Old Human Cells Rejuvenated – resveratrol in dark choco, berries and grapes

Old Human Cells Rejuvenated in Breakthrough Discovery on Aging

Summary: Resveratrol analogues appears to switch splicing factors back on, causing cells to look younger, start rejuvenating and behaving like young cells within hours of exposure, a new study reports.Source: University of Exeter.

A team led by Professor Lorna Harries, Professor of Molecular Genetics at the University of Exeter, has discovered a new way to rejuvenate inactive senescent cells. Within hours of treatment the older cells started to divide, and had longer telomeres – the ‘caps’ on the chromosomes which shorten as we age.

The researchers applied compounds called resveratrol analogues, chemicals based on a substance naturally found in red wine, dark chocolate, red grapes and blueberries, to cells in culture.

resve.JPG

This discovery, funded by the Dunhill Medical Trust, builds on earlier findings from the Exeter group that showed that a class of genes called splicing factors are progressively switched off as we age. The University of Exeter research team, working with Professor Richard Faragher and Dr Elizabeth Ostler from the University of Brighton, found that splicing factors can be switched back on with chemicals, making senescent cells not only look physically younger, but start to behave more like young cells and start dividing.

The researchers applied compounds called resveratrol analogues, chemicals based on a substance naturally found in red wine, dark chocolate, red grapes and blueberries, to cells in culture.

The chemicals caused splicing factors, which are progressively switched off as we age to be switched back on. Within hours, the cells looked younger and started to rejuvenate, behaving like young cells and dividing.

The research, Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence, is published in the journal, BMC Cell Biology.

The discovery has the potential to lead to therapies which could help people age better, without experiencing some of the degenerative effects of getting old. Most people by the age of 85 have experienced some kind of chronic illness, and as people get older they are more prone to stroke, heart disease and cancer.

Professor Harries said: “This is a first step in trying to make people live normal lifespans, but with health for their entire life. Our data suggests that using chemicals to switch back on the major class of genes that are switched off as we age might provide a means to restore function to old cells.”

Dr Eva Latorre, Research Associate at the University of Exeter, who carried out the experiments, was surprised by the extent and rapidity of the changes in the cells.

“When I saw some of the cells in the culture dish rejuvenating I couldn’t believe it. These old cells were looking like young cells. It was like magic,” she said. “I repeated the experiments several times and in each case the cells rejuvenated. I am very excited by the implications and potential for this research.”

As we age, our tissues accumulate senescent cells which are alive but do not grow or function as they should. These old cells lose the ability to correctly regulate the output of their genes. This is one reason why tissues and organs become susceptible to disease as we age. When activated, genes make a message that gives the instructions for the cell to behave in a certain way. Most genes can make more than one message, which determines how the cell acts.

cells

Splicing factors are crucial in ensuring that genes can perform their full range of functions. One gene can send out several messages to the body to perform a function – such as the decision whether or not to grow new blood vessels – and the splicing factors make the decision about which message to make.

As people age, the splicing factors tend to work less efficiently or not at all, restricting the ability of cells to respond to challenges in their environment. Senescent cells, which can be found in most organs from older people, also have fewer splicing factors.

Professor Harries added:

“This demonstrates that when you treat old cells with molecules that restore the levels of the splicing factors, the cells regain some features of youth. They are able to grow, and their telomeres – the caps on the ends of the chromosomes that shorten as we age – are now longer, as they are in young cells. Far more research is needed now to establish the true potential for these sort of approaches to address the degenerative effects of ageing. ”

Professor Richard Faragher of the University of Brighton, will today argue for more research into the degenerative effects of ageing in a debate into whether science should be used to extend people’s lifespans.

“At a time when our capacity to translate new knowledge about the mechanisms of ageing into medicines and lifestyle advice is limited only by a chronic shortage of funds, older people are ill-served by self-indulgent science fiction. They need practical action to restore their health and they need it yesterday,” he said.

Professor Faragher added: “Our discovery of cell rejuvenation using these simple compounds shows the enormous potential of ageing research to improve the lives of older people”

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Funding: Funding provided by Dunhill Medical Trust, University of Brighton, Glenn Foundation for Medical Research, BBSRC.

Source: Marie Woolf – University of Exeter
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to University of Exeter.
Original Research: Full open access research for “Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence” by Eva Latorre, Vishal C. Birar, Angela N. Sheerin, J. Charles C. Jeynes, Amy Hooper, Helen R. Dawe, David Melzer, Lynne S. Cox, Richard G. A. Faragher, Elizabeth L. Ostler and Lorna W. Harries in BMC Cell Biology. Published online October 17 2017 doi:10.1186/s12860-017-0147-7

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Abstract

Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

Background

Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence.

Results

Treatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists.

Conclusions

This is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.

“Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence” by Eva Latorre, Vishal C. Birar, Angela N. Sheerin, J. Charles C. Jeynes, Amy Hooper, Helen R. Dawe, David Melzer, Lynne S. Cox, Richard G. A. Faragher, Elizabeth L. Ostler and Lorna W. Harries in BMC Cell Biology. Published online October 17 2017 doi:10.1186/s12860-017-0147-7


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Natural communication breakdown in aging

A naturally produced compound rewinds aspects of age-related demise in mice.

Researchers have discovered a cause of aging in mammals that may be reversible.

The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

This image shows and labels the mitochondria.

“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”

This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

The findings are published Dec. 19 in Cell.

Communication breakdown

Mitochondria are often referred to as the cell’s “powerhouse,” generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.

Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.

Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.

The is the SIRT1 protein.

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

“This was at odds with what the literature suggested,” said Gomes.

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell’s ability to make energy, and signs of aging and disease become apparent.

“This particular component of the aging process had never before been described,” said Gomes.

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.

This is a diagram which shows what happens when the nucleus breaks down.

Cancer connection

Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.

One particularly important aspect of this finding involvesHIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.

“It’s certainly significant to find that a molecule that switches on in many cancers also switches on during aging,” said Gomes. “We’re starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age.”

“There’s clearly much more work to be done here, but if these results stand, then certain aspects of aging may be reversible if caught early,” said Sinclair.

The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.

Notes about this neurogenetics and aging research

The Sinclair lab is funded by the National Institute on Aging (NIA/NIH), the Glenn Foundation for Medical Research, the Juvenile Diabetes Research Foundation, the United Mitochondrial Disease Foundation and a gift from the Schulak family.

Written by David Cameron
Contact: David Cameron – Harvard University
Source: Harvard University press release
Image Source: The images are credited to Ana Gomes and are adapted from the Harvard press release.
Original Research: Abstract for “Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging” by Ana P. Gomes, Nathan L. Price, Alvin J.Y. Ling, Javid J. Moslehi, Magdalene K. Montgomery, Luis Rajman, James P. White, João S. Teodoro, Christiane D. Wrann, Basil P. Hubbard, Evi M. Mercken, Carlos M. Palmeira, Rafael de Cabo, Anabela P. Rolo, Nigel Turner, Eric L. Bell, and David A. Sinclair in Cell. Published online December 19 2013 doi:10.1016/j.cell.2013.11.037


Here are four foods that are good sources of resveratrol

Red Grapes

Grapes don’t have to be fermented to contain this antioxidant. It’s actually found in the skin of red grapes along with other nutrients, such as minerals manganese and potassium and vitamins K, C and B1.

Peanut Butter

Peanut butter is great for dressing up apples and celery, but it also contains some resveratrol (up to .13 mg per cup). Peanut butter is a great source of niacin and manganese.

Dark Chocolate

In dark chocolate, resveratrol blends nicely with other antioxidants and also minerals, such as iron, copper and manganese. Who doesn’t like chocolate?

Blueberries

Blueberries don’t have quite as much resveratrol as grapes, but they are also a great source of other antioxidants, dietary fiber, vitamins C and K and manganese.


NAD

Nicotinamide adenine dinucleotide (NADH) supplements can be used by people struggling with clinical depression, those affected by Alzheimer’s disease and Parkinson’s disease as well as people with long term chronic fatigue syndrome. The beneficial effects of nicotinamide adenine dinucleotide (NADH) will best be felt after supplementation goes on for some period of time. Each patient may respond to the supplement in a different way.

Some condition specific uses of NADH are discussed below in brief.

Nicotinamide adenine dinucleotide (NADH) facilitates in providing relief from a health condition known as chronic fatigue syndrome.

The nicotinamide adenine dinucleotide (NADH) is primarily found in the foods like fish, all poultry, and cattle, and in yeast containing food products.

Though it may be a little hard to find, NADH supplements can be found in some health food stores.

Nevertheless, it is yet to be ascertained whether the body is able to effectively take up or make use of the NADH obtained from the above mentioned sources. In addition to the sources mentioned above, NADH is also available in the form of a dietary supplement.

Deficiencies and susceptibility

A deficiency of nicotinamide adenine dinucleotide (NADH) can only happen if the diet is deficient in vitamin B3, and except in long term alcoholics, deficiencies of the vitamin B3 is almost unknown in the modern western world.

Diet and exercise for Alzheimer’s and Parkinson

tai chijogactionmouseresveratrolbbb brain capilliariesDEMENTIANVU

Recent studies report that diet can mediate the vasculoplastic reserve of the hippocampus. For example, consuming high levels of cocoa flavanols increased capillary density and enhanced dentate gyrus-associated cognitive function in cognitively normal healthy subjects. This suggests an interaction between vasculoplasticity and neuronal plasticity during normal aging and dementia, but how this relationship is affected by lifestyle and vascular risk factors is currently unclear and should be investigated in future studies.

Growing evidence supports the benefits of a Mediterranean diet in protecting against dementia and prolonging one’s cognitive reserve during aging. Age-related cognitive decline was attenuated in individuals consuming a Mediterranean diet, as found in a recent study of the Mediterranean-Dietary Approach to Systolic Hypertension (DASH)

Diet intervention for neurodegenerative delay. In comparing Mediterranean and Western diets, the primary difference is the source and proportion of dietary fats, with olive oil specifically being the main fat consumed in the Mediterranean diet and high levels of saturated fatty acids and simple carbohydrates being consumed in Western diets. Microvascular dysfunction is evident in rodent models fed unhealthy diets, namely, those fed diets of Western culture [219], high fat [220], and high cholesterol [221]. An intact BBB is needed for proper cholesterol metabolism. In CSF, decreased cholesterol levels correlate with decreased Aβ42 and increased CSF APPα and APPβ (products of APP processing) levels, supporting an association between disrupted cholesterol metabolism and increased amyloidogenesis.

Resveratrol is a biologically active plant-derived phytoalexin. Resveratrol has been shown to cross BBB and regulate expression of MMPs, reduce pericyte loss, maintain integrity of BBB, and promote Aβ clearance. Treatment with resveratrol completely reversed diabetes-induced vascular dysfunction by reducing capillary leakage, pericyte degeneration, and VEGF protein expression in the murine retina. An earlier study has shown that resveratrol inhibits RAGE expression in vascular cells , which is implicated in Aβ transport into the brain and accelerated Aβ pathology in a mousemodel].

Furthermore, long-term consumption of resveratrol reduced oxidative stress and prevented behavioral deficits in a rat model with disrupted NVU.

Olive oil is high in essential omega-3 fatty acids, the major component of which is docosahexaenoic acid (DHA), and has long been reported to benefit cognition and overall brain health.

DHA cannot be synthesized by the body and thus must be consumed, and the primary transporter of DHA from blood-to-brain is the major facilitator superfamily domain containing 2A (MFSD2A) at the BBB. Individuals with AD have lower CSF DHA lipid levels, and those with mild dementia have lower CSF α-liolenic acid levels. Interestingly, reduced MFSD2A expression at the BBB can lead to a loss of its important functions, including maintenance of BBB integrity and omega-3 fatty acid transport into the brain.

Transgenic APOE4 mice also exhibit reduced uptake of DHA into the brain compared with transgenic APOE2 mice, but whether this is related to reduced Mfsd2a expression is currently unknown. Additional studies are needed elucidate the underlying mechanisms of MFSD2A and fatty acids in relation to dementia and AD.

Exercise and environmental enrichment

Regular exercise and physical activity, particularly during midlife, are associated with improved cerebrovascular function and reduced rates of dementia and AD [236]. Individuals that exercised regularly for 28 days exhibited reduced plasma homocysteine levels and increased endothelial progenitor cells in peripheral blood, factors that protect against vascular damage and cognitive impairment .

Experimental studies in diabetic rats have shown that treadmill exercise maintains claudin-5 expression at the BBB compared to rats not receiving exercise.

Physical activity and cognitive stimulation in the form of enriched environment (e.g., tunnels, balls, ladders, and running wheel) accelerated Aβ enzymatic degradation and enhanced transvascular Aβ clearance, reducing Aβ accumulation in brains of AD transgenic mouse models.

Additionally, physical activity promoted Aβ clearance from brain to blood via upregulation of LRP1 and downregulation of RAGE at the BBB. Mice without access to a running wheel had decreased occludin tight junction levels and disrupted BBB integrity.

Sources of resveratrol

Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants in response to injury or when the plant is under attack by pathogens such as bacteria or fungi. Food sources of resveratrol include the skin of grapes, blueberries, raspberries, mulberries, and senna.

Here are 5 foods that are great sources of resveratrol:

Red Grapes

Grapes don’t have to be fermented to contain this antioxidant. It’s actually found in the skin of red grapes along with other nutrients, such as minerals manganese and potassium and vitamins K, C and B1.

Peanut Butter

Peanut butter is great for dressing up apples and celery, but it also contains some resveratrol (up to .13 mg per cup). Peanut butter is a great source of niacin and manganese.

Dark Chocolate

In dark chocolate, resveratrol blends nicely with other antioxidants and also minerals, such as iron, copper and manganese. Who doesn’t like chocolate?

Itadori Tea

Used in Japan and China as a traditional herbal remedy for the prevention of heart disease and strokes, itadori tea: contains resveratrol, consequently, The Journal of Agricultural Food Chemistry studies state that, ”For people who do not consume alcohol, Itadori tea may be a suitable substitute for red wine.”

Blueberries

Blueberries don’t have quite as much resveratrol as grapes, but they are also a great source of other antioxidants, dietary fiber, vitamins C and K and manganese.

For all of the above, it would be wise to choose organic sources to reduce pesticides, especially for red grapes, peanut butter and chocolate.

 Low doses of resveratrol improve cell survival as a component of cardio- and neuro-protection, while high doses increase cell death, so this is always something to keep in mind before purchasing supplements with the next greatest dose.

 “Reports on the benefits of red wine are almost two centuries old,” said Lindsay Brown, associate professor in the School of Biomedical Sciences at The University of Queensland

 * Resveratrol exhibits therapeutic potential for cancer chemoprevention as well as cardioprotection.

 “It sounds contradictory that a single compound can benefit the heart by preventing damage to cells, yet prevent cancer by causing cell death, said Brown. “The most likely explanation for this, still to be rigorously proved in many organs, is that low concentrations activate survival mechanisms of cells while high concentrations turn on the in-built death signals in these cells.”

 * Resveratrol may aid in the prevention of age-related disorders, such as neurodegenerative diseases, inflammation, diabetes, and cardiovascular disease.

 “The simplest explanation is that resveratrol turns on the cell’s own survival pathways, preventing damage to individual cells,” said Brown. “Further mechanisms help, including removing very reactive oxidants in the body and improving blood supply to cells.”

 * Low doses of resveratrol improve cell survival as a mechanism of cardio- and neuro-protection, while high doses increase cell death.

 “The key difference is probably the result of activation of the sirtuins in the nucleus,” said Brown. “Low activation reverses age-associated changes, while high activation increases the process of apoptosis or programmed cell death to remove cellular debris. Similar changes are seen with low-dose versus high-dose resveratrol: low-dose resveratrol produces cellular protection and reduces damage, while high-dose resveratrol prevents cancers.”

Source:

Neurovascular dysfunction and neurodegeneration in Dementia/Alzheimer’s disease

Amy R. Nelson, Melanie D. Sweeney, Abhay P. Sagare, Berislav V. Zlokovic

Department of Physiology and Biophysics and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA

 

Aging is a curable disease

Cambridge researcher Aubrey de Grey argues that aging is merely a disease — and a curable one at that. Humans age in seven basic ways, he says, all of which can be averted.

Aubrey de Grey, British researcher on aging, claims he has drawn a roadmap to defeat biological aging. He provocatively proposes that the first human beings who will live to 1,000 years old have already been born

A true maverick, Aubrey de Grey challenges the most basic assumption underlying the human condition — that aging is inevitable. He argues instead that aging is a disease — one that can be cured if it’s approached as “an engineering problem.” His plan calls for identifying all the components that cause human tissue to age, and designing remedies for each of them — forestalling disease and eventually pushing back death. He calls the approach Strategies for Engineered Negligible Senescence (SENS).

With his astonishingly long beard, wiry frame and penchant for bold and cutting proclamations, de Grey is a magnet for controversy. A computer scientist, self-taught biogerontologist and researcher, he has co-authored journal articles with some of the most respected scientists in the field.

But the scientific community doesn’t know what to make of him. In July 2005, the MIT Technology Review challenged scientists to disprove de Grey’s claims, offering a $20,000 prize (half the prize money was put up by de Grey’s Methuselah Foundation) to any molecular biologist who could demonstrate that “SENS is so wrong that it is unworthy of learned debate.” The challenge remains open; the judging panel includes TEDsters Craig Venter and Nathan Myhrvold. It seems that “SENS exists in a middle ground of yet-to-be-tested ideas that some people may find intriguing but which others are free to doubt,” MIT’s judges wrote. And while they “don’t compel the assent of many knowledgeable scientists,” they’re also “not demonstrably wrong.”

“Aubrey de Grey is a man of ideas, and he has set himself toward the goal of transforming the basis of what it means to be human.”
MIT Technology Review
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Quotes by Aubrey de Grey.
“It’s not just about life, of course; it’s about healthy life. Getting frail and miserable and dependent is no fun, whether or not dying may be fun.”

“[Anti-aging therapies will] never be perfect, but we’ll be able to fix the things that 200-year-olds die of before we have any 200-year-olds, and the same for 300 and 400 and so on.”

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