Amazing Science

Researchers have developed a biosynthetic “clock” that keeps cells from reaching normal levels of deterioration related to aging. They engineered a gene oscillator that switches between the two normal paths of aging, slowing cell degeneration and setting a record for life extension.

Aber-clam Lincoln, a quahog clam believed to be 214 years old found at Alligator Point, was released into the Gulf of Mexico Friday by his caretakers at the Gulf Specimen Marine Lab in Panacea.  Americorps member Blaine Parker dug up the two-century old mollusk while collecting shellfish to make chowder.  Parker said it is hefty enough to make two servings and has shells large enough to use as bowls to serve it in.  “We were just going to eat it, but we thought about it a while and figured it was probably pretty special. So, we didn’t want to kill it,” said Parker. 

Instead, he took it to the aquarium at the Gulf Specimen Marine Lab where he works as a specimen collector.  While most Ocean quahogs are within 2.8 to 4.3 inches in length and weigh up to a half pound, Lincoln checks in at 6 inches and weighs 2.6 pounds.  The clam has been drawing up to 100 visitors a day. 

Parker is a recent Eckerd College graduate with a degree in environmental studies and marine science. He said, a clam, like a tree, lays down annual growth bands, alternating bands of light on its shell, that scientists used to estimate its age.   There are 214 layers on the shell of the clam he found, which would mean it was likely born in 1809, the same year as Abraham Lincoln. It was also discovered on Presidents Day weekend. So, Parker named his find Aber-clam Lincoln. 

Quahogs occur in the Atlantic from Greenland south to North Carolina. They move about by being tossed in the surf, and crawl along the sand by expanding and contracting their muscle. 

With Lincoln being so old it is possible, like many Floridians, circumstances moved him south for him to become one of the oldest known Florida transplants. 

Quahogs are known to live 200 or more years. A 507-year-old clam, found in the Icelandic seabed and named Ming, broke the Guinness World Record for oldest animal when it was discovered in 2007. Scientists think an incredible low metabolic rates of Lincoln and other quahogs is responsible for their long life.

A University of Kansas study of the energy needs of 299 species of extinct and living bivalves found those with minimal energy requirements escaped extinction. 

Telomeres are "caps" of non-coding DNA sequences present at both tips of all chromosomes, which are extremely important in the aging process. These caps protect DNA as cells go through various life cycles of replication, however, each time a cell divides these telomeres are shortened and eventually contribute to disease and cellular aging. Now, exciting new research published in the Journal PNAS has shown that an experimental gene therapy could be used to halt the shortening of these telomere caps in mice and by doing so increase the life span of these animals by up to 41 percent compared to controls.

Telomere length can be considered a marker of biological age and its shortening is a hallmark of a process called cellular senescence, which limits the replication of DNA in old damaged cells. As we age, telomere caps become shorter and shorter until the cell's DNA becomes vulnerable to damage by cellular stresses that could lead to diseases such as cancer. Or the cell could ultimately reach senescence where it will no longer be able to replicate and so contribute to the aging process. For scientists looking at how to slow or even reverse aging, telomeres are of great interest. One of the reasons telomeres shorten over time is due to the reduced activity of an enzyme called telomerase which is responsible for maintaining the length of the telomere caps on chromosomes. The function of telomerase relies on a complex called telomerase reverse transcriptase (TERT). This complex activates telomerase, allowing the enzyme to be biologically active in cells, which in turn lengthens the telomeres on the tips of chromosomes.

The authors of the new study developed a gene therapy protocol using cytomegaloviruses (CMV) to deliver TERT to cells in different organs of mice. They wanted to see if it could increase telomerase activity responsible for lengthening telomere tips in biologically older animals versus those given a mock delivery as a control group. They then compare the results to normal wild-type animals of a similar biological age.  The scientists were able to successfully deliver the gene to the animals using their protocol.

They found the telomeres of chromosomes in some organs, such as the kidney, increased in length in TERT treated mice vs controls and that it had an overall positive effect on glucose metabolism which is known to decline during aging. The results also showed evidence that the treatment helped to prevent hair loss and improved the animal's motor activity and coordination. Moreover, the scientists say that the treatment with TERT did not increase the cancer risk of these animals, which is normally a concern in telomere research. Overall, TERT-treated animals had an extended lifespan of 41 percent compared to mock and wild-type control animals, which is a promising result.

Alongside TERT delivery, the authors used the same protocol with a gene for follistatin in a different cohort of mice. Follistatin is involved in maintaining skeletal muscle development, which is also known to decline as we age. The animals that received follistatin also had an increased lifespan of 32 percent, with similar benefits to those seen in the TERT-treated mice, illustrating both TERT and Follistatin may be able to offset biological aging in mouse models.

"We report CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity," the authors write. "Specifically, this treatment significantly improved glucose tolerance, physical performance, as well as preventing body mass loss and alopecia.

Further, telomere shortening associated with aging was ameliorated by TERT and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects." 

Going forward the scientists say that translational studies will be required to determine whether these results could be replicated in human subjects.

Over the last few decades, life expectancy has increased dramatically around the globe. The average person born in 1960, the earliest year the United Nations began keeping global data, could expect to live to 52.5 years of age. Today, the average is 72. In the UK, where records have been kept longer, this trend is even greater. In 1841, a baby girl was expected to live to just 42 years of age, a boy to 40. In 2016, a baby girl could expect to reach 83; a boy, 79.

The natural conclusion is that both the miracles of modern medicine and public health initiatives have helped us live longer than ever before – so much so that we may, in fact, be running out of innovations to extend life further. In September 2018, the Office for National Statistics confirmed that, in the UK at least, life expectancy has stopped increasing. Beyond the UK, these gains are slowing worldwide. This belief that our species may have reached the peak of longevity is also reinforced by some myths about our ancestors: it’s common belief that ancient Greeks or Romans would have been flabbergasted to see anyone above the age of 50 or 60, for example.

In fact, while medical advancements have improved many aspects of healthcare, the assumption that human life span has increased dramatically over centuries or millennia is misleading. Overall life expectancy, which is the statistic reflected in reports like those above, hasn’t increased so much because we’re living far longer than we used to as a species. It’s increased because more of us, as individuals, are making it that far.

“There is a basic distinction between life expectancy and life span,” says Stanford University historian Walter Scheidel, a leading scholar of ancient Roman demography. “The life span of humans – opposed to life expectancy, which is a statistical construct – hasn’t really changed much at all, as far as I can tell.”

Life expectancy is an average. If you have two children, and one dies before their first birthday but the other lives to the age of 70, their average life expectancy is 35. That’s mathematically correct – and it certainly tells us something about the circumstances in which the children were raised. But it doesn’t give us the full picture. It also becomes especially problematic when looking at eras, or in regions, where there are high levels of infant mortality. Most of human history has been blighted by poor survival rates among children, and that continues in various countries today.

A study led by Fernando Colchero, University of Southern Denmark and Susan Alberts, Duke University, North Carolina, that included researchers from 42 institutions across 14 countries, provides new insights into the aging theory "the invariant rate of aging hypothesis," which states that every species has a relatively fixed rate of aging.

"Human death is inevitable. No matter how many vitamins we take, how healthy our environment is or how much we exercise, we will eventually age and die," said Fernando Colchero.

A new study by EPFL researchers shows how RNA species called TERRA muster at the tip of chromosomes, where they help to prevent telomere shortening and premature cell aging.

Molecules that accumulate at the tip of chromosomes are known to play a key role in preventing damage to our DNA. Now, researchers at EPFL have unraveled how these molecules home in on specific sections of chromosomes—a finding that could help to better understand the processes that regulate cell survival in aging and cancer.

Much like an aglet of a shoelace prevents the end of the lace from fraying, stretches of DNA called telomeres form protective caps at the ends of chromosomes. But as cells divide, telomeres become shorter, making the protective cap less effective. Once telomeres get too short, the cell stops dividing. Telomere shortening and malfunction have been linked to cell aging and age-related diseases, including cancer.

Scientists have known that RNA species called TERRA help to regulate the length and function of telomeres. Discovered in 2007 by postdoc Claus Azzalin in the team of EPFL Professor Joachim Lingner, TERRA belongs to a class of molecules called noncoding RNAs, which are not translated into proteins but function as structural components of chromosomes. TERRA accumulates at chromosome ends, signaling that telomeres should be elongated or repaired.

However, it was unclear how TERRA got to the tip of chromosomes and remained there. “The telomere makes up only a tiny bit of the total chromosomal DNA, so the question is ‘how does this RNA find its home?’”, Lingner says. To address this question, postdoc Marianna Feretzaki and others in the teams of Joachim Lingner at EPFL and Lumir Krejci at Masaryk University set out to analyze the mechanism through which TERRA accumulates at telomeres, as well as the proteins involved in this process. The findings are published in Nature.

New study suggests that plasma exchange could be the key to unlocking the body’s regenerative capacities.

In 2005, University of California, Berkeley, researchers made the surprising discovery that making conjoined twins out of young and old mice — such that they share blood and organs — can rejuvenate tissues and reverse the signs of aging in the old mice. The finding sparked a flurry of research into whether a youngster’s blood might contain special proteins or molecules that could serve as a “fountain of youth” for mice and humans alike.

But a new study by the same team shows that similar age-reversing effects can be achieved by simply diluting the blood plasma of old mice — no young blood needed.

In the new study, the team found that replacing half of the blood plasma of old mice with a mixture of saline and albumin — where the albumin simply replaces protein that was lost when the original blood plasma was removed — has the same or stronger rejuvenation effects on the brain, liver and muscle than pairing with young mice or young blood exchange. Performing the same procedure on young mice had no detrimental effects on their health.

This discovery shifts the dominant model of rejuvenation away from young blood and toward the benefits of removing age-elevated, and potentially harmful, factors in old blood. “There are two main interpretations of our original experiments: The first is that, in the mouse joining experiments, rejuvenation was due to young blood and young proteins or factors that become diminished with aging, but an equally possible alternative is that, with age, you have an elevation of certain proteins in the blood that become detrimental, and these were removed or neutralized by the young partners,” said Irina Conboy, a professor of bioengineering at UC Berkeley who is the first author of the 2005 mouse-joining paper and senior author of the new study . “As our science shows, the second interpretation turns out to be correct. Young blood or factors are not needed for the rejuvenating effect; dilution of old blood is sufficient.”

The roundworm Caenorhabditis elegans is helping scientists understand how the brain controls aging, including age-related muscle atrophy.

While many of us worry about proteins aggregating in our brains as we age and potentially causing Alzheimer’s disease or other types of neurodegeneration, we may not realize that some of the same proteins are aggregating in our muscles, setting us up for muscle atrophy in old age.

University of California, Berkeley, scientists have now found brain cells that help clean up these tangles and prolong life — at least in worms and possibly mice. This could lead to drugs that improve muscle health or extend a healthy human lifespan.

The research team’s most recent discovery, published Jan. 24 in the journal Science, is that a mere four glial cells in the worm’s brain control the stress response in cells throughout its body and increase the worm’s lifespan by 75%. That was a surprise, since glial cells are often dismissed as mere support cells for the neurons that do the brain’s real work, like learning and memory.

This finding follows a 2013 study in which the UC Berkeley group reported that neurons help regulate the stress response in peripheral cells, though in a different way than glial cells, and lengthen a worm’s life by about 25%. In mice, boosting neuronal regulation increases lifespan by about 10%.

Together, these results paint a picture of the brain’s two-pronged approach to keeping the body’s cells healthy. When the brain senses a stressful environment — invading bacteria or viruses, for example — a subset of neurons sends electrical signals to peripheral cells to get them mobilized to respond to the stress, such as through breaking up tangles, boosting protein production and mobilizing stored fat. But because electrical signals produce only a short-lived response, the glial cells kick in to send out a long-lasting hormone, so far unidentified, that maintains a long-term, anti-stress response.

Wyss Institute, Harvard Medical School study offers hope for single genetic treatment for multiple age-related ills.

New research from the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School (HMS) suggests that it may be possible someday to tend to multiple ailments with one treatment.

In the Wyss study, a single administration of an adeno-associated virus (AAV)-based gene therapy, which delivered combinations of three longevity-associated genes to mice, dramatically improved or completely reversed multiple age-related diseases, suggesting that a systems-level approach to treating such diseases could improve overall health and lifespan. The research is reported in PNAS.

“The results we saw were stunning and suggest that holistically addressing aging via gene therapy could be more effective than the piecemeal approach that currently exists,” said first author Noah Davidsohn, a former research scientist at the Wyss Institute and HMS who is now chief technology officer of Rejuvenate Bio. “Everyone wants to stay as healthy as possible for as long as possible, and this study is a first step toward reducing the suffering caused by debilitating diseases.”

The study was conducted in the lab of Wyss core faculty member George Church as part of Davidsohn’s postdoctoral research into the genetics of aging. Davidsohn, Church, and their co-authors homed in on three genes that had been shown to confer increased health and lifespan benefits in mice that were genetically engineered to overexpress them: FGF21, sTGFβR2, and αKlotho. They hypothesized that providing extra copies of those genes to nonengineered mice via gene therapy would similarly combat age-related diseases and bring health benefits.

The team created separate gene therapy constructs for each gene using the AAV8 serotype as a delivery vehicle, and injected them into mouse models of obesity, Type 2 diabetes, heart failure, and renal failure both individually and in combination with the other genes to see whether there was a positive synergistic effect.

FGF21 caused complete reversal of weight gain and Type 2 diabetes in obese, diabetic mice following a single gene therapy administration, and its combination with sTGFβR2 reduced kidney atrophy by 75 percent in mice with renal fibrosis. Heart function in mice with heart failure improved by 58 percent when they were given sTGFβR2 alone or in combination with either of the other two genes, showing that a combined therapeutic treatment of FGF21 and sTGFβR2 could successfully treat all four age-related conditions, therefore improving health and survival. Administering all three genes together resulted in slightly worse outcomes, likely from an adverse interaction between FGF21 and αKlotho, which remains to be studied.

A new study from the University of Eastern Finland shows that a moderately high intake of dietary cholesterol or consumption of up to one egg per day is not associated with an elevated risk of stroke. Furthermore, no association was found in carriers of the apolipoprotein E phenotype 4 (APOE4), which affects cholesterol metabolism and is remarkably common among the Finnish population. The findings were published in theAmerican Journal of Clinical Nutrition.

Findings from earlier studies addressing the association of dietary cholesterol or egg intake with the risk of stroke have been contradictory. Some studies have found an association between high dietary cholesterol intake and an increased risk of stroke, while others have associated the consumption of eggs, which are high in cholesterol, with a reduced risk of stroke. For most people, dietary cholesterol plays a very small role in affecting their serum cholesterol levels. However, in carriers of APOE4 -- which significantly impacts cholesterol metabolism -- the effect of dietary cholesterol on serum cholesterol levels is greater.

In Finland, the prevalence of APOE4, which is a hereditary variant, is exceptionally high, with approximately one third of the population presenting as carriers. Yet, research data on the association between a high intake of dietary cholesterol and the risk of stroke in this population group has not been available until now.

The dietary habits of 1,950 men aged between 42 and 60 years with no baseline diagnosis of a cardiovascular disease were assessed at the onset the Kuopio Ischaemic Heart Disease Risk Factor Study, KIHD, in 1984-1989 at the University of Eastern Finland. APOE phenotype data were available for 1,015 of the men participating in the study. Of those, 32% were known carriers of APOE4.

During a follow-up of 21 years, 217 men were diagnosed with stroke. The study found that neither dietary cholesterol nor egg consumption was associated with the risk of stroke -- not even in carriers of APOE4.

An enzyme-blocking molecule can extend the lifespan of Caenorhabditis elegans roundworms by as much as 45 percent, largely by modulating a cannabinoid biological pathway, according to a new study.

Recent lab studies have shown that aging is a reversible process, an advancement that has prompted scientists to seek ways to stop the functional decline of cells and tissues, as well as restore their regenerative capacity. This includes researchers at the University at Buffalo, where chemical engineer Stelios Andreadis showed that the embryonic gene NANOG could reprogram senescent (aged) adult stem cells and skeletal muscle cells, thereby reversing the hallmarks of aging.

How exactly NANOG works, though, has been a mystery. Now, two new studies from Andreadis’ lab are helping to answer this question. One in Cell Reports explores the role NANOG plays in restoring mitochondrial function in aging stem cells. The other, published Feb. 16 in Nature Communications, sheds light on how it reverses aging in skeletal muscle.

The works builds upon the scientific community’s understanding of NANOG, which is named for the mythical land of youth in Irish folklore, and could help lead to the development of medicines that mimic the gene.

“With these studies, we discovered that NANOG reverses cellular senescence by restoring metabolic pathways that are active in younger cells. This brings us closer to developing improved treatments that will help alleviate suffering worldwide for people struggling with age-related illnesses,” said Andreadis, PhD, at SUNY.

An international team of 114 scientists, led by Penn State and Northeastern Illinois University, reports the most comprehensive study of aging and longevity to date comprising data collected in the wild from 107 populations of 77 species of reptiles and amphibians worldwide.

At 190 years old, Jonathan the Seychelles giant tortoise recently made news for being the "oldest living land animal in the world." Although, anecdotal evidence like this exists that some species of turtles and other ectotherms -- or 'cold-blooded' animals -- live a long time, evidence is spotty and mostly focused on animals living in zoos or a few individuals living in the wild. Now, an international team of 114 scientists, led by Penn State and Northeastern Illinois University, reports the most comprehensive study of aging and longevity to date comprising data collected in the wild from 107 populations of 77 species of reptiles and amphibians worldwide.

Research from the Babraham Institute has developed a method to ‘time jump’ human skin cells by 30 years, turning back the aging clock for cells without losing their specialized function. Work by researchers in the Institute’s Epigenetics research program has been able to partly restore the function of older cells, as well as rejuvenating the molecular measures of biological age. The research is published in the journal eLife and whilst at an early stage of exploration, it could revolutionize regenerative medicine.

How does it work?

As we age, our cells’ ability to function declines and the genome accumulates marks of aging. Regenerative biology aims to repair or replace cells including old ones. One of the most important tools in regenerative biology is our ability to create ‘induced’ stem cells. The process is a result of several steps, each erasing some of the marks that make cells specialized. In theory, these stem cells have the potential to become any cell type, but scientists aren’t yet able to reliably recreate the conditions to re-differentiate stem cells into all cell types.

The new method, based on the Nobel Prize winning technique scientists use to generate stem cells, overcomes the problem of entirely erasing cell identity by halting reprogramming part of the way through the whole process. This allowed researchers to find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialized cell function.

In 2007, Shinya Yamanaka was the first scientist to turn normal cells, which have a specific function, into stem cells which have the special ability to develop into any cell type. The full process of stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called 'maturation phase transient reprogramming’, exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.

Contrary to what science once suggested, older people with a declining sense of smell do not have comprehensively dampened olfactory ability for odors in general -- it simply depends upon the type of odor. Researchers at the University of Copenhagen reached this conclusion after examining a large group of older Danes' and their intensity perception of common food odors.

That older people aren't as good at smelling as they once were, is something that many can relate to. And, it has also been scientifically demonstrated. One's sense of smell gradually begins to decline from about the age of 55. Until now, it was believed that one's sense of smell broadly declined with increasing age. However, a study from the University of Copenhagen reports that certain food odors are significantly more affected than others.

The Department of Food Science's Eva Honnens de Lichtenberg Broge and her fellow researchers have tested the ability of older Danes to perceive everyday food odors. The researchers measured how intensely older adults perceived different food odors, as well as how much they liked the odors.

"Our study shows that the declining sense of smell among older adults is more complex than once believed. While their ability to smell fried meat, onions and mushrooms is markedly weaker, they smell orange, raspberry and vanilla just as well as younger adults. Thus, a declining sense of smell in older adults seems rather odor specific. What is really interesting is that how much you like an odor is not necessarily dependent on the intensity perception" says Eva Honnens de Lichtenberg Broge.

For example, liking of seemed to be largely unaffected for fried meat, onions and mushrooms, despite the largest decline in intensity perception was seen for these specific odors. Also the ability to smell coffee declined, among other things, though they didn't like the aroma of coffee to the same degree as younger adults.

The test subjects included 251 Danes between the ages of 60 and 98 and a control group consisting of 92 people between the ages of 20 and 39.

Even though people tend to remember fewer details about past events as time goes by, the details they do remember are retained with remarkable fidelity, according to a new study. This finding holds true regardless of the age of the person or the amount of time that elapsed since the event took place.

Scientists studying the complex relationship between aging and memory have found that in a controlled experiment, people can remember the details about past events with a surprising 94% accuracy, even accounting for age. These results, published in the journal Psychological Science, suggest that the stories we tell about past events are accurate, although details tend to fade with time.

“These results are surprising to many, given the general pessimism about memory accuracy among scientists and the prevalent idea that memory for one-time events is not to be trusted,” said Nicholas Diamond, the study’s lead researcher, a former graduate student at Baycrest’s Rotman Research Institute (RRI), and currently a postdoctoral researcher at the University of Pennsylvania.

“These results will be helpful for understanding memory in healthy aging.”Brian Levine, Baycrest’s Rotman Research Institute
About 400 academics, including memory scientists, surveyed as part of this study estimated memory accuracy to be around 40% at best, expecting this score to be even lower for older participants or when greater amounts of time had elapsed since the events.

“This study shows us that memory accuracy is actually quite good under normal circumstances, and it remains stable as we age,” said Brian Levine, a senior scientist at RRI and a professor of psychology and neurology at the University of Toronto and co-author on the study. “These results will be helpful for understanding memory in healthy aging.”

Scientists have estimated that the age of an individual does not indicate how likely they are to be infected by SARS-CoV-2. However, development of symptoms, progression of  the disease, and mortality are age-dependent.

There have been a large number of deaths due to the ongoing COVID-19 pandemic, and it has been shown that elderly individuals disproportionately develop severe symptoms and show higher mortality. 

A team of scientists, including Associate Professor Ryosuke Omori from the Research Center for Zoonoses Control at Hokkaido University, have modeled available data from Japan, Spain and Italy to show that susceptibility to COVID-19 is independent of age, while occurrence of symptomatic COVID-19, severity and mortality is likely dependent on age. Their results were published in the journal Scientific Reports on October 6, 2020.

Causes of mortality in elderly individuals may be due to two factors: how likely they are to be infected due to their advanced age (age-dependent susceptibility), which is reflected in the number of cases; and, how likely they will be affected by a severe form of the disease due to their advanced age (age-dependent severity), which is reflected in the mortality rate. These factors are not fully understood for COVID-19.

The scientists chose to analyse data from Italy, Spain and Japan to determine if any relationship between age, susceptibility and severity. These three countries were chosen as they have well recorded, publicly available data. As of May 2020, the mortality rate (number of deaths per 100,000) was 382.3 for Italy, 507.2 for Spain and 13.2 for Japan. However, despite the wide disparity in mortality rates, the age distribution of mortality (the proportional number of deaths per age group) was similar for these countries.

The WSU team’s findings suggest that Washingtonians who live in highly walkable, mixed‑age communities may be more likely to live to their 100th birthday.

When it comes to living to the ripe old age of 100, good genes help but don’t tell the full story. Where you live has a significant impact on the likelihood that you will reach centenarian age, suggests a new study conducted by scientists at Washington State University’s Elson S. Floyd College of Medicine.

Published in the International Journal of Environmental Research and Public Health and based on Washington State mortality data, the research team’s findings suggest that Washingtonians who live in highly walkable, mixed-age communities may be more likely to live to their 100th birthday. They also found socioeconomic status to be correlated, and an additional analysis showed that geographic clusters where the probability of reaching centenarian age is high are located in urban areas and smaller towns with higher socioeconomic status, including the Seattle area and the region around Pullman, Washington.

Old human cells return to a more youthful and vigorous state after being induced to briefly express a panel of proteins involved in embryonic development, according to a new study by researchers at the Stanford University School of Medicine. The researchers also found that elderly mice regained youthful strength after their existing muscle stem cells were subjected to the rejuvenating protein treatment and transplanted back into their bodies.

The proteins, known as Yamanaka factors, are commonly used to transform an adult cell into what are known as induced pluripotent stem cells, or iPS cells. Induced pluripotent stem cells can become nearly any type of cell in the body, regardless of the cell from which they originated. They've become important in regenerative medicine and drug discovery.

The study found that inducing old human cells in a lab dish to briefly express these proteins rewinds many of the molecular hallmarks of aging and renders the treated cells nearly indistinguishable from their younger counterparts.

"When iPS cells are made from adult cells, they become both youthful and pluripotent," said Vittorio Sebastiano, PhD, assistant professor of obstetrics and gynecology and the Woods Family Faculty Scholar in Pediatric Translational Medicine. "We've wondered for some time if it might be possible to simply rewind the aging clock without inducing pluripotency. Now we've found that, by tightly controlling the duration of the exposure to these protein factors, we can promote rejuvenation in multiple human cell types."

Sebastiano is the senior author of the study, which will be published online March 24 in Nature Communications. Former graduate student Tapash Sarkar, PhD, is the lead author of the article. "We are very excited about these findings," said study co-author Thomas Rando, MD, PhD, professor of neurology and neurological sciences and the director of Stanford's Glenn Center for the Biology of Aging. "My colleagues and I have been pursuing the rejuvenation of tissues since our studies in the early 2000s revealed that systemic factors can make old tissues younger. In 2012, Howard Chang and I proposed the concept of using reprogramming factors to rejuvenate cells and tissues, and it is gratifying to see evidence of success with this approach." Chang, MD, PhD, is a professor of dermatology and of genetics at Stanford.

Scientists at the MDI Biological Laboratory, in collaboration with scientists from the Buck Institute for Research on Aging in Novato, Calif., and Nanjing University in China, have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research.

The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists. The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

Because these pathways are “conserved,” meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.

“Despite the discovery in C. elegans of cellular pathways that govern aging, it hasn’t been clear how these pathways interact,” said Hermann Haller, M.D., president of the MDI Biological Laboratory. “By helping to characterize these interactions, our scientists are paving the way for much-needed therapies to increase healthy lifespan for a rapidly aging population.”

The elucidation of the cellular mechanisms controlling the synergistic response is the subject of a recent paper in the online journal Cell Reports entitled “Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity.” The authors include Jarod A. Rollins, Ph.D., and Aric N. Rogers, Ph.D., of the MDI Biological Laboratory.

“The synergistic extension is really wild,” said Rollins, who is the lead author with Jianfeng Lan, Ph.D., of Nanjing University. “The effect isn’t one plus one equals two, it’s one plus one equals five. Our findings demonstrate that nothing in nature exists in a vacuum; in order to develop the most effective anti-aging treatments we have to look at longevity networks rather than individual pathways.”

Scientists once thought that neurons, or possibly heart cells, were the oldest cells in the body. Now, Salk Institute researchers have discovered that the mouse brain, liver and pancreas contain populations of cells and proteins with extremely long lifespans -- some as old as neurons. The findings, demonstrating "age mosaicism," were published in Cell Metabolismon June 6, 2019.

The team's methods could be applied to nearly any tissue in the body to provide valuable information about lifelong function of non-dividing cells and how cells lose control over the quality and integrity of proteins and important cell structures during aging.

"We were quite surprised to find cellular structures that are essentially as old as the organism they reside in," says Salk Vice President, Chief Science Officer Martin Hetzer, senior author and professor. "This suggests even greater cellular complexity than we previously imagined and has intriguing implications for how we think about the aging of organs, such as the brain, heart and pancreas."

Explorers have dreamt for centuries of a Fountain of Youth, with healing waters that rejuvenate the old and extend life indefinitely.

SIRT6 is often called the "longevity gene" because of its important role in organizing proteins and recruiting enzymes that repair broken DNA; additionally, mice without the gene age prematurely, while mice with extra copies live longer. Researchers have long hypothesized that if more efficient DNA repair is required for a longer lifespan, organisms with longer lifespans may have evolved more efficient DNA repair regulators. Is SIRT6 activity therefore enhanced in longer-lived species?

To test this theory, the researchers analyzed DNA repair in 18 rodent species with lifespans ranging from 3 years (mice) to 32 years (naked mole rats and beavers). Scientists found that the rodents with longer lifespans also experience more efficient DNA repair because the products of their SIRT6 genes—the SIRT6 proteins—are more potent. That is, SIRT6 is not the same in every species. Instead, the gene has co-evolved with longevity, becoming more efficient so that species with a stronger SIRT6 live longer.

"The SIRT6 protein seems to be the dominant determinant of lifespan," Bohmann, one of the scientists, says. "We show that at the cell level, the DNA repair works better, and at the organism level, there is an extended lifespan."

The researchers then analyzed the molecular differences between the weaker SIRT6 protein found in mice versus the stronger SIRT6 found in beavers. They identified five amino acids responsible for making the stronger SIRT6 protein "more active in repairing DNA and better at enzyme functions," one member of the study says.

When the researchers inserted beaver and mouse SIRT6 into human cells, the beaver SIRT6 better reduced stress-induced DNA damage compared to when researchers inserted the mouse SIRT6. The beaver SIRT6 also better increased the lifespan of fruit flies versus fruit flies with mouse SIRT6.

Species with even more robust SIRT6?

Although it appears that human SIRT6 is already optimized to function, "we have other species that are even longer lived than humans," another study member says. Next steps in the research involve analyzing whether species that have longer lifespans than humans—like the bowhead whale, which can live more than 200 years—have evolved even more robust SIRT6 genes.