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  • Writer's pictureChris Toepker

12 Tools Quick Reference Library

Updated: Mar 29

In our vLogs, we have mentioned much of the research we've found along the way. Here they are, all in on handy place, covering...

  • Exercise, diet & aging

  • Dangers of alcohol use

  • Circadian rhythms

  • A few doctors, since we aren't (that is: medical-grade professionals we appreciate)

The majority are high-quality scientific studies. We've added a few popular-press articles and books at the end, for a fuller and easier-to-read side. Enjoy!

Exercise, diet & aging

  • Exercise reduces circulating biomarkers of cellular senescence in humans, Davis A. Englund, Ayumi E. Sakamoto

  • Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16,p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.

  • Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging, Benoit Lehallier, Maxim N. Shokhirev

  • We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, GDF11, GDF15, GHR, NAMPT, PAPPA, PLAU, PTEN, and SHC1) significantly extend life span when manipulated in mice or fish. By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.

  • Association of Ultraprocessed Food Consumption With Risk of Dementia, Huiping Li, Shu Li

  • During a total of 717,333 person-years of follow-up (median 10.0 years), 518 participants developed dementia, of whom 287 developed AD and 119 developed vascular dementia. In the fully adjusted model, consumption of UPF was associated with higher risk of dementia (hazard ratio [HR] for 10% increase in UPF 1.25; 95% CI 1.14–1.37), AD (HR 1.14; 95% CI 1.00–1.30), and vascular dementia (HR 1.28; 95% CI 1.06–1.55), respectively. In addition, replacing 10% of UPF weight in diet with an equivalent proportion of unprocessed or minimally processed foods was estimated to be associated with a 19% lower risk of dementia (HR 0.81; 95% CI 0.74–0.89).

  • Association Between Consumption of Ultraprocessed Foods and Cognitive Decline, Natalia Gomes Goncalves, Naomi Vidal Ferreira

  • A higher percentage of daily energy consumption of ultraprocessed foods was associated with cognitive decline among adults from an ethnically diverse sample. These findings support current public health recommendations on limiting ultraprocessed food consumption because of their potential harm to cognitive function. A total of 15 105 individuals were recruited and 4330 were excluded, leaving 10 775 participants whose data were analyzed. The mean (SD) age at the baseline was 51.6 (8.9) years, 5880 participants (54.6%) were women, 5723 (53.1%) were White, and 6106 (56.6%) had at least a college degree. During a median (range) follow-up of 8 (6-10) years, individuals with ultraprocessed food consumption above the first quartile showed a 28% faster rate of global cognitive decline (β = −0.004; 95% CI, −0.006 to −0.001; P = .003) and a 25% faster rate of executive function decline (β = −0.003, 95% CI, −0.005 to 0.000; P = .01) compared with those in the first quartile.

Dangers of alcohol use

  • Estimated Deaths Attributable to Excessive Alcohol Use Among US Adults Aged 20 to 64 Years, 2015 to 2019, Marissa B. Esser, Gregory Leung

  • Our findings suggest that an estimated annual mean of 140 557 deaths (men: 97 182 [69.1%]; women: 43 375 [30.9%]) could be attributed to excessive alcohol consumption in the US during the 2015-2019 study period, accounting for 5.0% of total deaths (Table 1). Among all adults aged 20 to 64 years, 694 660 annual mean total deaths were noted (men: 432 575 [66.3%]; women: 262 085 [37.7%]), and an estimated 89 697 of these (12.9%) were alcohol-attributable (64 998 [15.0%] among men and 24 699 [9.4%] among women). Our analysis showed that although the number and rate of alcohol-attributable deaths per 100 000 increased by age group, alcohol-attributable deaths accounted for a larger proportion of total deaths among younger groups: 19 782 of 77 973 total deaths (25.4%) among adults aged 20 to 34 years and 25 199 of 143 663 (17.5%) among those aged 35 to 49 years. The 3 leading causes of alcohol-attributable deaths by age group were the same for men and women (eg, adults aged 20-34 years: other poisonings, motor vehicle traffic crashes, and homicide; adults aged 35-49 years: other poisonings, alcoholic liver disease, and motor vehicle traffic crashes).

Circadian rhythms

  • National Institute of General Medical Sciences: What are they?

  • Natural factors in your body produce circadian rhythms. For humans, some of the most important genes in this process are the Period and Cryptochrome genes. These genes code for proteins that build up in the cell’s nucleus at night and lessen during the day. Studies in fruit flies suggest that these proteins help activate feelings of wakefulness, alertness, and sleepiness. However, signals from the environment also affect circadian rhythms. For instance, exposure to light at a different time of day can reset when the body turns on Period and Cryptochrome genes.

  • Genetics of Circadian Rhythms , Tomas Andreani, Taichi Q. Itoh

  • Nearly all organisms exhibit time dependent behavior and physiology across a 24 hour day known as circadian rhythms. These outputs are manifestations of endogenous cyclic gene expression patterns driven by the activity of a core transcription\translation feedback loop (TTFL). The TTFL is highly conserved across species and present in almost all mammalian cell types. This mechanism consists of a forward arm that drives gene expression and a negative arm that feeds back and inhibits the activity of the forward arm. Cyclic gene expression determines highly tissue specific functional activity regulating such processes as metabolic state, endocrine activity and neural excitability. Entrainment of these cellular clocks can be achieved through exogenous daily inputs such as light and food. Dysregulation of the TTFL has been shown to result in a wide range of disorders and diseases driving increased interest in circadian therapies.

Sleep & Heart Health

  • Elevated heart rate and nondipping heart rate as potential targets for melatonin: a review, Fedor Simko, Tomas Baka

  • Elevated heart rate is a risk factor for cardiovascular and all-cause mortalities in the general population and various cardiovascular pathologies. Insufficient heart rate decline during the night, that is, nondipping heart rate, also increases cardiovascular risk. Abnormal heart rate reflects an autonomic nervous system imbalance in terms of relative dominance of sympathetic tone. There are only a few prospective studies concerning the effect of heart rate reduction in coronary heart disease and heart failure. In hypertensive patients, retrospective analyses show no additional benefit of slowing down the heart rate by beta-blockade to blood pressure reduction. Melatonin, a secretory product of the pineal gland, has several attributes, which predict melatonin to be a promising candidate in the struggle against elevated heart rate and its consequences in the hypertensive population. First, melatonin production depends on the sympathetic stimulation of the pineal gland. On the other hand, melatonin inhibits the sympathetic system in several ways representing potentially the counter-regulatory mechanism to normalize excessive sympathetic drive. Second, administration of melatonin reduces heart rate in animals and humans. Third, the chronobiological action of melatonin may normalize the insufficient nocturnal decline of heart rate. Moreover, melatonin reduces the development of endothelial dysfunction and atherosclerosis, which are considered a crucial pathophysiological disorder of increased heart rate and pulsatile blood flow. The antihypertensive and antiremodeling action of melatonin along with its beneficial effects on lipid profile and insulin resistance may be of additional benefit. A clinical trial investigating melatonin actions in hypertensive patients with increased heart rate is warranted.

  • Deviations from normal bedtimes are associated with short-term increases in resting heart rate, Louis Faust, Keith Feldman

  • Despite proper sleep hygiene being critical to our health, guidelines for improving sleep habits often focus on only a single component, namely, sleep duration. Recent works, however, have brought to light the importance of another aspect of sleep: bedtime regularity, given its ties to cognitive and metabolic health outcomes. To further our understanding of this often-neglected component of sleep, the objective of this work was to investigate the association between bedtime regularity and resting heart rate (RHR): an important biomarker for cardiovascular health. Utilizing Fitbit Charge HRs to measure bedtimes, sleep and RHR, 255,736 nights of data were collected from a cohort of 557 college students. We observed that going to bed even 30 minutes later than one’s normal bedtime was associated with a significantly higher RHR throughout sleep (Coeff +0.18; 95% CI: +0.11, +0.26 bpm), persisting into the following day and converging with one’s normal RHR in the early evening. Bedtimes of at least 1 hour earlier were also associated with significantly higher RHRs throughout sleep; however, they converged with one’s normal rate by the end of the sleep session, not extending into the following day. These observations stress the importance of maintaining proper sleep habits, beyond sleep duration, as high variability in bedtimes may be detrimental to one’s cardiovascular health.

  • Scientists discover why the heart slows down at night, Will Slater

  • The vagus nerve - one of the nerves of the autonomic nervous system which supplies internal organs including the heart - has long been thought to be responsible for the slower night-time heart rates. But the study discovered that the vagus nerve is unlikely to be directly involved and instead the sinus node - the heart’s natural pacemaker - has its own clock, a biological clock. The sinus node, they find, knows when it is night and slows the heart rate accordingly.

  • A Validation of Six Wearable Devices for Estimating Sleep, Heart Rate and Heart Rate Variability in Healthy Adults, Dean J. Miller, Charli Sargent

  • The primary aim of this study was to examine the validity of six commonly used wearable devices, i.e., Apple Watch S6, Garmin Forerunner 245 Music, Polar Vantage V, Oura Ring Generation 2, WHOOP 3.0 and Somfit, for assessing sleep. The secondary aim was to examine the validity of the six devices for assessing heart rate and heart rate variability during, or just prior to, night-time sleep. Fifty-three adults (26 F, 27 M, aged 25.4 ± 5.9 years) spent a single night in a sleep laboratory with 9 h in bed (23:00–08:00 h). Participants were fitted with all six wearable devices—and with polysomnography and electrocardiography for gold-standard assessment of sleep and heart rate, respectively. Compared with polysomnography, agreement (and Cohen’s kappa) for two-state categorisation of sleep periods (as sleep or wake) was 88% (κ = 0.30) for Apple Watch; 89% (κ = 0.35) for Garmin; 87% (κ = 0.44) for Polar; 89% (κ = 0.51) for Oura; 86% (κ = 0.44) for WHOOP and 87% (κ = 0.48) for Somfit. Compared with polysomnography, agreement (and Cohen’s kappa) for multi-state categorisation of sleep periods (as a specific sleep stage or wake) was 53% (κ = 0.20) for Apple Watch; 50% (κ = 0.25) for Garmin; 51% (κ = 0.28) for Polar; 61% (κ = 0.43) for Oura; 60% (κ = 0.44) for WHOOP and 65% (κ = 0.52) for Somfit. Analyses regarding the two-state categorisation of sleep indicate that all six devices are valid for the field-based assessment of the timing and duration of sleep. However, analyses regarding the multi-state categorisation of sleep indicate that all six devices require improvement for the assessment of specific sleep stages. As the use of wearable devices that are valid for the assessment of sleep increases in the general community, so too does the potential to answer research questions that were previously impractical or impossible to address—in some way, we could consider that the whole world is becoming a sleep laboratory.

Time-restricted eating: disease risk & sleep quality

  • Time-Restricted Eating to Prevent and Manage Chronic Metabolic Diseases, Amandine Chaix, Emily N.C. Mangoogian

  • Molecular clocks are present in almost every cell to anticipate daily recurring and predictable changes, such as rhythmic nutrient availability, and to adapt cellular functions accordingly. At the same time, nutrient-sensing pathways can respond to acute nutrient imbalance and modulate and orient metabolism so cells can adapt optimally to a declining or increasing availability of nutrients. Organismal circadian rhythms are coordinated by behavioral rhythms such as activity–rest and feeding–fasting cycles to temporally orchestrate a sequence of physiological processes to optimize metabolism. Basic research in circadian rhythms has largely focused on the functioning of the self-sustaining molecular circadian oscillator, while research in nutrition science has yielded insights into physiological responses to caloric deprivation or to specific macronutrients. Integration of these two fields into actionable new concepts in the timing of food intake has led to the emerging practice of time-restricted eating. In this paradigm, daily caloric intake is restricted to a consistent window of 8–12 h. This paradigm has pervasive benefits on multiple organ systems.

  • Time-Restricted Eating: Benefits, Mechanisms, and Challenges in Translation, Prashant Regmi, Leonie K. Heilbronn

  • Eating out of phase with daily circadian rhythms induces metabolic desynchrony in peripheral metabolic organs and may increase chronic disease risk. Time-restricted eating (TRE) is a dietary approach that consolidates all calorie intake to 6- to 10-h periods during the active phase of the day, without necessarily altering diet quality and quantity. TRE reduces body weight, improves glucose tolerance, protects from hepatosteatosis, increases metabolic flexibility, reduces atherogenic lipids and blood pressure, and improves gut function and cardiometabolic health in preclinical studies. This review discusses the importance of meal timing on the circadian system, the metabolic health benefits of TRE in preclinical models and humans, the possible mechanisms of action, the challenges we face in implementing TRE in humans, and the possible consequences of delaying initiation of TRE.

  • Time-restricted feeding improves adaptation to chronically alternating light-dark cycles, Maaike Schilperoort, Rosa van den Berg

  • Disturbance of the circadian clock has been associated with increased risk of cardio-metabolic disorders. Previous studies showed that optimal timing of food intake can improve metabolic health. We hypothesized that time-restricted feeding could be a strategy to minimize long term adverse metabolic health effects of shift work and jetlag. In this study, we exposed female FVB mice to weekly alternating light-dark cycles (i.e. 12 h shifts) combined with ad libitum feeding, dark phase feeding or feeding at a fixed clock time, in the original dark phase. In contrast to our expectations, long-term disturbance of the circadian clock had only modest effects on metabolic parameters. Mice fed at a fixed time showed a delayed adaptation compared to ad libitum fed animals, in terms of the similarity in 24 h rhythm of core body temperature, in weeks when food was only available in the light phase. This was accompanied by increased plasma triglyceride levels and decreased energy expenditure, indicating a less favorable metabolic state. On the other hand, dark phase feeding accelerated adaptation of core body temperature and activity rhythms, however, did not improve the metabolic state of animals compared to ad libitum feeding. Taken together, restricting food intake to the active dark phase enhanced adaptation to shifts in the light-dark schedule, without significantly affecting metabolic parameters.

  • Diurnal transcriptome landscape of a multi-tissue response to time-restricted feeding in mammals, Shaunak Deota, Terry Lin

  • Time-restricted feeding (TRF) is an emerging behavioral nutrition intervention that involves a daily cycle of feeding and fasting. In both animals and humans, TRF has pleiotropic health benefits that arise from multiple organ systems, yet the molecular basis of TRF-mediated benefits is not well understood. Here, we subjected mice to isocaloric ad libitum feeding (ALF) or TRF of a western diet and examined gene expression changes in samples taken from 22 organs and brain regions collected every 2 h over a 24-h period. We discovered that TRF profoundly impacts gene expression. Nearly 80% of all genes show differential expression or rhythmicity under TRF in at least one tissue. Functional annotation of these changes revealed tissue- and pathway-specific impacts of TRF. These findings and resources provide a critical foundation for future mechanistic studies and will help to guide human time-restricted eating (TRE) interventions to treat various disease conditions with or without pharmacotherapies.

  • Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans, Humaira Jamshed, Robbie A. Beyl

  • Time-restricted feeding (TRF) is a form of intermittent fasting that involves having a longer daily fasting period. Preliminary studies report that TRF improves cardiometabolic health in rodents and humans. Here, we performed the first study to determine how TRF affects gene expression, circulating hormones, and diurnal patterns in cardiometabolic risk factors in humans. Eleven overweight adults participated in a 4-day randomized crossover study where they ate between 8 am and 2 pm (early TRF (eTRF)) and between 8 am and 8 pm (control schedule). Participants underwent continuous glucose monitoring, and blood was drawn to assess cardiometabolic risk factors, hormones, and gene expression in whole blood cells. Relative to the control schedule, eTRF decreased mean 24-hour glucose levels by 4 ± 1 mg/dl (p = 0.0003) and glycemic excursions by 12 ± 3 mg/dl (p = 0.001). In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene SIRT1 and the autophagy gene LC3A (all p < 0.04), while in the evening, it tended to increase brain-derived neurotropic factor (BNDF; p = 0.10) and also increased the expression of MTOR (p = 0.007), a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes (p < 0.05). eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.

  • A pilot feasibility study exploring the effects of a moderate time-restricted feeding intervention on energy intake, adiposity and metabolic physiology in free-living human subjects, Rona Antoni, Tracey M. Robertson

  • This pilot study explored the feasibility of a moderate time-restricted feeding (TRF) intervention and its effects on adiposity and metabolism. For 10 weeks, a free-living TRF group delayed breakfast and advanced dinner by 1·5 h each. Changes in dietary intake, adiposity and fasting biochemistry (glucose, insulin, lipids) were compared with controls who maintained habitual feeding patterns. Thirteen participants (29 (SEM 2) kg/m2) completed the study. The average daily feeding interval was successfully reduced in the TRF group (743 (SEM 32) to 517 (SEM 22) min/d; P < 0·001; n 7), although questionnaire responses indicated that social eating/drinking opportunities were negatively impacted. TRF participants reduced total daily energy intake (P = 0·019) despite ad libitum food access, with accompanying reductions in adiposity (P = 0·047). There were significant between-group differences in fasting glucose (P = 0·008), albeit driven primarily by an increase among controls. Larger studies can now be designed/powered, based on these novel preliminary qualitative and quantitative data, to ascertain and maximise the long-term sustainability of TRF.

  • Fasting promotes acute hypoxic adaptation by suppressing mTOR-mediated pathways, Rushou Zhao, Xingcheng Zhao

  • Rapid adaptation to a hypoxic environment is an unanswered question that we are committed to exploring. At present, there is no suitable strategy to achieve rapid hypoxic adaptation. Here, we demonstrate that fasting preconditioning for 72 h reduces tissue injuries and maintains cardiac function, consequently significantly improving the survival rates of rats under extreme hypoxia, and this strategy can be used for rapid hypoxic adaptation. Mechanistically, fasting reduces blood glucose and further suppresses tissue mTOR activity. On the one hand, fasting-induced mTOR inhibition reduces unnecessary ATP consumption and increases ATP reserves under acute hypoxia as a result of decreased protein synthesis and lipogenesis; on the other hand, fasting-induced mTOR inhibition improves mitochondrial oxygen utilization efficiency to ensure ATP production under acute hypoxia, which is due to the significant decrease in ROS generation induced by enhanced mitophagy. Our findings highlight the important role of mTOR in acute hypoxic adaptation, and targeted regulation of mTOR could be a new strategy to improve acute hypoxic tolerance in the body.

Sleep, Wakefulness & Alertness

  • Sharper in the morning: Cognitive time of day effects revealed with high-frequency smartphone testing. Hannah Wilks, Andrew J. Aschenbrenner

  • Decades of research has established a shift from an "eveningness" preference to a "morningness" preference with increasing age. Accordingly, older adults typically have better cognition in morning hours compared to evening hours. We present the first known attempt to capture circadian fluctuations in cognition in individuals at risk for Alzheimer disease (AD) using a remotely administered smartphone assessment that samples cognition rapidly and repeatedly over several days. Older adults (N = 169, aged 61-94 years; 93% cognitively normal) completed four brief smartphone-based testing sessions per day for 7 consecutive days at quasi-random time intervals, assessing associate memory, processing speed, and visual working memory. Scores completed during early hours were averaged for comparison with averaged scores completed during later hours. Mixed effects models evaluated time of day effects on cognition. Additional models included clinical status and cerebrospinal fluid (CSF) biomarkers for beta amyloid (Aβ42) and phosphorylated tau181 (pTau). Models with terms for age, gender, education, APOE ε4 status, and clinical status revealed significantly worse performance on associate memory in evening hours compared to morning hours. Contemporaneously reported mood and fatigue levels did not moderate relationships. Using CSF data to classify individuals with and without significant AD pathology, there were no group differences in performance in morning hours, but subtle impairment emerged in associate memory in evening hours in those with CSF-confirmed AD pathology. These findings indicate that memory is worse in evening hours in older adults, that this pattern is consistent across several days, and is independent of measures of mood and fatigue. Further, they provide preliminary evidence of a "cognitive sundowning" in the very earliest stages of AD. Time of day may be an important consideration for assessments in observational studies and clinical trials in AD populations.

  • Circadian Rhythms in Attention, Pablo Valdez

  • Attention is a cognitive process crucial for human performance. It has four components: tonic alertness, phasic alertness, selective attention, and sustained attention. All the components of attention show homeostatic (time awake, sleep deprivation) and circadian (time of day) variations. The time course of the circadian rhythms in attention is important to program work and school-related activities. The components of attention reach their lowest levels during nighttime and early hours in the morning, better levels occur around noon, and even higher levels can be observed during afternoon and evening hours. However, this time course can be modulated by chronotype, sleep deprivation, age, or drugs. Homeostatic and circadian variations have also been found in other basic cognitive processes (working memory and executive functions), with a time course similar to that observed for attention. Data reviewed in this paper suggests the need to consider circadian rhythms, age, and chronotype of the person, when programming schedules for work, study, school start time, school testing, psychological testing, and neuropsychological assessment.

  • Caffeine and coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals, K J Acheson, B Zahorska-Markiewicz

  • A series of four trials was carried out to investigate the effects of caffeine and coffee on the metabolic rate and substrate utilization in normal weight and obese individuals. In the first trial 8 mg/kg caffeine was compared with a placebo in normal weight subjects. Metabolic rate increased significantly during the 3 hr after caffeine ingestion. While plasma glucose, insulin, and carbohydrate oxidation did not change significantly, plasma free fatty acid levels rose from 432 +/- 31 to 848 +/- 135 muEq/liter and were accompanied by significant increases in fat oxidation during the last hour of the test. In the second and third trials the effects of coffee providing 4 mg/kg caffeine were studied in control and obese subjects. Metabolic rate increased significantly in both groups; however, significant increases in fat oxidation were only observed in the control group. Plasma free fatty acids did not change in the obese. In the fourth trial, coffee was taken with a 3080 kJ meal. The thermic effect of the meal was significantly greater after coffee than after decaffeinated coffee and again fat oxidation was significantly greater after coffee. In conclusion caffeine/coffee stimulates the metabolic rate in both control and obese individuals; however, this is accompanied by greater oxidation of fat in normal weight subjects.

  • Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition, Shinji Saiki, Yukiko Sasazawa

  • Caffeine is one of the most frequently ingested neuroactive compounds. All known mechanisms of apoptosis induced by caffeine act through cell cycle modulation or p53 induction. It is currently unknown whether caffeine-induced apoptosis is associated with other cell death mechanisms, such as autophagy. Herein we show that caffeine increases both the levels of microtubule-associated protein 1 light chain 3-II and the number of autophagosomes, through the use of western blotting, electron microscopy and immunocytochemistry techniques. Phosphorylated p70 ribosomal protein S6 kinase (Thr389), S6 ribosomal protein (Ser235/236), 4E-BP1 (Thr37/46) and Akt (Ser473) were significantly decreased by caffeine. In contrast, ERK1/2 (Thr202/204) was increased by caffeine, suggesting an inhibition of the Akt/mTOR/p70S6K pathway and activation of the ERK1/2 pathway. Although insulin treatment phosphorylated Akt (Ser473) and led to autophagy suppression, the effect of insulin treatment was completely abolished by caffeine addition. Caffeine-induced autophagy was not completely blocked by inhibition of ERK1/2 by U0126. Caffeine induced reduction of mitochondrial membrane potentials and apoptosis in a dose-dependent manner, which was further attenuated by the inhibition of autophagy with 3-methyladenine or Atg7 siRNA knockdown. Furthermore, there was a reduced number of early apoptotic cells (annexin V positive, propidium iodide negative) among autophagy-deficient mouse embryonic fibroblasts treated with caffeine than in their wild-type counterparts. These results support previous studies on the use of caffeine in the treatment of human tumors and indicate a potential new target in the regulation of apoptosis.

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