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Journal: NPJ aging and mechanisms of disease

128

Light is necessary for life, but prolonged exposure to artificial light is a matter of increasing health concern. Humans are exposed to increased amounts of light in the blue spectrum produced by light-emitting diodes (LEDs), which can interfere with normal sleep cycles. The LED technologies are relatively new; therefore, the long-term effects of exposure to blue light across the lifespan are not understood. We investigated the effects of light in the model organism, Drosophila melanogaster, and determined that flies maintained in daily cycles of 12-h blue LED and 12-h darkness had significantly reduced longevity compared with flies maintained in constant darkness or in white light with blue wavelengths blocked. Exposure of adult flies to 12 h of blue light per day accelerated aging phenotypes causing damage to retinal cells, brain neurodegeneration, and impaired locomotion. We report that brain damage and locomotor impairments do not depend on the degeneration in the retina, as these phenotypes were evident under blue light in flies with genetically ablated eyes. Blue light induces expression of stress-responsive genes in old flies but not in young, suggesting that cumulative light exposure acts as a stressor during aging. We also determined that several known blue-light-sensitive proteins are not acting in pathways mediating detrimental light effects. Our study reveals the unexpected effects of blue light on fly brain and establishes Drosophila as a model in which to investigate long-term effects of blue light at the cellular and organismal level.

102

NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD+ in whole blood demonstrated that NRPT significantly increases the concentration of NAD+ in a dose-dependent manner. NAD+ levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD+ levels was sustained throughout the entire 8-week trial. NAD+ levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD+ levels sustainably.

Concepts: Clinical trial, Blood, Effectiveness, Nicotinamide adenine dinucleotide, Clinical research, Placebo, Adenine, Adverse event

62

Mammals receive light information through the eyes, which perform two major functions: image forming vision to see objects and non-image forming adaptation of physiology and behavior to light. Cone and rod photoreceptors form images and send the information via retinal ganglion cells to the brain for image reconstruction. In contrast, nonimage-forming photoresponses vary widely from adjustment of pupil diameter to adaptation of the circadian clock. nonimage-forming responses are mediated by retinal ganglion cells expressing the photopigment melanopsin. Melanopsin-expressing cells constitute 1-2% of retinal ganglion cells in the adult mammalian retina, are intrinsically photosensitive, and integrate photic information from rods and cones to control nonimage-forming adaptation. Action spectra of ipRGCs and of melanopsin photopigment peak around 480 nm blue light. Understanding melanopsin function lets us recognize considerable physiological effects of blue light, which is increasingly important in our modern society that uses light-emitting diode. Misalignment of circadian rhythmicity is observed in numerous conditions, including aging, and is thought to be involved in the development of age-related disorders, such as depression, diabetes, hypertension, obesity, and cancer. The appropriate regulation of circadian rhythmicity by proper lighting is therefore essential. This perspective introduces the potential risks of excessive blue light for human health through circadian rhythm disruption and sleep deprivation. Knowing the positive and negative aspects, this study claims the importance of being exposed to light at optimal times and intensities during the day, based on the concept of the circadian clock, ultimately to improve quality of life to have a healthy and longer life.

Concepts: Sleep, Retina, Eye, Photoreceptor cell, Circadian rhythm, Rod cell, Cone cell, Photosensitive ganglion cell

60

The progressive increase of the aged population worldwide mandates new strategies to ensure sustained health and well-being with age. The development of better and/or new vaccines against pathogens that affect older adults is one pivotal intervention in approaching this goal. However, the functional decline of various physiological systems, including the immune system, requires novel approaches to counteract immunosenescence. Although important progress has been made in understanding the mechanisms underlying the age-related decline of the immune response to infections and vaccinations, knowledge gaps remain, both in the areas of basic and translational research. In particular, it will be important to better understand how environmental factors, such as diet, physical activity, co-morbidities, and pharmacological treatments, delay or contribute to the decline of the capability of the aging immune system to appropriately respond to infectious diseases and vaccination. Recent findings suggest that successful approaches specifically targeted to the older population can be developed, such as the high-dose and adjuvanted vaccines against seasonal influenza, the adjuvanted subunit vaccine against herpes zoster, as well as experimental interventions with immune-potentiators or immunostimulants. Learning from these first successes may pave the way to developing novel and improved vaccines for the older adults and immunocompromised. With an integrated, holistic vaccination strategy, society will offer the opportunity for an improved quality of life to the segment of the population that is going to increase most significantly in numbers and proportion over future decades.

Concepts: Immune system, Infectious disease, Malaria, Vaccine, Vaccination, Infection, Immunology, Immunity

31

Dietary restriction (DR) extends animal lifespan, but imposes fitness costs. This phenomenon depends on dietary essential amino acids (EAAs) and TOR signalling, which exert systemic effects. However, the roles of specific tissues and cell-autonomous transcriptional regulators in diverse aspects of the DR phenotype are unknown. Manipulating relevant transcription factors (TFs) specifically in lifespan-limiting tissues may separate the lifespan benefits of DR from the early-life fitness costs. Here, we systematically analyse transcription across organs of Drosophila subjected to DR or low TOR and predict regulatory TFs. We predict and validate roles for the evolutionarily conserved GATA family of TFs, and identify conservation of this signal in mice. Importantly, restricting knockdown of the GATA TF srp to specific fly tissues recapitulated the benefits but not the costs of DR. Together, our data indicate that the GATA TFs mediate effects of dietary amino acids on lifespan, and that by manipulating them in specific tissues it is possible to reap the fitness benefits of EAAs, decoupled from a cost to longevity.

Concepts: DNA, Protein, Gene, Gene expression, Evolution, Amino acid, RNA, Essential amino acid

26

A long-standing belief is that aging (senescence) is the result of stochastic damage accumulation. Alternatively, senescent pathology may also result from late-life, wild-type gene action (i.e., antagonistic pleiotropy, as argued by Williams) leading to non-adaptive run-on of developmental programs (or quasi-programs) (as suggested more recently by Blagosklonny). In this study, we use existing and new data to show how uterine tumors, a prominent form of senescent pathology in the nematode Caenorhabditis elegans, likely result from quasi-programs. Such tumors develop from unfertilized oocytes which enter the uterus and become hypertrophic and replete with endoreduplicated chromatin masses. Tumor formation begins with ovulation of unfertilized oocytes immediately after exhaustion of sperm stocks. We show that the timing of this transition between program and quasi-program (i.e., the onset of senescence), and the onset of tumor formation, depends upon the timing of sperm depletion. We identify homology between uterine tumors and mammalian ovarian teratomas, which both develop from oocytes that fail to mature after meiosis I. In teratomas, futile activation of developmental programs leads to the formation of differentiated structures within the tumor. We report that older uterine tumors express markers of later embryogenesis, consistent with teratoma-like activation of developmental programs. We also present evidence of coupling of distal gonad atrophy to oocyte hypertrophy. This study shows how the Williams Blagosklonny model can provide a mechanistic explanation of this component of C. elegans aging. It also suggests etiological similarity between teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs.

9

Lipid peroxides are generated by oxidative stress in cells, and contribute to ageing and neurodegenerative disease. The eye is at special risk for lipid peroxidation because photoreceptors possess amplified sensory membranes rich in peroxidation-susceptible polyunsaturated fatty acids. Light-induced lipid peroxidation in the retina contributes to retinal degeneration, and lipid peroxidation has been implicated in the progression of age-associated ocular diseases such as age-related macular degeneration (AMD). Here, we show that exposing Drosophila melanogaster to strong blue light induces oxidative stress including lipid peroxidation that results in retinal degeneration. Surprisingly, very young flies are resilient to this acute light stress, suggesting they possess endogenous neuroprotective mechanisms. While lipophilic antioxidants partially suppressed blue light-induced retinal degeneration in older flies, we find that overexpression of cytochrome b5 (Cyt-b5) completely suppressed both blue light-induced lipid peroxidation and retinal degeneration. Our data identify Cyt-b5 as a neuroprotective factor that targets light-induced oxidative damage, particularly lipid peroxidation. Cyt-b5 may function via supporting antioxidant recycling, thereby providing a strategy to prevent oxidative stress in ageing photoreceptors that would be synergistic with dietary antioxidant supplementation.

Concepts: Nutrition, Fatty acids, Antioxidant, Oxidative stress, Oxidative phosphorylation, Reactive oxygen species, Macular degeneration, Vitamin E

8

Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a target of NDGA and provide mechanistic insight into its role in longevity.

7

There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life- and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extract from the plant Solidago virgaurea subsp. alpestris, which exhibited weak senolytic activity, delayed the acquisition of a senescent phenotype and induced a papillary phenotype with improved functionality in human dermal fibroblasts. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.

Concepts: Gene, Gene expression, Cancer, Natural selection, Signal transduction, Organism, Growth hormone, Skin

6

Statins and/or PCSK9 inhibitors cause the regression of coronary atheroma and reduce clinical events. However, it currently remains unclear whether these drugs modulate coronary atheroma calcification in vivo. Coronary artery calcium (CAC) scores (Agatston Units, AUs) were estimated in 120 patients receiving coronary computed tomographic angiography (CCTA) (63% males; median age 56 years). The CAC scores were compared among the three groups: (1) neither statin nor PCSK9 inhibitor therapy, (2) statin monotherapy, and (3) statin and PCSK9 inhibitor combination therapy in an unpaired cross-sectional study. Additionally, CCTA was performed twice at an interval in 15 patients undergoing statin monotherapy to compare the previous (baseline) and subsequent (follow-up) CAC scores in a paired longitudinal study. In addition, a PCSK9 inhibitor was administered to 16 patients undergoing statin therapy. Before and after that, CCTA was performed twice to compare the previous and subsequent CAC scores in a paired longitudinal study. The unpaired cross-sectional study and paired longitudinal study consist of completely different patients. Among 120 patients, 40 (33%) had a CAC score >100 AUs. The median CAC score increased in the following order: statin group, statin and PCSK9 group, and no-statin-no-PCSK9 group. Annual CAC score progression was 29.7% by statin monotherapy and 14.3% following the addition of the PCSK9 inhibitor to statin therapy. The annual rate of CAC with the combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy. CAC may be prevented with PCSK9 Inhibitor.