Abstract
Age-associated decline in retina function is largely responsible for the irreversible vision deterioration in the elderly population. It is also an important risk factor for the development of degenerative and angiogenic diseases. However, the molecular mechanisms involved in the process of aging in the retina remain largely elusive. This study investigated the role of mTORC1 signaling in aging of the retina. We showed that mTORC1 was activated in old-aged retina, particularly in the ganglion cells. The role of mTORC1 activation was further investigated in Chx10-Cre;Tsc1fx/fx mouse (Tsc1-cKO). Activation of mTORC1 was found in bipolar and some of the ganglion and amacrine cells in the adult Tsc1-cKO retina. Bipolar cell hypertrophy and Müller gliosis were observed in Tsc1-cKO since 6 weeks of age. The abnormal endings of bipolar cell dendritic tips at the outer nuclear layer resembled that of the old-aged mice. Microglial cell activation became evident in 6-week-old Tsc1-cKO. At 5 months, the Tsc1-cKO mice exhibited advanced features of old-aged retina, including the expression of p16Ink4a and p21, expression of SA-β-gal in ganglion cells, decreased photoreceptor cell numbers, decreased electroretinogram responses, increased oxidative stress, microglial cell activation, and increased expression of immune and inflammatory genes. Inhibition of microglial cells by minocycline partially prevented photoreceptor cell loss and restored the electroretinogram responses. Collectively, our study showed that the activation of mTORC1 signaling accelerated aging of the retina by both cell autonomous and nonautonomous mechanisms. Our study also highlighted the role of microglia cells in driving the decline in retina function.
Highlights
Visual functions, including visual acuity, visual field sensitivity, contrast sensitivity, and dark adaptation threshold, deteriorate with age [1]
We found that the bipolar cells of the 24-month-old retina had aberrant dendritic tips ending at outer nuclear layer (ONL) (arrows in Figure 1(d)), which was consistent with previous report [31]
We showed that Mammalian target of rapamycin complex 1 (mTORC1) signaling was upregulated in naturally aged C57BL/6 retina, and the upregulation of mTORC1 signaling in Chx10-expression retinal cells accelerated the aging process and caused retinal degeneration
Summary
Visual functions, including visual acuity, visual field sensitivity, contrast sensitivity, and dark adaptation threshold, deteriorate with age [1]. Using Chx10-cre driven Tsc conditional knockout mice (Tsc1-cKO), Choi et al found that the activation of mTORC1 in Chx10-expressing cells shortened retinal progenitor cell cycle and subsequently accelerated progenitor cell differentiation and retina development [10]. In the OXYS rat, a rat model of accelerated aging due to overproduction of free radicals, rapamycin treatment ameliorated the incidence and severity of retinal degeneration [23] It is not known whether mTORC1 signaling played a direct role in retina aging and neural retinal cell senescence. To further study the effect of mTORC1 activation on retina aging, we used the adult Tsc1-cKO mice and found that the ablation of Tsc in Chx10-expressing cells accelerated retinal aging as evidenced by progressively declined ERG responses, the elevation of oxidative stress level, the activation of microglial cells, the expression of senescence-related proteins, and a gene expression profile with features of aging retina. Our results suggested that microglial cell activation is an important factor which lead to overall functional deterioration in the retina
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