Over a third of older adults in the U.S. experience significant vision loss, which decreases independence and is a biomarker of decreased health span. As the global aging population is expanding, it is imperative to uncover strategies to increase health span and reduce the economic burden of this age-related disease. While there are some treatments available for age-related vision loss, such as surgical removal of cataracts, many causes of vision loss, such as dry age-related macular degeneration (AMD), remain poorly understood and no treatments are currently available. Therefore, it is necessary to better understand the factors that contribute to disease progression for age-related vision loss and to uncover methods for disease prevention. One such factor is the effect of diet on ocular diseases. There are many reviews regarding micronutrients and their effect on eye health. Here, we discuss the impact of dietary patterns on the incidence and progression of age-related eye diseases, namely AMD, cataracts, diabetic retinopathy, and glaucoma. Then, we focus on the specific role of dietary carbohydrates, first by outlining the physiological effects of carbohydrates on the body and then how these changes translate into eye and age-related ocular diseases. Finally, we discuss future directions of nutrition research as it relates to aging and vision loss, with a discussion of caloric restriction, intermittent fasting, drug interventions, and emerging randomized clinical trials. This is a rich field with the capacity to improve life quality for millions of people so they may live with clear vision for longer and avoid the high cost of vision-saving surgeries.

The glyoxalase system is critical for the detoxification of advanced glycation end-products (AGEs). AGEs are toxic compounds resulting from the non-enzymatic modification of biomolecules by sugars or their metabolites through a process called glycation. AGEs have adverse effects on many tissues, playing a pathogenic role in the progression of molecular and cellular aging. Due to the age-related decline in different anti-AGE mechanisms, including detoxifying mechanisms and proteolytic capacities, glycated biomolecules are accumulated during normal aging in our body in a tissue-dependent manner. Viewed in this way, anti-AGE detoxifying systems are proposed as therapeutic targets to fight pathological dysfunction associated with AGE accumulation and cytotoxicity. Here, we summarize the current state of knowledge related to the protective mechanisms against glycative stress, with a special emphasis on the glyoxalase system as the primary mechanism for detoxifying the reactive intermediates of glycation. This review focuses on glyoxalase 1 (GLO1), the first enzyme of the glyoxalase system, and the rate-limiting enzyme of this catalytic process. Although GLO1 is ubiquitously expressed, protein levels and activities are regulated in a tissue-dependent manner. We provide a comparative analysis of GLO1 protein in different tissues. Our findings indicate a role for the glyoxalase system in homeostasis in the eye retina, a highly oxygenated tissue with rapid protein turnover. We also describe modulation of the glyoxalase system as a therapeutic target to delay the development of age-related diseases and summarize the literature that describes the current knowledge about nutritional compounds with properties to modulate the glyoxalase system.

Age is the biggest risk factor for cataracts, and aberrant oxidative modifications are correlated with age-related cataracts, suggesting that proper redox regulation is important for lens clarity. The lens has very high levels of antioxidants, including ascorbate and glutathione that aid in keeping the lens clear, at least in young animals and humans. We summarize current functional and genetic data supporting the hypothesis that impaired regulation of oxidative stress leads to redox dysregulation and cataract. We will focus on the essential endogenous antioxidant glutathione and the exogenous antioxidant vitamin C/ascorbate. Additionally, gene expression in response to oxidative stress is regulated in part by the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2 [NFE2L2]), thus we will summarize our data regarding cataracts in Nrf2-/- mice. In this work, we discuss the function and integration of these capacities with the objective of maintaining lens clarity.

Ubiquitinylation drives many cellular processes by targeting proteins for proteasomal degradation. Ubiquitin conjugation enzymes promote ubiquitinylation and, thus, degradation of protein substrates. Ubiquitinylation is a well‐known posttranslational modification controlling cell‐cycle transitions and levels or/and activation levels of ubiquitin‐conjugating enzymes change during development and cell cycle. Progression through the cell cycle is tightly controlled by CDK inhibitors such as p27 ^Kip1 . Here we show that, in contrast to promoting its degradation, the ubiquitin‐conjugating enzyme UBCH7/UBE2L3 specifically protects p27 ^Kip1 from degradation. Overexpression of UBCH7/UBE2L3 stabilizes p27 ^Kip1 and delays the G ₁ ‐to‐S transition, while depletion of UBCH7/UBE2L3 increases turnover of p27 ^Kip1 . Levels of p21 ^Cip1/Waf1 , p57 ^Kip2 , cyclin A and cyclin E, all of which are also involved in regulating the G ₁ /S transition are not affected by UBCH7/UBE2L3 depletion. The effect of UBCH7/UBE2L3 on p27 ^Kip1 is not due to alteration of the levels of any of the ubiquitin ligases known to ubiquitinylate p27 ^Kip1 . Rather, UBCH7/UBE2L3 catalyzes the conjugation of heterotypic ubiquitin chains on p27 ^Kip1 that are proteolytically incompetent. These data reveal new controls and concepts about the ubiquitin proteasome system in which a ubiquitin‐conjugating enzyme selectively inhibits and may even protect, rather than promote degradation of a crucial cell‐cycle regulatory molecule.—Whitcomb, E. A., Tsai, Y. C., Basappa, J., Liu, K., le Feuvre, A. K., Weissman, A.M., Taylor, A. Stabilization of p27Kip1/CDKN1B by UBCH7/UBE2L3 catalyzed ubiquitinylation: a new paradigm in cell‐cycle control. FASEB J. 33, 1235–1247 (2019). www.fasebj.org

Events within and transitions between the phases of the eukaryotic cell cycle are tightly controlled by transcriptional and post-translational processes. Prominent among them is a profound role for the ubiquitin proteasome proteolytic pathway. The timely degradation of proteins balances the increases in gene products dictated by changes in transcription. Of the dozens of ubiquitin conjugating enzymes, or E2s, functions in control of the cell cycle have been defined for only UbcH10 and Ubc3/Cdc34. Each of these E2s works primarily with one ubiquitin ligase or E3. Here we show that another E2, UbcH7 is a regulator of S phase of the cell cycle. Over-expression of UbcH7 delays entry into S phase whereas depletion of UbcH7 increases the length of S phase and decreases cell proliferation. Additionally, the level of the checkpoint kinase Chk1 increases upon UbcH7 depletion while the level of phosphorylated PTEN decreases. Taken together, these data indicate that the length of S phase is controlled in part by UbcH7 through a PTEN/Akt/Chk1 pathway. Potential mechanisms by which UbcH7 controls Chk1 levels both directly and indirectly, as well as the length of S phase are discussed and additional functions for UbcH7 are reviewed.

Purpose: During lens fiber cell differentiation, organelles are removed in an ordered manner to ensure lens clarity. A critical step in this process is removal of the cell nucleus, but the mechanisms by which this occurs are unclear. In this study, we investigate the role of a cyclin-dependent kinase 1 (CDK1) regulatory loop in controlling lens fiber cell denucleation (LFCD). Methods: We examined lens differentiation histologically in two different vertebrate models. An embryonic chick lens culture system was used to test the role of CDK1, cell division cycle 25 (CDC25), WEE1, and PP2A in LFCD. Additionally, we used three mouse models that express high levels of the CDK inhibitor p27 to test whether increased p27 levels affect LFCD. Results: Using chick lens organ cultures, small-molecule inhibitors of CDK1 and CDC25 inhibit LFCD, while inhibiting the CDK1 inhibitory kinase WEE1 potentiates LFCD. Additionally, treatment with an inhibitor of PP2A, which indirectly inhibits CDK1 activity, also increased LFCD. Three different mouse models that express increased levels of p27 through different mechanisms show impaired LFCD. Conclusions: Here we define a conserved nonmitotic role for CDK1 and its upstream regulators in controlling LFCD. We find that CDK1 functionally interacts with WEE1, a nuclear kinase that inhibits CDK1 activity, and CDC25 activating phosphatases in cells where CDK1 activity must be exquisitely regulated to allow for LFCD. We also provide genetic evidence in multiple in vivo models that p27, a CDK1 inhibitor, inhibits lens growth and LFCD.