Sugar-Sweetened Beverages and Cancer Risk: A Narrative Review.

Cancer continues to be a major public health challenge worldwide, not only for being one of the leading causes of death but also because the number of incident cases is projected to grow in the next decades. Meanwhile, sugar-sweetened beverages (SSB) consumption has risen since the past century and constitutes a considerable fraction of added sugars in daily diet. Several studies have analyzed the relationship between SSB intake and health and found substantial evidence for effects on obesity, type 2 diabetes and metabolic syndrome. However, there is little knowledge about the relationship of SSB with cancer risk. It may be speculated that there is an indirect relationship between SSB and cancer through obesity and metabolic syndrome, but obesity-independent associations through hormonal imbalances or chronic inflammation could also exist. In this review, we describe the epidemiological evidence of the association of SSB and the risk of cancer in adults. Although the epidemiological evidence linking SSB consumption and cancer risk is still limited, prospective studies suggest that high SSB intake may increase the risk of obesity-related cancers, breast and prostate cancer.

Extraction of Lipophilic Antioxidants from Native Tomato Using Green Technologies.

Research background: Tomato (Solanum lycopersicum L.) fruit is highly consumed worldwide and contains high amounts of carotenoids and tocopherols, two powerful antioxidants. Native tomato genotypes are rarely used in large-scale market but serve as a reservoir to diversify the species gene pool and can be employed to obtain functional compounds. Extraction methods are currently changing towards cleaner procedures that are more efficient and environmentally friendly, including avoiding toxic or polluting solvents. Experimental approach: In this study, factorial and fractional factorial designs were used to evaluate the efficiency of digestive enzymes, sonication and green solvents to obtain lipophilic antioxidant extracts from native tomato. To monitor the efficiency of the extraction process, spectrophotometric quantification of total carotenoids and antioxidant activity was carried out, and then individual quantification of carotenoids and tocopherols in the extracts was done by HPLC. Results and conclusions: Digestive enzymes and sonication increased the carotenoid content and the antioxidant activity of the obtained extracts when applied individually. However, when these treatments were applied together and in combination with isopropyl acetate, a green solvent, the obtained extracts had the highest carotenoid and tocopherol contents as well as the maximal antioxidant activity. A correlation analysis suggested that antioxidant activity resulted from synergistic effects rather than individual compounds. Tomato extracts were obtained through a rapid and environmentally friendly extraction method and their antioxidant activity was enhanced. Novelty and scientific contribution: Tomato fruits have been the subject of numerous studies; however, functional compound extraction through environmentally friendly methods remains an attractive use of native tomato fruit, enhancing its limited production and harnessing a large amount of tomato product industry. There are few reports where environmentally friendly extraction methods are combined; even rarer are those where green solvents are also used. In this work, the combination of different environmentally friendly extraction methods improved the extraction of carotenoids and tocopherols and allowed to establish a more efficient process. These results could stimulate the use of clean technologies and make the native tomato more attractive for industrial or compound extraction processes.

Achiote (Bixa orellana) Lipophilic Extract, Bixin, and δ-tocotrienol Effects on Lifespan and Stress Resistance in Caenorhabditis elegans.

The onset of many degenerative diseases related to aging has been associated with a decrease in the activity of antistress systems, and pharmacological interventions increasing stress resistance could be effective to prevent the development of such diseases. Achiote is a valuable source of carotenoid and tocotrienols, which have antioxidant activity. In this work, we explore the capacity of an achiote seed extract and its main compounds to modulate the lifespan and antistress responses on Caenorhabditis elegans, as well as the mechanisms involved in these effects. Achiote lipophilic extract, bixin, and δ-tocotrienol were applied on nematodes to carry out lifespan, stress resistance, and fertility assays. The achiote seed extract increased the median and maximum lifespan up to 35% and 27% and increased resistance against oxidative and thermal stresses without adverse effects on fertility. The beneficial effects were mimicked by a bixin+δ-tocotrienol mixture. All the effects on lifespan and stress resistance were independent of caloric restriction but dependent on the insulin/insulin growth factor-1 pathway. This study could provide insights for further research on a new beneficial use of this important crop in health and nutraceutical applications beyond its use as a source of natural pigments.

Environmentally friendly achiote seed extracts with higher δ-tocotrienol content have higher in vitro and in vivo antioxidant activity than the conventional extract.

Achiote (Bixa orellana) is highly appreciated as a condiment and as the main source of bixin and tocotrienols, both having antioxidant properties. To explore the possibility of maximizing the antioxidant activity of achiote seed extracts using clean methodologies, the use of sonication and green solvents were tested. Ethyl lactate, isopropyl acetate, and ethanol combined with probe sonication produced the best results, obtaining similar bixin contents but higher δ-tocotrienol contents, as well as significantly higher in vitro and in vivo antioxidant activity compared with the maceration method extract, requiring low energy and saving time and solvents. The probe-sonicated achiote extract with the highest δ-tocotrienol content was better at increasing the Caenorhabditis elegans resistance to oxidative stress than the extract obtained through maceration. This is the first report about the effect of sonication combined with green solvents on the bixin and δ-tocotrienol content in achiote seed extracts and its relevance on the in vitro and in vivo antioxidant activity.

Beer and its non-alcoholic compounds in health and disease.

Moderate alcohol consumption has been associated with beneficial effects on human health. Specifically, consumption of red wine and beer has shown a J-shape relation with many important diseases. While a role of ethanol cannot be excluded, the high content of polyphenols in both beverages has been proposed to contribute to these effects, with beer having the advantage over wine that it is lower in alcohol. In addition to ethanol, beer contains a wide variety of compounds with known medicinal potential such as kaempferol, quercetin, tyrosol and phenolic acids, and it is the main dietary source for the flavones xanthohumol and 8-prenylnaringenin, and bitter acids such as humulones and lupulones. Clinical and pre-clinical evidence for the protective effects of moderate beer consumption against cardiovascular disease and other diseases has been accumulating since the 1990s, and the non-alcoholic compounds of beer likely exert most of the observed beneficial effects. In this review, we summarize and discuss the effects of beer consumption in health and disease as well as the clinical potential of its non-alcoholic compounds which may be promising candidates for new therapies against common chronic diseases.

Some naturally occurring compounds that increase longevity and stress resistance in model organisms of aging.

Humans and other organisms show age-related signs of deterioration, which makes aging an interesting process to study. In the present work, we review the anti-aging evidence of several of the most promising natural compounds. Quercetin, rapamycin, resveratrol, spermidine, curcumin or sulforaphane administration increase longevity and stress resistance in model organisms such as yeasts, nematodes, flies and mice. Even more, rapamycin, resveratrol, and curcumin are currently in preclinical tests on the Interventions Testing Program of the National Institute on Aging due to their encouraging results in model organisms. The potential mechanisms underlying the beneficial effects of these compounds are briefly described.

Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan.

Genetic studies indicate that protein homeostasis is a major contributor to metazoan longevity. Collapse of protein homeostasis results in protein misfolding cascades and the accumulation of insoluble protein fibrils and aggregates, such as amyloids. A group of small molecules, traditionally used in histopathology to stain amyloid in tissues, bind protein fibrils and slow aggregation in vitro and in cell culture. We proposed that treating animals with such compounds would promote protein homeostasis in vivo and increase longevity. Here we show that exposure of adult Caenorhabditis elegans to the amyloid-binding dye Thioflavin T (ThT) resulted in a profoundly extended lifespan and slowed ageing. ThT also suppressed pathological features of mutant metastable proteins and human ß-amyloid-associated toxicity. These beneficial effects of ThT depend on the protein homeostasis network regulator heat shock factor 1 (HSF-1), the stress resistance and longevity transcription factor SKN-1, molecular chaperones, autophagy and proteosomal functions. Our results demonstrate that pharmacological maintenance of the protein homeostatic network has a profound impact on ageing rates, prompting the development of novel therapeutic interventions against ageing and age-related diseases.

Stem Cell Models: A Guide to Understand and Mitigate Aging?

Aging is studied either on a systemic level using life span and health span of animal models, or on the cellular level using replicative life span of yeast or mammalian cells. While useful in identifying general and conserved pathways of aging, both approaches provide only limited information about cell-type specific causes and mechanisms of aging. Stem cells are the regenerative units of multicellular life, and stem cell aging might be a major cause for organismal aging. Using the examples of hematopoietic stem cell aging and human pluripotent stem cell models, we propose that stem cell models of aging are valuable for studying tissue-specific causes and mechanisms of aging and can provide unique insights into the mammalian aging process that may be inaccessible in simple model organisms.

Vanillic Acid Improves Stress Resistance and Substantially Extends Life Span in Caenorhabditis elegans.

Aging is the root cause of several pathologies like neurological and cardiovascular diseases. Identifying compounds that improve health span and extend life span, called geroprotectors, could be crucial to preventing or at least delaying the onset of age-related diseases. In this regard, the nematode Caenorhabditis elegans (C. elegans) is emerging as an easy, efficient, low-cost model system to screen natural products and identify novel geroprotectors. Phenolic acids can be found in a wide range of natural products that are part of the human diet. Vanillic acid (VA) is a phenolic acid that has previously been attributed with antioxidant, anti-inflammatory, and neuroprotective features. To determine whether these beneficial health effects amount to an extension of health span and life span, in this work, we thoroughly explore the effect of VA on C. elegans stress resistance and life span. We found that VA increases thermotolerance (19.4%), reduces protein aggregation (between 30% and 40%), improves motility, and extends life span by almost 50%, an extent hardly ever achieved with a natural compound. The increased thermotolerance induced by VA is independent of the insulin/insulin-like growth factor-1 signaling pathway but requires heat shock factor-1 and is associated with increased heat shock protein-4 (HSP-4) and hsp-16.2 expression. These results provide new insight into understanding the therapeutical properties of VA and warrant further investigation of VA as a novel geroprotector.

Longitudinal Functional Study of Murine Aging: A Resource for Future Study Designs.

Aging is characterized by systemic declines in tissue and organ functions. Interventions that slow these declines represent promising therapeutics to protect against age-related disease and improve the quality of life. In this study, several interventions associated with lifespan extension in invertebrates or improvement of age-related disease were tested in mouse models to determine if they were effective in slowing tissue aging in a broad spectrum of functional assays. Benzoxazole, which extends the lifespan of Caenorhabditis elegans, slowed age-related femoral bone loss in mice. Rates of change were established for clinically significant parameters in untreated mice, including kyphosis, blood glucose, body composition, activity, metabolic measures, and detailed parameters of skeletal aging in bone. These findings have implications for the study of preclinical physiological aging and therapies targeting aging. Finally, an online application was created that includes the calculated rates of change and that enables power and variance to be calculated for many clinically important metrics of aging with an emphasis on bone. This resource will help in future study designs employing novel interventions in aging mice. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Factors associated with healthy aging in septuagenarian and nonagenarian Mexican adults.

OBJECTIVE: To examine the factors associated with healthy aging in a cohort of Mexican adults after a follow-up of 14 years. STUDY DESIGN: Participants were part of a prospective cohort of the Mexican Healthy Aging Study (MHAS), from which we included 5142 individuals aged 63 years or more. MAIN OUTCOME: Healthy aging, defined as reaching age 77 or 90 without major chronic conditions or physical limitations. MEASURES: Information on age, education, marital status, smoking, alcohol consumption, physical activity, self-perceived depression, health conditions and history of age-related diseases was collected at baseline and follow-up. RESULTS: Among the overall cohort, 57.8% experienced healthy survival to age 77 and 42.2% had died before age 77 or were undergoing normal aging. Participants with long-lived parents and who exercised had a lower risk of being non-healthy agers. Being overweight, obese or a smoker increased the risk of being a non-healthy ager. Physically active participants had increased odds of healthy aging at age 77 (OR: 1.17; 95% CI: 1.01-1.46) and at age 90 (OR: 1.5; 95% CI: 1.01-2.24). Depression had a negative relationship with healthy aging at age 90 (OR: 0.66; 95% CI: 0.45- 0.97). Maternal longevity was associated with healthy aging only at age 77 (OR = 1.34; 95% CI: 1.04-1.72). CONCLUSIONS: Our findings support the view that a combination of genetic and behavioral factors is associated with healthy aging. In accordance with findings in Caucasian populations, our data suggest for the first time that there might also be a genetic determinant for healthy ageing in Latin Americans.

BCL-2 and BAX proteins expression throughout the light-dark cycle and modifications induced by sleep deprivation and rebound in adult rat brain.

It has been suggested that sleep has a restorative function; however, experimental support is limited. Hence, we investigated whether changes in the level of antiapoptotic BCL-2 protein and proapoptotic BAX protein occur during sleep deprivation (SD) and sleep rebound, and evaluated the spontaneous changes in these proteins, along the light-dark cycle, in the adult male Wistar rat. Estimations were made in the prefrontal cortex, hippocampus, striatum, and pons. We observed that BCL-2 exhibited diurnal variations in the prefrontal cortex and striatum, whereas BAX varied in the striatum and showed only small variations in the pons as measured by immunoblotting. The BCL-2/BAX ratio exhibited diurnal variations in the prefrontal cortex and striatum. BCL-2 and BAX levels were affected by 24 hr of total SD and 24 hr of sleep rebound. SD decreased the BCL-2/BAX ratio in the prefrontal cortex and pons. Sleep rebound increased the BCL-2/BAX ratio in the hippocampus. In conclusion, the BCL-2/BAX ratio is high during the dark phase as compared with the light phase in the prefrontal cortex and during the light phase as compared with the dark phase in the striatum. SD decreased the BCL-2/BAX ratio in the prefrontal cortex and pons, whereas sleep rebound increased it in the hippocampus. These changes point out structures in the brain that express these proteins as a response to the light-dark cycle. Similarly, SD and sleep rebound seem to change these proteins expression in some other brain structures, suggesting that cellular vulnerability might be altered by these changes.

Acarbose improves health and lifespan in aging HET3 mice.

To follow-up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log-rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%-11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2-(2-hydroxyphenyl) benzothiazole (HBX), and INT-767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose-control drugs in humans.

Effect of NMDA antagonists on the death of cerebellar granule neurons at different ages.

Cerebellar granule neurons (CGN) are the most abundant neuronal type in the cerebellum. During development, these cells migrate from the external to the internal granule layer (IGL), where they receive excitatory glutamatergic and cholinergic contacts from mossy fibers. During this period of development a large proportion of CGN are eliminated via apoptosis. In vitro studies have demonstrated that when CGN are obtained from rats at postnatal day 8 (P8), the sustained activation of N-methyl-D-aspartate (NMDA) receptor at 2-4 days in vitro rescues neurons from cell death. The NMDA action on cultured CGN could mimic the in vivo actions of the transient activation of the glutamate receptors by the transmitter released by mossy fibers by P12. However, some results suggest that glutamate stimulation could be relevant for CGN at earlier stages of development. In this study we evaluated the effect of NMDA receptor stimulation or blockade on the cell death of both in vivo and cultured CGN obtained from P2 to P8 rats. Our results showed that the blockade of NMDA receptors with the antagonists D,L-2-amino-5-phosphonovaleric acid or dizocilpine (MK-801) reduces cell survival to 20-40%, whereas NMDA treatment increases neuronal survival by approximately 50-60%. In vivo, the treatment with MK-801 reduced the number of apoptotic CGN in the molecular layer (ML) from P5 to P8. These results suggest that NMDA receptor stimulation plays a critical role in the regulation of CGN death during the first week of rat cerebellar development.

Effect of N-methyl-D-aspartate receptor blockade on caspase activation and neuronal death in the developing rat cerebellum.

In vitro studies have demonstrated that N-methyl-D-aspartate (NMDA) receptor activation rescue cerebellar granule neurons (CGN) from apoptotic death. It has been suggested that this effect mimics the transient glutamate receptors activation by mossy fibers during cerebellar development. We reported previously that CGN from postnatal days 2-4 (P2-P4) rats increased cell survival in response to NMDA treatment. In this study, we evaluated the effect of dizocilpine (MK-801) administrated for three consecutive days on the apoptotic death of CGN during development. MK-801 treatment decreased the large number of CGN condensed nuclei found at P8, but this drug increased the proportion of condensed nuclei at P16. We also found a high activity of caspases during the first postnatal week that decreased during development. MK-801 treatment did not modify the activity of caspase-8 at any age, but decreased caspase-9 activity at P8 and increased the activity of caspase-1 (76%) at P8, caspase-3 (160%) at P16 and caspase-9 (50%) at P12. These results suggest that NMDA receptor stimulation regulates the activity of caspases in a differential way and plays an important role in the in vivo CGN death during postnatal development.

Curcumin and insulin resistance-Molecular targets and clinical evidences.

Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), the main component of the Indian spice turmeric, has been used in traditional medicine to improve diabetes and its comorbidities. Since the last two decades, scientific research has shown that in addition to its antioxidant properties, curcumin could also work as protein homeostasis regulator and it is able to modulate other intracellular pathways. Curcumin supplementation has been proposed to improve insulin resistance (IR) through the activation of the insulin receptor and its downstream pathways in several experimental models, pointing out that its clinical use may be a good and innocuous strategy to improve IR-related diseases. IR is associated with many diseases and syndromes like carbohydrate intolerance, diabetes, metabolic syndrome, and cardiovascular disease. Therefore, it is imperative to identify safe therapeutic interventions aimed to reduce side effects that could lead the patient to leave the treatment. To date, many clinical trials have been carried out using turmeric and curcumin to improve metabolic syndrome, carbohydrate intolerance, diabetes, and obesity in individuals with IR. Results so far are inconclusive because dose, time of treatment, and type of curcumin can change the study outcome significantly. However, there is some clinical evidence suggesting a beneficial effect of curcumin on IR. In this review, we discuss the factors that could influence curcumin effects in clinical trials aimed to improve IR and related diseases, and the conclusions that can be drawn from results obtained so far. © 2016 BioFactors, 42(6):561-580, 2016.

Prolonged waking reduces human immunodeficiency virus glycoprotein 120- or tumor necrosis factor alpha-induced apoptosis in the cerebral cortex of rats.

The human immunodeficiency virus (HIV) induces neuronal death, presumably by apoptosis. This effect may be triggered by the glycoprotein 120 (HIVgp120) released by HIV when infecting a cell, and mediated by tumor necrosis factor alpha (TNFalpha), a pro-inflammatory cytokine. Both molecules, HIVgp120 and TNFalpha, increase sleep when administered acutely in the brain. On the other hand, sleep deprivation increases the levels of several growth factors. In this context, we challenged rats with HIVgp120 or TNFalpha simultaneously with sleep deprivation. Our results indicate that both HIVgp120 and TNFalpha increase neuronal death in the rat cerebral cortex, but not hippocampus, and that this effect is completely prevented by total deprivation of sleep. These results suggest that acute total deprivation of sleep protects against the HIVgp120 and TNFalpha deleterious effects.

Myosin Va is proteolysed in rat cerebellar granule neurons after excitotoxic injury.

Cerebellar granule neurons when exposed to glutamate die through an excitotoxic mechanism induced by overactivation of glutamate receptors. This kind of cell death is mediated by an overload of intracellular calcium involving calpain activation, a Ca2+ -dependent intracellular cysteine protease, among other intracellular responses. On the other hand, class V myosins are proteins that move cargo along actin filaments and one of its members, myosin Va, is involved in vesicles transport. Here we studied the effect of excitotoxicity on myosin Va in cultured cerebellar granule neurons. Western blot analysis of control cultures shows a band corresponding to myosin Va as well as an 80 kDa band corresponding to its proteolytic product by calpain. When cells are exposed to glutamate (500 microM), kainate (100 microM) or NMDA (150 microM) during 3-24 h, the proteolytic processing of myosin Va is markedly increased. This proteolysis is inhibited by leupeptin (100 microM) and calpain inhibitor I (50 microM). These inhibitors also significantly improve the morphological appearance of the neurons possibly through the preservation of the cytoskeleton integrity. Our results suggest that myosin Va is a target for calpain I during an excitotoxic injury and could lead to a new area of research to address the participation of molecular motors in neurotoxicity.

Pharmacological lifespan extension of invertebrates.

There is considerable interest in identifying small, drug-like compounds that slow aging in multiple species, particularly in mammals. Such compounds may prove to be useful in treating and retarding age-related disease in humans. Just as invertebrate models have been essential in helping us understand the genetic pathways that control aging, these model organisms are also proving valuable in discovering chemical compounds that influence longevity. The nematode Caenorhabditis elegans has numerous advantages for such studies including its short lifespan and has been exploited by a number of investigators to find compounds that impact aging. Here, we summarize the progress being made in identifying compounds that extend the lifespan of invertebrates, and introduce the challenges we face in translating this research into human therapies.