RESUMO
Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.
Assuntos
Envelhecimento Saudável , Hialuronan Sintases , Ácido Hialurônico , Longevidade , Ratos-Toupeira , Animais , Camundongos , Ácido Hialurônico/biossíntese , Ácido Hialurônico/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/prevenção & controle , Camundongos Transgênicos , Ratos-Toupeira/genética , Longevidade/genética , Longevidade/imunologia , Longevidade/fisiologia , Hialuronan Sintases/genética , Hialuronan Sintases/metabolismo , Envelhecimento Saudável/genética , Envelhecimento Saudável/imunologia , Envelhecimento Saudável/fisiologia , Transgenes/genética , Transgenes/fisiologia , Transcriptoma , Neoplasias/genética , Neoplasias/prevenção & controle , Estresse Oxidativo , Gerociência , Rejuvenescimento/fisiologiaRESUMO
Involvement of extracellular matrix (ECM) components in aging and age-related neurodegeneration is not well understood. The role of hyaluronan (HA), a major extracellular matrix glycosaminoglycan, in malignancy and inflammation is gaining new understanding. In particular, the differential biological effects of high molecular weight (HMW-HA) and low molecular weight hyaluronan (LMW-HA), and the mechanism behind such differences are being uncovered. Tightly regulated in the brain, HA can have diverse effects on cellular development, growth and degeneration. In this review, we summarize the homeostasis and signaling of HA in healthy tissue, discuss its distribution and ontogeny in the central nervous system (CNS), summarize evidence for its involvement in age-related neurodegeneration and Alzheimer Disease (AD), and assess the potential of HA as a therapeutic target in the CNS.