“Polygenic basis and biomedical consequences of telomere length variation”, Veryan Codd, Qingning Wang, Elias Allara, Crispin Musicha, Stephen Kaptoge, Svetlana Stoma, Tao Jiang, Stephen E. Hamby, Peter S. Braund, Vasiliki Bountziouka, Charley A. Budgeon, Matthew Denniff, Chloe Swinfield, Manolo Papakonstantinou, Shilpi Sheth, Dominika E. Nanus, Sophie C. Warner, Minxian Wang, Amit V. Khera, James Eales, Willem H. Ouwehand, John R. Thompson, Emanuele Di Angelantonio, Angela M. Wood, Adam S. Butterworth, John N. Danesh, Christopher P. Nelson, Nilesh J. Samani (2021-10-05; genetics / heritable):
Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence.
Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal linksbetween LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants.
We identified 197 independent sentinel variants associated with LTL at138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL.
Overall, we furnish new insights into the genetic regulation of LTL,reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.
Stem cell (SC) exhaustion is a hallmark of aging. However, the process of SC depletion during aging has not been observed in live animals, and the underlying mechanism contributing to tissue deterioration remains obscure.
We find that, in aged mice, epithelial cells escape from the hair follicle (HF) SC compartment to the dermis, contributing to HF miniaturization. Single-cellRNA-seq and assay for transposase-accessible chromatin using sequencing (ATAC-seq) reveal reduced expression of cell adhesion and extracellular matrix genes in aged HF-SCs, many of which are regulated by Foxc1 and Nfatc1. Deletion of Foxc1 and Nfatc1 recapitulates HF miniaturization and causes hair loss. Live imaging captures individual epithelial cells migrating away from the SC compartment and HF disintegration.
This study illuminates a hitherto unknown activity of epithelial cells escaping from their niche as a mechanism underlying SC reduction and tissue degeneration. Identification of homeless epithelial cells in aged tissues provides a new perspective for understanding aging-associated diseases.
"…Dr. Yi, like most scientists, had assumed that with age the stem cells died in a process known as stem cell exhaustion. He expected that the death of a hair follicle’s stem cells meant that the hair would turn white and, when enough stem cells were lost, the strand of hair would die. But this hypothesis had not been fully tested. Together with a graduate student, Chi Zhang, Dr. Yi decided that to understand the aging process in hair, he needed to watch individual strands of hair as they grew and aged.
Ordinarily, researchers who study aging take chunks of tissue from animals of different ages and examine the changes. There are 2 drawbacks to this approach, Dr. Yi said. First, the tissue is already dead. And it is not clear what led to the changes that are observed or what will come after them.
He decided his team would use a different method. They watched the growth of individual hair follicles in the ears of mice using a long wavelength laser that can penetrate deep into tissue. They labeled hair follicles with a green fluorescent protein, anesthetized the animals so they did not move, put their ear under the microscope and went back again and again to watch what was happening to the same hair follicle. What they saw was a surprise: When the animals started to grow old and gray and lose their hair, their stem cells started to escape their little homes in the bulge. The cells changed their shapes from round to amoeba-like and squeezed out of tiny holes in the follicle. Then they recovered their normal shapes and darted away. Sometimes, the escaping stem cells leapt long distances, in cellular terms, from the niche where they lived. The stem cells then vanished, perhaps consumed by the immune system.
“If I did not see it for myself I would not have believed it”, Dr. Yi said. “It’s almost crazy in my mind.”
But why? Dr. Yi and his colleagues’ next step was to ask if genes are controlling the process. They discovered 2—FOXC1 and NFATC1—that were less active in older hair follicle cells. Their role was to imprison stem cells in the bulge. So the researchers bred mice that lacked those genes to see if they were the master controllers. By the time the mice were 4 to 5 months old, they started losing hair. By age 16 months, when the animals were middle-aged, they looked ancient: They had lost a lot of hair and the sparse strands remaining were gray.
Now the researchers want to save the hair stem cells in aging mice.
This story of the discovery of a completely unexpected natural process makes Dr. Chuong wonder what remains to be learned about living creatures. “Nature has endless surprises waiting for us”, he said. “You can see fantastic things.”"]
Lithium is a nutritional trace element, used clinically as an anti-depressant. Preclinically, lithium has neuroprotective effects in invertebrates and mice, and it can also extend lifespan in fission yeast, C. elegans and Drosophila. An inverse correlation of human mortality with the concentration of lithium in tap water suggests a possible, evolutionarily conserved mechanism mediating longevity.
Here, we assessed the effects of lithium treatment on lifespan and ageing parameters in mice. Lithium has a narrow therapeutic dose range, and overdosing can severely affect organ health.
Within the tolerable dosing range, we saw some mildly positive effects of lithium on health span but not on lifespan.
2021-devito.pdf: “Extending human healthspan and longevity: a symposium report”, Loren M. DeVito, Nir Barzilai, Ana Maria Cuervo, Laura J. Niedernhofer, Sofiya Milman, Morgan Levine, Daniel Promislow, Luigi Ferrucci, George A. Kuchel, Joan Mannick, Jamie Justice, Mitzi M. Gonzales, James L. Kirkland, Pinchas Cohen, Judith Campisi (2021-09-08):
For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face substantial barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.
[Keywords: biological aging, healthspan, hallmarks of aging, geroscience, longevity]
…On May 19, 2021, experts in geroscience met virtually at the New York Academy of Sciences’ symposium, “Extending Human HealthSpan and Longevity”, organized by Stephanie Lederman, Glenda Greenwald, Orla Smith, Nir Barzilai, James L. Kirkland, and Judith Campisi, to discuss the molecular mechanisms that contribute to longevity and how those insights show that disease emergence can be prevented or reversed by repurposing or developing novel therapies that target these processes. This report summarizes the speakers’ presentations at the one-day symposium.
More VEGF, more life span and health span: Advanced aging is celebrated but its ill effects of deterioration at the cell, tissue, and organ levels are not. Grunewald et al. provide evidence for the vascular theory of aging, which reports that an age-related decrease of vascular function is a driver of organismal aging at large (see the Perspective by Augustin & Kipnis). Vascular endothelial growth factor (VEGF) signaling insufficiency underlies this vascular insufficiency in aged mice. A modest compensatory increase in circulatory VEGF was sufficient to preserve a young-like vascular homeostasis, alleviate multiple adverse age-related processes, and ameliorate a host of age-associated pathologies in mice.
Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function.
Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, “inflammaging” (age-related multi-organ chronic inflammation), and increased tumor burden.
These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.
Introduction: All body cells rely on blood vessels (BVs) for the provision of oxygen and other blood-borne substances and, in certain settings, also for the provision of endothelial-derived paracrine factors. Like other organ systems, the vascular system undergoes aging, which leads to progressive functional deterioration. Given the centrality of BVs to organ homeostasis, it has been hypothesized that vascular aging is an upstream, founding factor in organismal aging, but experimental support for this proposition is limited. Vascular aging involves both large and small vessels, with the latter marked by capillary rarefaction, i.e., age-related failure to maintain adequate microvascular density (MVD). A key homeostatic mechanism preventingMVD reduction relies on the angiogenic activity of vascularendothelial growth factor (VEGF), which by virtue of its hypoxic inducibility, constantly acts to replenish lost vessels and match vascular supply to the tissue needs. The reason(s) that VEGF fails to do so during aging is unknown.
Rationale: Compromised vascular function is expected to perturb organ homeostasis in ways conducive for the development of age-related frailties and diseases. Accordingly, counteracting critical facets of vascular aging might be a useful approach for their alleviation. The presumption that insufficient vascular supply in aging is underlined by VEGF signaling insufficiency, primarily (but not exclusively) because of its indispensable role in preventing capillary loss, led us to investigate whether securing a young-like level of VEGF signaling might rectify capillary loss and its sequelae. On the premise that deteriorated vascular function is an upstream driver of multi-organ malfunctioning, it is envisioned that its rectification might confer comprehensive geroprotection.
Results: Although VEGF production is not substantially reducedduring mouse aging, longitudinal monitoring revealed that VEGF signaling was greatly reduced in multiple key organs. This was associated with increased production of soluble VEGFR1 (sVEGFR1) generated through an age-related shift in alternative splicing of VEGFR1mRNAand its activity as a VEGF trap. A modest increase ofcirculatory VEGF using a transgenic VEGF gain-of-function system oradeno-associated virus (AAV)–assisted VEGF transduction maintained amore youthful level of VEGF signaling and provided protection from age-related capillary loss, compromised perfusion, and reduced tissue oxygenation. Aging hallmarks such as mitochondrial dysfunction, compromised metabolic flexibility, endothelial cell senescence, and inflammaging were alleviated in VEGF-treated mice. Conversely, VEGF loss of function by conditional induction of transgenic sFlt1 in endothelial cells accelerated the development of these adverse age-related phenotypes. VEGF-treated mice lived longer and had an extended health span, as reflected by reduced abdominal fat accumulation, reduced liver steatosis, reduced muscle loss (sarcopenia) associated with better preservation of muscle-generating force, reduced bone loss (osteoporosis), reduced kyphosis, and reduced burden of spontaneous tumors.
Conclusion: The study provides compelling evidence for the proposition that vascular aging is a hierarchically high driver of overall organismal aging. It places VEGF signaling insufficiency at center stage to multi-organ aging and suggests that its undoing might confer comprehensive geroprotection.
Developments in life expectancy and the growing emphasis on biological and ‘healthy’ aging raise a number of important questions for health scientists and economists alike. Is it preferable to make lives healthier by compressing morbidity, or longer by extending life? What are the gains from targeting aging itself compared to efforts to eradicate specific diseases? Here we analyze existing data to evaluate the economic value of increases in life expectancy, improvements in health and treatments that target aging.
We show that a compression of morbidity that improves health is more valuable than further increases in life expectancy, and that targeting aging offers potentially larger economic gains than eradicating individual diseases. We show that a slowdown in aging that increases life expectancy by 1 year is worth US$38 trillion, and by 10 years, US$367 trillion.
Ultimately, the more progress that is made in improving how we age, the greater the value of further improvements.
…The economic value of gains from targeting aging are large because delaying aging produces complementarities between health and longevity, affect a large number of diseases due to the rising prevalence of age-related comorbidities, and create synergies arising from competing risks. Crucially, delaying aging leads to a virtuous circle in which slowing aging begets demand for further slowing in aging. This virtuous circle arises because society’s gains from delaying aging rise with the average age of society, increase with the quality of life in old age, and depend on the number of older people. This provides a distinctive dynamic to targeting aging compared to treatments aimed at specific diseases, in which gains diminish once successful treatments are discovered.
2021-yousefzadeh.pdf: “An aged immune system drives senescence and ageing of solid organs”, Matthew J. Yousefzadeh, Rafael R. Flores, Yi Zhu, Zoe C. Schmiechen, Robert W. Brooks, Christy E. Trussoni, Yuxiang Cui, Luise Angelini, Kyoo-A Lee, Sara J. McGowan, Adam L. Burrack, Dong Wang, Qing Dong, Aiping Lu, Tokio Sano, Ryan D. O''Kelly, Collin A. McGuckian, Jonathan I. Kato, Michael P. Bank, Erin A. Wade, Smitha P. S. Pillai, Jenna Klug, Warren C. Ladiges, Christin E. Burd, Sara E. Lewis, Nicholas F. LaRusso, Nam V. Vo, Yinsheng Wang, Eric E. Kelley, Johnny Huard, Ingunn M. Stromnes, Paul D. Robbins, Laura J. Niedernhofer (2021-05-12):
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein, in mousehematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence,, in the immune system only. We show that Vav-iCre+/−;Ercc1−/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice,,. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/−;Ercc1−/fl or aged wild-type mice into young mice induced senescenceintrans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/−;Ercc1−/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Carbohydrate restriction, used since the 1700s to prolong survival in people with diabetes, fell out of favor after the discovery of insulin. Despite costly pharmacological and technological developments in the last few decades, current therapies do not achieve optimal outcomes, and most people with diabetes remain at high risk for microvascular and macrovascular complications. Recently, low-carbohydrate diets have regained popularity, with preliminary evidence of benefit for body weight, postprandial hyperglycemia, hyperinsulinemia, and other cardiometabolic risk factors in type 2 diabetes and, with more limited data, in type 1 diabetes. High-quality, long-term trials are needed to assess safety concerns and determine whether this old dietary approach might help people with diabetes attain clinical targets more effectively, and at a lower cost, than conventional treatment.
Caloric restriction (CR) has been shown repeatedly to prolong the lifespan in laboratory animals, with its benefits dependent on molecular targets forming part of the nutrient signaling network, including the NAD-dependent deacetylase silent mating type informationregulation 2 homologue 1 (SIRT1). It has been hypothesized that thestilbene resveratrol (RSV) may counteract age-related and obesity-related diseases similarly to CR. In yeast and worms, RSV-promoted longevity also depended on SIRT1. While it remainsunclear whether RSV can prolong lifespans in mammals, some studies inrodents supplemented with RSV have reported lowered body weight (BW) and fat mass, improved insulin sensitivity, lowered cholesterol levels, increased fitness, and mitochondrial biogenesis. Molecular mechanisms possibly leading to such changes include altered gene transcription and activation of SIRT1, AMP-activated kinase (AMPK), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). However, some mouse models did not benefit fromRSV treatment to the same extent as others. We conducted a literature search on PubMed(15 April, 2020) for trials directly comparing RSV application to CR feeding in mice. In most studies retrieved by this systematic PubMedsearch, mice supplemented with RSV did not show statistically-significant reductions of BW, glucose, or insulin. Moreover, in some of these studies, RSV and CR treatments affectedmolecular targets differently and/or findings on RSV and CR impactsvaried between trials. We discuss those RSV-induced changes in gene transcription hypothesized to partly counteract age-related alterations. Although there may be a moderate effect of RSV supplementation on parameters such as insulin sensitivity toward a more CR-like profile in mice, data are inconsistent. Likewise, RSV supplementation trials in humans report controversial findings. While we consider that RSV may, under certain circumstances, moderately mimic some aspects of CR, current evidence does not fully support its use to prevent or treat age-related or obesity-related diseases.
Question: Do vitamin D, omega-3, and a strength-training exercise program alone or in combination prevent 6 health outcomes among relatively healthy adults aged 70 years or older?
Findings: In this randomized trial that included 2157 adults aged 70 years or older, 3-year treatment with vitamin D3 (2000 IU/d), with omega-3 fatty acids (1 g/d), or with a strength-training exercise program did not result in statistically-significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rate, or cognition.
Meaning: These findings do not support the use of vitamin D, omega-3, or a strength-training exercise program for these clinical outcomes among relatively healthy older adults. Abstract
Importance: The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear.
Objective: To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults.
Design, Setting, and Participants: Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017.
Interventions: Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D3, 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D3 and omega-3s (n = 265); vitamin D3 and exercise (n = 275); vitamin D3 alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270).
Main Outcomes and Measures: The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and p < 0.01 was required for statistical-significance.
Results: Among 2157 randomized participants (mean age, 74.9 years; 61.7% women), 1900 (88%) completed the study. Median follow-up was 2.99 years. Overall, there were no statistically-significant benefits of any intervention individually or in combination for the 6 end points at 3 years. For instance, the differences in mean change in systolic BP with vitamin D vs no vitamin D and with omega-3s vs no omega-3s were both −0.8 (99% CI, –2.1 to 0.5) mm Hg, with p < 0.13 and p < 0.11, respectively; the difference in mean change in diastolic BP with omega-3s vs no omega-3s was –0.5 (99% CI, –1.2 to 0.2) mm Hg; p = 0.06); and the difference in mean change in IR of infections with omega-3s vs no omega-3s was –0.13 (99% CI, –0.23 to –0.03), with an IR ratio of 0.89 (99% CI, 0.78–1.01; p = 0.02). No effects were found on the outcomes of SPPB, MoCA, and incidence of nonvertebral fractures). A total of 25 deaths were reported, with similar numbers in all treatment groups.
Conclusions and Relevance: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically-significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes.
2020-braude.pdf: “Surprisingly long survival of premature conclusions about naked mole-rat biology”, Stan Braude, Susanne Holtze, Sabine Begall, Julia Brenmoehl, Hynek Burda, Philip Dammann, Delphine del Marmol, Ekaterina Gorshkova, Yoshiyuki Henning, Andreas Hoeflich, Annika Höhn, Tobias Jung, Dania Hamo, Arne Sahm, Yury Shebzukhov, Radim Š umbera, Satomi Miwa, Mikhail Y. Vyssokikh, Thomas von Zglinicki, Olga Averina, Thomas B. Hildebrandt (2020-10-30):
Naked mole-rats express many unusual traits for such a small rodent. Their morphology, social behaviour, physiology, and ageing have been well studied over the past half-century. Many early findings and speculations about this subterranean species persist in the literature, although some have been repeatedly questioned or refuted. While the popularity of this species as a natural-history curiosity, and oversimplified story-telling in science journalism, might have fuelled the perpetuation of such misconceptions, an accurate understanding of their biology is especially important for this new biomedical model organism. We review 28 of these persistent myths about naked mole-rat sensory abilities, ecophysiology, social behaviour, development and ageing, and where possible we explain how these misunderstandings came about.
Ecophysiology and environment:
naked mole-rats are hairless
naked mole-rats are strictly subterranean and never go above ground
naked mole-rats have unusually long burrows
naked mole-rats are the only poikilothermic mammals
naked mole-rats have uniquely low thyroid hormone levels
naked mole-rat burrows are hypoxic and hypercapnic
Naked mole-rats are blind
naked mole-rats have degenerated hearing
naked mole-rats are the most vocal rodents because they live in large groups
naked mole-rats feel no pain
Social behaviour and reproduction:
naked mole-rats are the only eusocial mammals
colonies have castes of breeders and non-breeders, involving frequent workers, infrequent workers, non-workers, and dispersers
colonies have up to three male breeders (pashas)
colonies have a single queen
not all females can become queens
queens suppress workers with pheromones
queens shove workers to get them to work
naked mole-rats never leave their natal colonies
naked mole-rats are inbred
Development, longevity, ageing and senescence:
the GH/IGF axis is impaired in naked mole-rats
naked mole-rats are long-lived because they have low oxidative stress and damage
naked mole-rat cells do not display cellular senescence
naked mole-rats are immune to disease
naked mole-rats do not get tumours or cancer
naked mole-rats have extremely large hyaluronan
naked mole-rat cells have early contact inhibition that prevents cancer
naked mole-rats are non-ageing
naked mole-rats are the single member of a taxonomic family
C60 is a potent antioxidant that has been reported to substantially extend the lifespan of rodents when formulated in olive oil (C60-OO) or extra virgin olive oil (C60-EVOO). Despite there being no regulated form of C60-OO, people have begun obtaining it from online sources and dosing it to themselves or their pets, presumably with the assumption of safety and efficacy. In this study, we obtain C60-OO from a sample of online vendors, and find marked discrepancies in appearance, impurity profile, concentration, and activity relative to pristine C60-OO formulated in-house. We additionally find that pristine C60-OO causes no acute toxicity in a rodent model but does form toxic species that can cause statistically-significant morbidity and mortality in mice in under 2 weeks when exposed to light levels consistent with ambient light. Intraperitoneal injections of C60-OO did not affect the lifespan of CB6F1 female mice. Finally, we conduct a lifespan and health span study in males and females C57BL/6 J mice comparing oral treatment with pristine C60-EVOO and EVOO alone versus untreated controls. We failed to observe statistically-significant lifespan and health span benefits of C60-EVOO or EVOO supplementation compared to untreated controls, both starting the treatment in adult or old age. Our results call into question the biological benefit of C60-OO in aging.
Caloric restriction (CR) is a strategy that attenuates aging in multiple nonhuman species. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials are part of a research program aiming to test the effects of CR on aging and longevity biomarkers in humans. Building on CALERIE phase 1, CALERIEphase 2 (CALERIE 2) was the largest study to date to assess sustained CR in healthy humans without obesity. In a 24-month randomized controlled trial comprising 218 participants at baseline, CALERIE 2 showed that moderate CR, 11.9% on average, induced improvements in aging-related biomarkers without adversely affecting psychological or behavioral outcomes. The objectives of this report are to summarize and review the highlights of CALERIE 2 and report previously unpublished results on eating disorder symptoms and cognitive function. This article specifically summarizes the physiological, psychological, aging, behavioral, and safety results of the trial. Also provided are research directions beyond CALERIE 2 that highlight important opportunities to investigate the role of CR in aging, longevity, and health span in humans.
Manipulations to set back biological age and extend lifespan in animal models are well established, and translation to humans has begun. The length of human life makes it impractical to evaluate results by plotting mortality curves, so surrogate markers of age have been suggested and, at present, the best established surrogates are DNA methylation clocks. Herein we report on a randomized, controlled clinical trial designed to be a first step in evaluating the effect of a diet and lifestyle intervention on biological age. Compared to participants in the control group (n = 20), participants in the treatment group tested an average 3.23 years younger at the end of the eight-week program according to the Horvath DNAmAge clock (p = 0.018). Those in the treatment group (n = 18) tested an average 1.96 years younger at the end of the program compared to the same individuals at the beginning with a strong trend towards statistical-significance (p = 0.066 for within group change). This is the first such trial to demonstrate a potential reversal of biological age. In this study, the intervention was confined to diet and lifestyle changes previously identified as safe to use. The prescribed program included multiple components with documented mechanistic activity on epigenetic pathways, including moderate exercise, breathing exercises for stress, and a diet rich in methyl donor nutrients and polyphenols.
It has recently been found possible to estimate age, mortality risk, or general health by looking merely at the epigenome. The models used to do so are referred to as epigenetic (or methylation) clocks.
Epigenetic clocks are increasingly becoming a popular choice for scientists in the field of aging research to measure the putative efficacy of anti-aging interventions. They may make it possible to get results before full Kaplan-Meier curves are available, and they could serve, at least seemingly, as a replacement for a host of other biomarkers. I recommend reading the introductory sections of “The Longevity FAQ” as well as those about epigenetics before reading this post as it gives some more context.
Even with a small number of the CpGs of the epigenome measured, it has been possible to construct clocks that accurately track age and health. We still don’t know exactly why the clocks work, just that they do. There is some interesting evidence pointing out to at least part of the pattern seem in the aged epigenome being causal, not just a reflection of the overall condition of the tissue or organism, so we may soon see the epigenome becoming a target for novel drugs. If you want to continue reading about this, Bell et. al 2019’s review (from where I extract the table below) and Raj & Horvath 2020 are the best starting points.
Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD+ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.
It has been noted for quite some time that DNA methylation levels decline with age. The importance of this change remained unknown until it became possible to measure methylation status of specific sites on the DNA.
It was observed that while the methylation of some sites does indeed decrease with age, that of others increase or remain unchanged. The application of machine learning methods to these quantitative changes in multiple sites, allowed the generation of a highly accurate estimator of age, called the epigenetic clock. The application of this clock on large human epidemiological data sets revealed that discordance between the predicted (epigenetic age) and chronological age is associated with many age-related pathologies, particularly when the former is greater than the latter. The epigenetic clock clearly captures to some degree, biological features that accompany the ageing process.
Despite the ever-increasing scope of pathologies that are found to be associated with accelerated epigenetic ageing, the basic principles that underlie the ticking of the clock remain elusive. Here, we describe the known molecular and cellular attributes of the clock and consider their properties, and proffer opinions as to how they may be connected and what might be the underlying mechanism. Emerging from these considerations is the inescapable view that epigenetic ageing begins from very early moments after the embryonic stem cell stage and continues un-interrupted through the entire life-course.
This appears to be a consequence of processes that are necessary for the development of the organism from conception and to maintain it thereafter through homeostasis. Hence, while the speed of ageing can, and is affected by external factors, the essence of the ageing process itself is an integral part of, and the consequence of the development of life.
Impact statement: The field of epigenetic ageing is relatively new, and the speed of its expansion presents a challenge in keeping abreast with new discoveries and their implications. Several reviews have already addressed the great number of pathologies, health conditions, life-style, and external stressors that are associated with changes to the rate of epigenetic ageing. While these associations highlight and affirm the ability of epigenetic clock to capture biologically meaningful changes associated with age, they do not inform us about the underlying mechanisms.
In this very early period since the development of the clock, there have been rather limited experimental research that are aimed at uncovering the mechanism. Hence, the perspective that we proffer is derived from available but nevertheless limited lines of evidence that together provide a seemingly coherent narrative that can be tested. This, we believe would be helpful towards uncovering the workings of the epigenetic clock.
Background: Few randomized trials have evaluated the effect of reducing red meat intake on clinically important outcomes.
Purpose: To summarize the effect of lower versus higher red meat intake on the incidence of cardiometabolic and cancer outcomes in adults.
Data Sources: EMBASE, CENTRAL, CINAHL, Web of Science, andProQuest from inception to July 2018 and MEDLINE from inception to April 2019, without language restrictions.
Study Selection: Randomized trials (published in any language) comparing diets lower in red meat with diets higher in red meat that differed by a gradient of at least 1 serving per week for 6 months or more.
Data Extraction: Teams of 2 reviewers independently extracted data and assessed the risk of bias and the certainty of the evidence.
Data Synthesis: Of 12 eligible trials, a single trial enrolling 48 835 women provided the most credible, though still low-certainty, evidence that diets lower in red meat may have little or no effect on all-cause mortality (hazard ratio [HR], 0.99 [95% CI, 0.95 to 1.03]), cardiovascular mortality (HR, 0.98 [CI, 0.91 to 1.06]), and cardiovascular disease (HR, 0.99 [CI, 0.94 to 1.05]). That trial also provided low-certainty to very-low-certainty evidence that diets lower in red meat may have little or no effect on total cancer mortality (HR, 0.95 [CI, 0.89 to 1.01]) and the incidence of cancer, including colorectal cancer (HR, 1.04 [CI, 0.90 to 1.20]) and breast cancer (HR, 0.97 [0.90 to 1.04]).
Limitations: There were few trials, most addressing only surrogate outcomes, with heterogeneous comparators and small gradients in red meat consumption between lower versus higher intake groups.
Conclusion: Low-certainty to very-low-certainty evidence suggests that diets restricted in red meat may have little or no effect on major cardiometabolic outcomes and cancer mortality and incidence.
Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5-year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
2019-vrselja.pdf: “Restoration of brain circulation and cellular functions hours post-mortem”, Zvonimir Vrselja, Stefano G. Daniele, John Silbereis, Francesca Talpo, Yury M. Morozov, André M. M. Sousa, Brian S. Tanaka, Mario Skarica, Mihovil Pletikos, Navjot Kaur, Zhen W. Zhuang, Zhao Liu, Rafeed Alkawadri, Albert J. Sinusas, Stephen R. Latham, Stephen G. Waxman, Nenad Sestan (2019-05-17):
The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval.
2019-rose.pdf: “A longitudinal big data approach for precision health”, Sophia Miryam Schüssler-Fiorenza Rose, Kévin Contrepois, Kegan J. Moneghetti, Wenyu Zhou, Tejaswini Mishra, Samson Mataraso, Orit Dagan-Rosenfeld, Ariel B. Ganz, Jessilyn Dunn, Daniel Hornburg, Shannon Rego, Dalia Perelman, Sara Ahadi, M. Reza Sailani…
Diabetics on metformin have lower morality than non-diabetics and other diabetics.
Diabetics on metformin have less cancer than non-diabetics and other diabetics.
Diabetics on metformin have less cardiovascular disease than other diabetics.
Metformin appears to extend health and life spans independent of its effect on diabetes.
Metformin may be able to extend health and lifespans in the general population.
This systematic review investigated whether the insulin sensitizer metformin has a geroprotective effect in humans.
Pubmed and Embase were searched along with databases of unpublished studies. Eligible research investigated the effect of metformin on all-cause mortality or diseases of ageing relative to non-diabetic populations or diabetics receiving other therapies with adjustment for disease control achieved. Overall, 260 full-texts were reviewed and 53 met the inclusion criteria.
Diabetics taking metformin had statistically-significantly lower all-cause mortality than non-diabetics (hazard ratio (HR) = 0.93, 95% CI 0.88–0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR = 0.72, 95% CI 0.65–0.80), insulin (HR = 0.68, 95% CI 0.63–0.75) or sulphonylurea (HR = 0.80, 95% CI 0.66–0.97). Metformin users also had reduced cancer compared to non-diabetics (rate ratio = 0.94, 95% CI 0.92–0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR = 0.76, 95% CI 0.66–0.87) or insulin (HR = 0.78, 95% CI 0.73–0.83).
Differences in baseline characteristics were observed which had the potential to bias findings, although statistical adjustments were made.
The apparent reductions in all-cause mortality and diseases of ageing associated with metformin use suggest that metformin could be extending life and healthspans by acting as a geroprotective agent.
About 15 years ago, one of us (G.J.L.) got an uncomfortable phone call from a colleague and collaborator. After nearly a year of frustrating experiments, this colleague was about to publish a paper1 chronicling his team’s inability to reproduce the results of our high-profile paper2 in a mainstream journal. Our study was the first to show clearly that a drug-like molecule could extend an animal’s lifespan. We had found over and over again that the treatment lengthened the life of a roundworm by as much as 67%. Numerous phone calls and e-mails failed to identify why this apparently simple experiment produced different results between the labs. Then another lab failed to replicate our study. Despite more experiments and additional publications, we couldn’t work out why the labs were getting different lifespan results. To this day, we still don’t know. A few years later, the same scenario played out with different compounds in other labs…In another, now-famous example, two cancer labs spent more than a year trying to understand inconsistencies6. It took scientists working side by side on the same tumour biopsy to reveal that small differences in how they isolated cells—vigorous stirring versus prolonged gentle rocking—produced different results. Subtle tinkering has long been important in getting biology experiments to work. Before researchers purchased kits of reagents for common experiments, it wasn’t unheard of for a team to cart distilled water from one institution when it moved to another. Lab members would spend months tweaking conditions until experiments with the new institution’s water worked as well as before. Sources of variation include the quality and purity of reagents, daily fluctuations in microenvironment and the idiosyncratic techniques of investigators7. With so many ways of getting it wrong, perhaps we should be surprised at how often experimental findings are reproducible.
…Nonetheless, scores of publications continued to appear with claims about compounds that slow ageing. There was little effort at replication. In 2013, the three of us were charged with that unglamorous task…Our first task, to develop a protocol, seemed straightforward.
But subtle disparities were endless. In one particularly painful teleconference, we spent an hour debating the proper procedure for picking up worms and placing them on new agar plates. Some batches of worms lived a full day longer with gentler technicians. Because a worm’s lifespan is only about 20 days, this is a big deal. Hundreds of e-mails and many teleconferences later, we converged on a technique but still had a stupendous three-day difference in lifespan between labs. The problem, it turned out, was notation—one lab determined age on the basis of when an egg hatched, others on when it was laid. We decided to buy shared batches of reagents from the start. Coordination was a nightmare; we arranged with suppliers to give us the same lot numbers and elected to change lots at the same time. We grew worms and their food from a common stock and had strict rules for handling. We established protocols that included precise positions of flasks in autoclave runs. We purchased worm incubators at the same time, from the same vendor. We also needed to cope with a large amount of data going from each lab to a single database. We wrote an iPad app so that measurements were entered directly into the system and not jotted on paper to be entered later. The app prompted us to include full descriptors for each plate of worms, and ensured that data and metadata for each experiment were proofread (the strain names MY16 and my16 are not the same). This simple technology removed small recording errors that could disproportionately affect statistical analyses.
Once this system was in place, variability between labs decreased. After more than a year of pilot experiments and discussion of methods in excruciating detail, we almost completely eliminated systematic differences in worm survival across our labs (see ‘Worm wonders’)…Even in a single lab performing apparently identical experiments, we could not eliminate run-to-run differences.
…We have found one compound that lengthens lifespan across all strains and species. Most do so in only two or three strains, and often show detrimental effects in others.
Objectives: To systematically synthesize information on safe landing strategies for a fall, and quantitatively examine the effects of the strategies to reduce the risk of injury from a fall.
Data Sources: PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library.
Study Selection: Databases were searched using the combinations of keywords of “falls”, “strategy”, “impact”, and “load.” Randomized controlled trials, cohort studies, pre-post studies, and cross-sectional studies were included.
Data Extraction: Fall strategies were extracted and categorized by falling direction. Measurements of impact loads that reflect the risk of injuries were extracted (eg, impact velocity, impact force, fall duration, impact angle). Hedges’ g was used as effect size to quantify the effect of a protective landing strategy to reduce the impact load.
Data Synthesis: A total of 7 landing strategies (squatting, elbow flexion, forward rotation, martial arts rolling, martial arts slapping, relaxed muscle, stepping) in 13 studies were examined. In general, all strategies, except for the martial arts slapping technique, statistically-significantly reduced impact load (g values = 0.73–2.70). Squatting was an efficient strategy to reduce impact in backward falling (g = 1.77), while elbow flexion with outstretched arms was effective in forward falling (g = 0.82). Also, in sideways falling strategies, martial arts rolling (g = 2.70) and forward rotation (g = 0.82) were the most efficient strategies to reduce impact load.
Conclusions: The results showed that landing strategies have a statistically-significant effect on reducing impact load during a fall and might be effective to reduce the impact load of falling. The current study also highlighted limitations of the previous studies that focused on a young population and self-initiated falls. Further investigation with elderly individuals and unexpected falls is necessary to verify the effectiveness and suitability of the strategies for at-risk populations in real-life falls.
[Keywords: accidental falls, movement, wounds and injuries]
Background: Despite not being licensed for human consumption, the Internet has triggered renewed, widespread interest and availability of 2,4-Dinitrophenol (DNP). DNP, a cellular metabolic poison, causes thermogenesis resulting in fat burning and weight loss. Whilst extensively available for purchase online, research on user experiences of DNP is limited.
Methods: A netnographic approach was used to describe user experiences of DNP via online public websites. Public websitesdiscussing DNP were identified and a purposeful sample selected. Discussion threads were downloaded and a textual qualitative analysis conducted. Four themes containing 71 categories were generated.
Results: There exists a plethora of communal folk pharmacological advice and recommendations for DNP manufacture and use, together with associated harms and outcomes. The efficacy and untoward effects of DNP were described and discussed alongside the notion that DNP should only be used by experienced bodybuilders. Dosage and regimes for optimal use were also described.
Conclusion: This unique study provides a rich examination of the knowledge, attitudes, and motivations of DNP users, illustrating the important role of online public websites in sharing information. Further understanding of DNP users and the online communities in which they reside is warranted to facilitate engagement and formulate appropriate and effective policy responses.
One of the main advantages of Bayesian analyses of clinical trials is their ability to formally incorporate skepticism about large treatment effects through the use of informative priors. We conducted a simulation study to assess the performance of informative normal, Student-t, and beta distributions in estimating relative risk (RR) or odds ratio (OR) for binary outcomes. Simulation scenarios varied the prior standard deviation (SD; level of skepticism of large treatment effects), outcome rate in the control group, true treatment effect, and sample size. We compared the priors with regards to bias, mean squared error (MSE), and coverage of 95% credible intervals. Simulation results show that the prior SD influenced the posterior to a greater degree than the particular distributional form of the prior. For RR, priors with a 95% interval of 0.50–2.0 performed well in terms of bias, MSE, and coverage under most scenarios. For OR, priors with a wider 95% interval of 0.23–4.35 had good performance. We recommend the use of informative priors that exclude implausibly large treatment effects in analyses of clinical trials, particularly for major outcomes such as mortality.
Background: The effects of intermittent, high dose vitamin D treatment in older adults have not been documented. We conducted a meta-analysis to provide a quantitative assessment of the efficiency of intermittent, high dose vitamin D treatment on falls, fractures, and mortality among older adults.
Methods: Electronic databases were searched for randomized controlled trials (RCTs) on high dose, intermittent vitamin D supplementation among older adults. Two researchers independently screened the literature according to specified inclusive and exclusive criteria to extract the data. Meta-analysis was performed by using Review Manager 5.1.0 software.
Results: Nine trials were included in this meta-analysis. High dose, intermittent vitamin D therapy did not decrease all-cause mortality among older adults. The risk ratio (95% CI) was 1.04 (0.91-1.17). No benefit was seen in fracture or fall prevention. The risk ratio for hip fractures (95% CI) was 1.17 (0.97-1.41) while for non-vertebral fractures (95% CI) it was 1.06 (0.91-1.22), and the risk ratio for falls (95% CI) was 1.02 (0.96-1.08). Results remained robust after sensitivity analysis.
Conclusion: Supplementation of intermittent, high dose vitamin D may not be effective in preventing overall mortality, fractures, or falls among older adults. The route of administration of vitamin D supplements may well change the physiological effects.
Background: Vitamin D and related compounds have been used to prevent osteoporotic fractures in older people. This is the third update of a Cochrane review first published in 1996.
Objectives: To determine the effects of vitamin D or related compounds, with or without calcium, for preventing fractures in post-menopausal women and older men.
Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to December 2012), the Cochrane Central Register of Controlled Trials(2012, Issue 12), MEDLINE (1966to November Week 3 2012), EMBASE (1980 to 2012 Week 50), CINAHL (1982to December 2012), BIOSIS (1985 to 2013-01-03), Current Controlled Trials (December 2012) and reference lists of articles.
Selection criteria: Randomised or quasi-randomised trials that compared vitamin D or related compounds, alone or with calcium, against placebo, no intervention or calcium alone, and that reported fracture outcomes in older people. The primary outcome was hip fracture. Data collection and analysis
Two authors independently assessed trial risk of selection bias and aspects of methodological quality, and extracted data. Data were pooled, where possible, using the fixed-effect model, or the random-effects model when heterogeneity between studies appeared substantial. Main results
We included 53 trials with a total of 91,791 participants. Thirty-one trials, with sample sizes ranging from 70 to 36,282 participants, examined vitamin D (including 25-hydroxy vitamin D) with or without calcium in the prevention of fractures in community, nursing home or hospital inpatient populations. Twelve of these 31 trials had participants with a mean or median age of 80 years or over.
Another group of 22 smaller trials examined calcitriol or alfacalcidol (1-alphahydroxyvitamin D3), mostly with participants who had established osteoporosis. These trials were carried out in the setting of institutional referral clinics or hospitals.
In the assessment of risk of bias for random sequence generation, 21 trials (40%) were deemed to be at low risk, 28 trials (53%) at unclear risk and four trials at high risk (8%). For allocation concealment, 22 trials were at low risk (42%), 29 trials were at unclear risk (55%) and two trials were at high risk (4%).
There is high quality evidence that vitamin D alone, in the formats and doses tested, is unlikely to be effective in preventing hip fracture (11 trials, 27,693 participants; risk ratio (RR) 1.12, 95% confidence intervals (CI) 0.98 to 1.29) or any new fracture (15 trials, 28,271 participants; RR 1.03, 95% CI 0.96 to 1.11).
There is high quality evidence that vitamin D plus calcium results in a small reduction in hip fracture risk (nine trials, 49,853 participants; RR 0.84, 95% confidence interval (CI) 0.74 to 0.96; P value 0.01). In low-risk populations (residents in the community: with an estimated eight hip fractures per 1000 per year), this equates to one fewer hip fracture per 1000 older adults per year (95% CI 0 to 2). In high risk populations (residents in institutions: with an estimated 54 hip fractures per 1000 per year), this equates to nine fewer hip fractures per 1000 older adults per year (95% CI 2 to 14).
There is high quality evidence that vitamin D plus calcium is associated with a statistically-significant reduction in incidence of new non-vertebral fractures. However, there is only moderate quality evidence of an absence of a statistically-significant preventive effect on clinical vertebral fractures. There is high quality evidence that vitamin D plus calcium reduces the risk of any type of fracture (10 trials, 49,976 participants; RR 0.95, 95% CI 0.90 to 0.99).
In terms of the results for adverse effects: mortality was not adversely affected by either vitamin D or vitamin D plus calcium supplementation (29 trials, 71,032 participants, RR 0.97, 95% CI 0.93 to 1.01). Hypercalcaemia, which was usually mild (2.6 to 2.8 mmol/L), was more common in people receiving vitamin D or an analogue, with or without calcium (21 trials, 17,124 participants, RR 2.28, 95% CI 1.57 to 3.31), especially for calcitriol (four trials, 988 participants, RR 4.41, 95% CI 2.14 to 9.09), than in people receiving placebo or control. There was also a small increased risk of gastrointestinal symptoms (15 trials, 47,761 participants, RR 1.04, 95% CI 1.00 to 1.08), especially for calcium plus vitamin D (four trials, 40,524 participants, RR 1.05, 95% CI 1.01 to 1.09), and a statistically-significant increase in renal disease (11 trials, 46,548 participants, RR 1.16, 95% CI 1.02 to 1.33). Other systematic reviews have found an increased association of myocardial infarction with supplemental calcium; and evidence of increased myocardial infarction and stroke, but decreased cancer, with supplemental calcium plus vitamin D, without an overall effect on mortality.
Authors’ conclusions: Vitamin D alone is unlikely to prevent fractures in the doses and formulations tested so far in older people. Supplements of vitamin D and calcium may prevent hip or any type of fracture. There was a small but statistically-significant increase in gastrointestinal symptoms and renal disease associated with vitamin D and calcium. This review found that there was no increased risk of death from taking calcium and vitamin D.
[Essay by psychiatrist about care of the dying in American healthcare: people die agonizing, slow, expensive deaths, prolonged by modern healthcare, deprived of all dignity and joy by disease and decay. There is little noble about it.]
You will become bedridden, unable to walk or even to turn yourself over. You will become completely dependent on nurse assistants to intermittently shift your position to avoid pressure ulcers. When they inevitably slip up, your skin develops huge incurable sores that can sometimes erode all the way to the bone, and which are perpetually infected with foul-smelling bacteria. Your limbs will become practically vestigial organs, like the appendix, and when your vascular disease gets too bad, one or more will be amputated, sacrifices to save the host. Urinary and fecal continence disappear somewhere in the process, so you’re either connected to catheters or else spend a while every day lying in a puddle of your own wastes until the nurses can help you out…
Somewhere in the process your mind very quietly and without fanfare gives up the ghost. It starts with forgetting a couple of little things, and progresses…They don’t remember their own names, they don’t know where they are or what they’re doing there, and they think it’s the 1930s or the 1950s or don’t even have a concept of years at all. When you’re alert and oriented “x0”, the world becomes this terrifying place where you are stuck in some kind of bed and can’t move and people are sticking you with very large needles and forcing tubes down your throat and you have no idea why or what’s going on.
So of course you start screaming and trying to attack people and trying to pull the tubes and IV lines out. Every morning when I come in to work I have to check the nurses’ notes for what happened the previous night, and every morning a couple of my patients have tried to pull all of their tubes and lines out. If it’s especially bad they try to attack the staff, and although the extremely elderly are really bad at attacking people this is nevertheless Unacceptable Behavior and they have to be restrained ie tied down to the bed. A presumably more humane alternative sometimes used instead or in addition is to just drug you up on all of those old-timey psychiatric medications that actual psychiatrists don’t use anymore because of their bad reputation…Nevertheless, this is the way many of my patients die. Old, limbless, bedridden, ulcerated, in a puddle of waste, gasping for breath, loopy on morphine, hopelessly demented, in a sterile hospital room with someone from a volunteer program who just met them sitting by their bed.
…I work in a Catholic hospital. People here say the phrase “culture of life” a lot, as in “we need to cultivate a culture of life.” They say it almost as often as they say “patient-centered”. At my hospital orientation, a whole bunch of nuns and executives and people like that got up and told us how we had to do our part to “cultivate a culture of life.”
And now every time I hear that phrase I want to scream. 21st century American hospitals do not need to “cultivate a culture of life”. We have enough life. We have life up the wazoo. We have more life than we know what to do with. We have life far beyond the point where it becomes a sick caricature of itself. We prolong life until it becomes a sickness, an abomination, a miserable and pathetic flight from death that saps out and mocks everything that made life desirable in the first place. 21st century American hospitals need to cultivate a culture of life the same way that Newcastle needs to cultivate a culture of coal, the same way a man who is burning to death needs to cultivate a culture of fire.
And so every time I hear that phrase I want to scream, or if I cannot scream, to find some book of hospital poetry that really is a book of hospital poetry and shove it at them, make them read it until they understand. There is no such book, so I hope it will be acceptable if I just rip off of Wilfred Owen directly:
If in some smothering dreams you too could pace
Behind the gurney that we flung him in,
And watch the white eyes writhing in his face,
His hanging face, like a devil’s sack of sin;
If you could hear, at every jolt, the blood
Come gargling from the froth-corrupted lungs,
Obscene with cancer, bitter with the cud
Of vile, incurable sores on innocent tongues
My friend, you would not so pontificate
To reasoners beset by moral strife
The old lie: we must try to cultivate
A culture of life.
Studies in mammals have demonstrated that hyperglycemia and hyperinsulinemia are important factors in aging and cancer. Inactivation of insulin/insulin-like signaling increases lifespan in nematodes, fruit flies, and mice. Life-prolonging effects of caloric restriction are in part due to reduction in IGF-1, insulin, and glucose levels. Antidiabetic biguanides such as metformin, which reduce hyperglycemia and hyperinsulinemia by decreasing insulin resistance, extend lifespan, and inhibit carcinogenesis in rodents. Will antidiabetic biguanides increase lifespan in humans?
Introduction: It has been suggested that vitamin D is effective to prevent mortality. However, there is no consistent conclusion that the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment. We conducted a meta-analysis regarding this issue in an effort to provide a more robust answer.
Methods: A comprehensive search in a number of databases, including MEDLINE, Embase and The Cochrane Central Register of Controlled Trials, was conducted for collecting randomized controlled trials (RCTs) on vitamin D supplementation preventing mortality. Two investigators independently screened the literature according to the inclusive and exclusive criteria and the relative data were extracted. Data analysis was performed by using Review Manager 5.0 software.
Results: Data from forty-two RCT s were included. Vitamin D therapy significantly decreased all-cause mortality with a duration of follow-up longer than 3 years with a RR (95% CI) of 0.94 (0.90-0.98). No benefit was seen in a shorter follow-up periods with a RR (95% CI) of 1.04 (0.97-1.12). Results remain robust after sensitivity analysis. The following subgroups of long-term follow-up had significantly fewer deaths: female only, participants with a mean age younger than 80, daily dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, the combination of vitamin D and calcium significantly reduced mortality and vitamin D alone also had a trend to decrease mortality in a longer time follow up.
Conclusions: The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration.
Context: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.
Objective: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1,CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.
Design, Setting, and Participants: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.
Main Outcome Measure: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.
Results: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.
Conclusion: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.
Introduction: Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium.
Subjects and Methods: Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies.
Results: The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62–77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06).
Conclusion: Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.
Context: Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease.
Objective: The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes.
Design and Methods: We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RR) and the weighted mean differences across trials.
Results: We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (CI), 0.93, 1.00; p = 0.08], myocardial infarction (RR, 1.02; 95% CI, 0.93, 1.13; p = 0.64), and stroke (RR, 1.05; 95% CI, 0.88, 1.25; p = 0.59). These analyses were associated with minimal heterogeneity. There were no statistically-significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with statistically-significant heterogeneity, and the pooled estimates were trivial in absolute terms.
Conclusions: Trial data available to date are unable to demonstrate a statistically-significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best.
Objectives: To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.
Design: Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebocontrolled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal women. Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.
Results: In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16,718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (p = 0.05 for clinical myocardial infarction or stroke, p = 0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), p = 0.04), stroke (1.20 (1.00 to 1.43), p = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), p = 0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), p = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), p = 0.009).
Conclusions: Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.
Background and Aims: To assess the influence of body composition changes on circulating serum visfatin after following 12 weeks of energy restricted diet intervention. We also examined the possible role of visfatin in glucose metabolism and in obesity-associated low-grade inflammation.
Methods and Results: A total of 78 obese (BMI 34.0 ± 2.8 kg/m2) women aged 36.7±7 y volunteered to participate in the study. We measured by DXA body fat mass (FM) and lean mass (LM). Fasting serum visfatin, glucose, insulin, adiponectin, leptin, IL-1β, IL-6, IL-8, TNF-α and CRP concentrations were analyzed before and after theintervention and HOMA and QUIKI indexes were calculated. Mean weightloss 7.7 ± 3.0 kg and HOMA decreased in 24 ± 35%. Serum visfatin concentration change was negatively associated with LM difference (p < 0.05), whereas no statistically-significant relationship was observed with FM changes after energy restricted diet intervention. Changes in circulating serum visfatin levels were statistically-significantly and inversely associated with HOMA-IR (p< 0.01) and positively with QUICKI index (p < 0.02) after energy restricted diet intervention, regardless of achieved body weight loss. We did not find any statistically-significant association between changes in visfatin levels and IL-1β, IL-6, IL-8, TNF-α and CRP levels after dietary intervention (all p > 0.2).
Conclusion: Circulating visfatin concentration is associated with sensitivity improvement achieved after energy restricted diet intervention induced weight loss. Furthermore, LM changes could be an influencing factor on visfatin concentrations and consequently, on the improvement of insulin sensitivity after weight loss in obese non-diabetic women. Our findings did not provide any evidence for a role of visfatin increase on low-grade inflammation after weight loss.
Context: Effects of long-term calcium, with or without vitamin D, on hip bone mineral density (BMD) and bone turnover in sunny climates have not been reported.
Objective: The aim was to evaluate the effect of vitamin D added to calcium supplementation on hip dual-energy x-ray absorptiometry BMD and calcium-related analytes.
Design, Setting, and Participants: The study was a 5-yr randomized, controlled, double-blind trial of 120 community-dwelling women aged 70–80 yr.
Intervention: The interventions were 1200 mg/d calcium with placebo vitamin D (Ca group) or with 1000 IU/d vitamin D2 (CaD group), or double placebo (control).
Main Outcome Measures: Hip BMD, plasma 25-hydroxyvitamin D,biomarkers of bone turnover, PTH, and intestinal calcium absorption were measured.
Results: Hip BMD was preserved in CaD (−0.17%) and Ca (0.19%) groups but not controls (−1.27%) at yr 1 and maintained in the CaD group only at yr 3 and 5. The beneficial effects were mainly in those with baseline 25-hydroxyvitamin D levels below the median (68 nmol/liter). At yr 1, compared with controls, the Ca and CaD groups had 6.8 and 11.3% lower plasma alkaline phosphatase, respectively (p ≤ 0.02), and 28.7 and 34.5% lower urinary deoxypyridinoline to creatinine ratio, respectively (p ≤ 0.05). At 5 yr, this suppression was maintained only in the CaD group. CaD reduced PTH at 3 and 5 yr cf. controls (27.8 and 31.3%, p ≤ 0.005) in those with baseline PTH levels above the median (3.6 pmol/liter). Therapy did not affect intestinal calcium absorption at high carrier loads.
Conclusions: Addition of vitamin D to calcium has long-term beneficial effects on bone density in elderly women living in a sunny climate, probably mediated by a long-term reduction in bone turnover rate.
Objective: To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.
Design: Pragmatic open randomised controlled trial.
Setting: Practice nurse led clinics in primary care.
Participants: 3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.
Intervention: Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).
Main Outcome Measures: Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).
Results: 69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.
Conclusion: We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436,controlled trials registry.
Objectives: To determine the effectiveness of vitamin D and home-based quadriceps resistance exercise on reducing falls and improving the physical health of frail older people after hospital discharge.
Design: Multicenter, randomized, controlled trial with a factorial design.
Setting: Five hospitals in Auckland, New Zealand, and Sydney, Australia.
Participants: Two hundred forty-three frail older people.
Interventions: Patients were randomized to receive a single dose of vitamin D (calciferol, 300,000 IU) or placebo tablets and 10 weeks of high-intensity home-based quadriceps resistance exercise or frequency-matched visits.
Measurements: The primary endpoints were physical health according to the short-form health survey at 3 months and falls over 6 months. Physical performance and self-rated function were secondary endpoints. Assessments took place in the participants’ homes at 3 and 6 months after randomization and were performed by blinded assessors.
Results: There was no effect of either intervention on physical health or falls, but patients in the exercise group were at increased risk of musculoskeletal injury (risk ratio = 3.6, 95% confidence interval = 1.5–8.0). Vitamin D supplementation did not improve physical performance, even in those who were vitamin D deficient (<12 ng/mL) at baseline.
Conclusion: Neither vitamin D supplementation nor a home-based program of high-intensity quadriceps resistance exercise improved rehabilitation outcomes in frail older people after hospitalization. There was no effect of vitamin D on physical performance, and the exercises increased the risk of musculoskeletal injury. These findings do not support the routine use of these interventions at these dosages in the rehabilitation of frail older people.
Objective: To determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.
Design: Randomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.
Setting and Participants: 2686 people (2037 men and 649 women) aged 65–85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.
Main Outcome Measures: Fracture incidence and total mortality by cause.
Results: After five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, p = 0.04) for any first fracture and 0.67 (0.48 to 0.93, p = 0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, p = 0.18). Findings were consistent in men and women and in doctors and the general practice population.
Conclusion: Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community.
Antagonistic pleiotropy, the evolutionary theory of senescence, posits that age related somatic decline is the inevitable late-life by-product of adaptations that increase fitness in early life. That concept, coupled with recent findings in oncology and gerontology, provides the foundation for an integrative theory of vertebrate senescence that reconciles aspects of the ‘accumulated damage’ ‘metabolic rate’, and ‘oxidative stress’ models. We hypothesize that (1) in vertebrates, a telomeric fail-safe inhibits tumor formation by limiting cellular proliferation. (2) The same system results in the progressive degradation of tissue function with age. (3) These patterns are manifestations of an evolved antagonistic pleiotropy in which extrinsic causes of mortality favor a species-optimal balance between tumor suppression and tissue repair. (4) With that trade-off as a fundamental constraint, selection adjusts telomere lengths—longer telomeres increasing the capacity for repair, shorter telomeres increasing tumor resistance. (5) In environments where extrinsically induced mortality is frequent, selection against senescence is comparatively weak as few individuals live long enough to suffer a substantial phenotypic decline. The weaker the selection against senescence, the further the optimal balance point moves toward shorter telomeres and increased tumor suppression. The stronger the selection against senescence, the farther the optimal balance point moves toward longer telomeres, increasing the capacity for tissue repair, slowing senescence and elevating tumor risks. (6) In iteroparous organisms selection tends to co-ordinate rates of senescence between tissues, such that no one organ generally limits life-span. A subsidiary hypothesis argues that senescent decline is the combined effect of (1) uncompensated cellular attrition and (2) increasing histological entropy. Entropy increases due to a loss of the intra-tissue positional information that normally regulates cell fate and function. Informational loss is subject to positive feedback, producing the ever-accelerating pattern of senescence characteristic of iteroparous vertebrates. Though telomere erosion begins early in development, the onset of senescence should, on average, be deferred to the species-typical age of first reproduction, the balance point at which selection on this trade-off should allow exhaustion of replicative capacity to overtake some cell lines. We observe that captive-rodent breeding protocols, designed to increase reproductive output, simultaneously exert strong selection against reproductive senescence and virtually eliminate selection that would otherwise favor tumor suppression. This appears to have greatly elongated the telomeres of laboratory mice. With their telomeric failsafe effectively disabled, these animals are unreliable models of normal senescence and tumor formation. Safety tests employing these animals likely overestimate cancer risks and underestimate tissue damage and consequent accelerated senescence.
The long term effects of hormone replacement therapy (HRT) and vitamin D3 (Vit D) on bone mineral density (BMD) were studied. A total of 464 nonosteoporotic early postmenopausal women from the Kuopio Osteoporosis Study (n = 13100) were randomized to 4 groups: (1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate), (2) Vit D3 (300 and 100 IU/day during the fifth year), (3) HRT and Vit D combined, and (4) placebo. Lumbar (L2–L4)and femoral neck BMD were determined by dual x-ray absorptiometry(DXA) at baseline and after 2.5 and 5 yr of treatment.
Intention to treat analysis (n = 464) showed that after 5 yr, lumbar BMD remained unchanged in the HRT and HRT plus Vit D groups[+ 0.2% (p = 0.658) and +0.9% (p = 0.117), respectively], whereas lumbar BMD decreased by 4.6% in the Vit D group and by 4.5% in the placebo group (p < 0.001 in both). The loss of femoral neck BMD was less inthe HRT (−1.4%; p = 0.005) and HRT plus Vit D (−1.3%; p = 0.003) groups than in the Vit D and placebo groups (−4.3%; p < 0.001 in both). Among those 370 women who complied with the 5-yr treatment, the effect was more pronounced: lumbar BMD had increased by 1.5% in theHRT (p = 0.009) and by 1.8% in the HRT plus Vit D group (p = 0.005), with a plateau after 2.5 yr, whereas lumbar BMD had decreased in both the Vit D and placebo groups (4.6% and 4.7%; p < 0.001, respectively). Femoral neck BMD decreased again less in the HRT(−0.4%) and HRT plus Vit D (−0.6%) groups than in the Vit D and placebo groups (−4.4% in both).
This study confirms the positive long term effect of HRT on BMD also seen in intention to treat analysis. The data suggest that low dose vitamin D3 supplementation does not prevent bone loss in healthy, nonosteoporotic, early postmenopausal women, and it confers no benefit additional to that of HRT alone.
We have found that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type.
This lifespan extension, the largest yet reported in any organism, requires the activity of a second gene, daf-16. Both genes also regulate formation of the dauer larva, a developmentally arrested larval form that is induced by crowding and starvation and is very long-lived.
Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation. daf-2 and daf-16 provide entry points into understanding how lifespan can be extended.