at 8 mg/kg/day for 3 months.
(A) Hematopoietic cancer incidence of rapamycin-treated (15 male) and vehicle-treated (14 male) mice. (B) Incidence of multiple organ invasion of hematopoietic tumors in rapamycin-treated (9 male) …
Figure 4 with 3 supplements
Rapamycin feeding at 126 ppm for 3 months extends life expectancy.
(A, C, E) Body weight of (A) sex-pooled, (C) male, and (E) female mice measured weekly after starting rapamycin and eudragit treatment. *p<0.05. Survival of (B) sex-pooled control and …
Figure 4—figure supplement 1
Food intake of mice receiving 126 ppm eRapa or eudragit control.
Food intake measured weekly by weighing the food given to each cage and the food remaining on the wire rack in each cage after 5–7 days.
Figure 4—figure supplement 2
Effects of 126 ppm eRapa treatment on lifespan in male and female mice.
(A) Survival plots of sex-pooled mice treated with 126 ppm eudragit or eRapa for 90 days starting around 600 days of age. Note: although the curves start at age=0 to represent all of life, we have …
Figure 4—figure supplement 3
Inclusion of non-age-related deaths does not alter survival outcomes.
(A, B). Survival plots of (A) male and (B) sex-pooled mice fed 126 ppm eudragit or eRapa for 90 days including deaths during the treatment period from non-age-related causes.(A) N=38 vehicle …
Figure 5 with 1 supplement
Rapamycin decreases fecal pellet size.
(A) Photograph of feces collected from rapamycin-injected and vehicle-injected animals at 3 months of the treatment. (B) Photograph of feces collected from rapamycin-fed and eudragit-fed animals at …
Figure 5—figure supplement 1
Rapamycin decreases fecal pellet size persistently after cessation of treatment.
(A) Weight of freshly excreted fecal pellets collected from rapamycin-injected and vehicle-injected male animals at 3 months of the treatment. N = 13 Vehicle, N = 19 Rapamycin. (B) Weight of fecal …
Figure 6 with 3 supplements
Rapamycin changes the composition of gut microbiota and increases segmented filamentous bacteria.
(A) Violin plots representing the Log2 16S rRNA gene abundance for operation taxonomy units (OTUs) in fecal samples that are significantly differentially prevalent at a false discovery rate of 0.05 …
Figure 6—figure supplement 1
Effect of rapamycin on the fecal microbiome.
(A) Heatmap of the Log2 16S rRNA gene abundance by mouse (column) and operation taxonomy units (OTU)s (row). The clustering is done on a subset of the OTUs with total abundance of more than 10 and …
Figure 6—figure supplement 2
Bacterial DNA in fecal samples significantly different between control and rapamycin.
(A). Prevalence distribution of operation taxonomy units (OTUs) (Log2 of 16 rRNA gene abundance) in fecal samples that have p-values less than 0.05 using the R package metagenomeSeq, contrasting …
Figure 6—figure supplement 3
Bacterial composition in fecal samples at phylum level.
(A) Stacked bar plot showing the proportion of phylum within each fecal sample. b1-5 indicate mouse batches that were shipped at a different time. F and M indicate female and male, respectively. …
Tables
Table 1
Sex-segregated comparison of median and mean post-treatment life expectancy for mice receiving rapamycin by injection (8 mg/kg/day) or feeding (128 ppm). M: males, F: females.
| Median life expectancy (days) | Percent life expectancy increase | Mean life expectancy (days) | Percent life expectancy increase | |
|---|---|---|---|---|
| Vehicle M | 231 | 235 | ||
| Rapamycin (8mg/kg/day) M | 372 | 61 | 358 | 53 |
| Vehicle F | 161 | 177 | ||
| Rapamycin (8mg/kg/day) F | 161 | 0 | 171 | -3 |
| Eudragit M | 193 | 199 | ||
| Rapamycin (126 ppm) M | 279 | 44.6 | 242 | 21 |
| Eudragit F | 184 | 175 | ||
| Rapamycin (126 ppm) F | 256 | 39 | 240 | 37 |
Table 2
Sex-segregated comparison of median and mean lifespan for mice receiving rapamycin by injection (8 mg/kg/day) or feeding (128 ppm). M: males, F: females.
| Median lifespan (days) | Percent median lifespan increase | Mean lifespan (days) | Percent mean lifespan increase | |
|---|---|---|---|---|
| Vehicle M | 925 | 929 | ||
| Rapamycin (8mg/kg/day) M | 1054 | 14 | 1050 | 13 |
| Vehicle F | 847 | 858 | ||
| Rapamycin (8mg/kg/day) F | 847 | 0 | 853 | -1 |
| Eudragit M | 914 | 912 | ||
| Rapamycin (126 ppm) M | 1037 | 14 | 984 | 8 |
| Eudragit F | 879 | 883 | ||
| Rapamycin (126 ppm) F | 960 | 9 | 951 | 8 |
Table 3
Sex-pooled comparison of median and mean post-treatment life expectancy for mice receiving rapamycin by injection (8 mg/kg/day) or feeding (128 ppm).
| Median life expectancy (days) | Percent life expectancy increase | Mean Life expectancy (days) | Percent life expectancy increase | |
|---|---|---|---|---|
| Vehicle | 188 | 204 | ||
| Rapamycin (8mg/kg/day) | 231 | 22 | 257 | 26 |
| Eudragit | 190 | 188 | ||
| Rapamycin (126 ppm) | 270 | 42 | 257 | 37 |
Table 4
Sex-pooled comparison of median and mean lifespan for mice receiving rapamycin by injection (8 mg/kg/day) or feeding (128 ppm).
| Median lifespan (days) | Percent median lifespan increase | Mean lifespan (days) | Percent mean lifespan increase | |
|---|---|---|---|---|
| Vehicle | 874 | 892 | ||
| Rapamycin (8mg/kg/day) | 922 | 5 | 944 | 5 |
| Eudragit | 885 | 899 | ||
| Rapamycin (126 ppm) | 996 | 13 | 968 | 8 |
