Rapamycin treatment attenuates age-associated periodontitis in mice

Abstract

Interventions that target biological mechanisms of aging have great potential to enhance quality of life by delaying morbidity and mortality. The FDA-approved drug rapamycin is a compelling candidate for such an intervention. In a previous study, it was reported that 3 months of rapamycin treatment is sufficient to increase life expectancy and remodel the gut microbiome in aged mice. Transient treatment with rapamycin or a rapamycin derivative has also been shown to delay immune stem cell senescence and rejuvenate immune function in aged mice and elderly people. Periodontal disease is an important age-related disease involving altered immune function, pathological changes to the oral microbiome, and systemic inflammation. Periodontal disease is defined clinically by loss of alveolar bone and by connective tissue degeneration. Here, we describe significant alveolar bone loss during aging in two different mouse strain backgrounds and report that rapamycin treatment is sufficient to reverse age-associated periodontal disease in mice. Partial restoration of youthful levels of alveolar bone is observed in 22-month-old rapamycin-treated mice as rapidly as 8 weeks after initiation of treatment. To the best of our knowledge, this represents the first intervention shown to substantially prevent or reverse age-associated alveolar bone loss. These findings suggest the possibility that inhibition of mTOR with rapamycin or other pharmacological agents may be useful to treat a clinically relevant condition for which there is currently no effective treatment.

Keywords: Aging; Dental health; Gum disease; Healthspan; Immune function; Inflammation; Mice; Microbiome; Oral health; Rapamycin; Teeth; mTOR.

Fig. 1

Aging is associated with alveolar bone loss in female C57BL6/JNia mice. Representative a, b palatal and c, d buccal aspect microCT scans of alveolar bone in young (2–3 month) and old (24 month) mice. Yellow lines represent distance between the cementoenamel junction (CEJ) to the alveolar bone crest (ABC) as landmarked by an observer who was blinded to the identity of each animal. The larger distance in panel d compared to panel c is indicative of alveolar bone loss in the aged animal compared to the young animal

Fig. 2

A single 8 week treatment with rapamycin attenuates alveolar bone loss in aged C57BL/6JNia mice. Female 22-month-old C57BL/6JNia mice were treated with either a control diet or 14 ppm encapsulated rapamycin diet for 8 weeks. MicroCT image analysis indicated less alveolar bone loss in the rapamycin-treated mice at the end of the treatment period compared to control animals. Representative images of a control and b rapamycin-treated mice after 8 weeks. c Measured periodontal bone levels in 2–3 month young (n = 3), 9–10 month adult (n = 4), 24-month-old control (n = 7) animals, and 24-month-old animals that had received rapamycin for 8 weeks (n = 6). Boxplot shows median, 25th, and 75th percentile, with the whiskers at the 10th and 90th percentile. Total distance was measured from CEJ-ABC buccal and palatal aspect for all mice. Rapamycin-treated animals had significantly greater alveolar bone levels compared to age-matched controls (p < 0.005)

Fig. 3

Lifelong treatment with rapamycin preserves alveolar bone levels in UM-HET3 mice. a Representative buccal aspect scans from 35 to 37-month female UM-HET3 mice treated either drug-free control chow (n = 5) or 42 ppm encapsulated rapamycin (n = 6) beginning at 9 months of age. Visual inspection indicates preservation of alveolar bone levels in rapamycin-treated mice compared to vehicle controls. b Representative palatal aspect scans. c Boxplot showing total distance measured from CEJ-ABC for the buccal aspect only. Rapamycin-treated animals had significantly greater alveolar bone levels compared to controls (p < 0.005)