Tag Archives: aging
The aging global population is the greatest challenge faced by 21st-century healthcare systems. Even COVID-19 is, in a sense, a disease of aging. The risk of death from the virus roughly doubles for every nine years of life, a pattern that is almost identical to a host of other illnesses. But why are old people vulnerable to so many different things?
It turns out that a major hallmark of the aging process in many mammals is inflammation. By that, I don’t mean intense local response we typically associate with an infected wound, but a low grade, grinding, inflammatory background noise that grows louder the longer we live. This “inflammaging” has been shown to contribute to the development of atherosclerosis (the buildup of fat in arteries), diabetes, high blood pressure , frailty, cancer and cognitive decline.
Now a new study published in Nature reveals that microglia — a type of white blood cells found in the brain — are extremely vulnerable to changes in the levels of a major inflammatory molecule called prostaglandin E2 (PGE2). The team found that exposure to this molecule badly affected the ability of microglia and related cells to generate energy and carry out normal cellular processes.
Fortunately, the researchers found that these effects occurred only because of PGE2’s interaction with one specific receptor on the microglia. By disrupting it, they were able to normalize cellular energy production and reduce brain inflammation. The result was improved cognition in aged mice. This offers hope that the cognitive impairment associated with growing older is a transient state we can potentially fix, rather than the inevitable consequence of aging of the brain. Levels of PGE2 increase as mammals age for a variety of reasons — one of which is probably the increasing number of cells in different tissues entering a state termed cellular senescence. This means they become dysfunctional and can cause damage to tissue by releasing PGE2 and other inflammatory molecules.
But the researchers also found that macrophages — another type of white blood cells related to microglia — from people over the age of 65 made significantly more PGE2 than those from young people. Intriguingly, exposing these white blood cells to PGE2 suppressed the ability of their mitochondria — the nearest thing a cell has to batteries — to function. This meant that the entire pattern of energy generation and cellular behavior was disrupted.
Although PGE2 exerts its effects on cells through a range of receptors, the team were able to narrow down the effect to interaction with just one type (the “EP2 receptor” on the macrophages). They showed this by treating white blood cells, grown in the lab, with drugs that either turned this receptor on or off. When the receptor was turned on, cells acted as if they had been exposed to PGE2. But when they were treated with the drugs that turned it off, they recovered. That’s all fine, but it was done in a petri dish. What would happen in an intact body?
The researchers took genetically modified animals in which the EP2 receptor had been removed and allowed them to grow old. They then tested their learning and memory by looking at their ability to navigate mazes (something of a cliche for researchers) and their behavior in an “object location test.” This test is a bit like someone secretly entering your house, swapping your ornaments around on the mantelpiece and then sneaking out again. The better the memory, the longer the subject will spend looking suspiciously at the new arrangement, wondering why it has changed.
It turned out that the old genetically modified mice learned and remembered just as well as their young counterparts. These effects could be duplicated in normal old mice by giving them one of the drugs that could turn the EP2 receptor off for one month. So it seems possible that inhibiting the interaction of PGE2 with this particular receptor may represent a new approach to treating late-life cognitive disorders.
Taking a regular afternoon nap may be linked to better mental agility, suggests research published in the online journal General Psychiatry. It seems to be associated with better locational awareness, verbal fluency, and working memory, the findings indicate. Longer life expectancy and the associated neurodegenerative changes that accompany it, raise the prospect of dementia, with around 1 in 10 people over the age of 65 affected in the developed world.
As people age, their sleep patterns change, with afternoon naps becoming more frequent. But research published to date hasn’t reached any consensus on whether afternoon naps might help to stave off cognitive decline and dementia in older people or whether they might be a symptom of dementia.
The researchers explored this further in 2214 ostensibly healthy people aged at least 60 and resident in several large cities around China, including Beijing, Shanghai, and Xian. In all, 1534 took a regular afternoon nap, while 680 didn’t. All participants underwent a series of health checks and cognitive assessments, including the Mini Mental State Exam (MMSE) to check for dementia. The average length of night time sleep was around 6.5 hours in both groups. Afternoon naps were defined as periods of at least five consecutive minutes of sleep, but no more than 2 hours, and taken after lunch. Participants were asked how often they napped during the week; this ranged from once a week to every day.
The dementia screening tests included 30 items that measured several aspects of cognitive ability, and higher function, including visuo-spatial skills, working memory, attention span, problem solving, locational awareness and verbal fluency. The MMSE cognitive performance scores were significantly higher among the nappers than they were among those who didn’t nap. And there were significant differences in locational awareness, verbal fluency, and memory.
This is an observational study, and so can’t establish cause. And there was no information on the duration or timing of the naps taken, which may be important.
Inhibiting certain enzymes involved in abnormal gene transcription may offer a way to restore memory loss associated with Alzheimer’s disease, a new study in mice suggests.
The findings could pave the way toward new treatments for Alzheimer’s disease (AD).
“By treating AD mouse models with a compound to inhibit these enzymes, we were able to normalize gene expression, restore neuronal function, and ameliorate cognitive impairment,” says senior author Zhen Yan, a professor in the department of physiology and biophysics in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.
Alzheimer’s disease alters the expression of genes in the prefrontal cortex, a key region of the brain controlling cognitive processes and executive functions.
When they focused on gene changes caused by epigenetic processes (those not related to changes in DNA sequences) such as aging, the researchers could reverse elevated levels of harmful genes that cause memory deficits in AD.
In the new paper in Science Advances, the team reports they reversed the upregulation of genes involved in impairing cognitive function.
Studies have shown that gut microbes can influence several aspects of the host’s life, including aging. Given the complexity and heterogeneity of the human gut environment, elucidating how a specific microbial species contributes to longevity has been challenging.
To explore the influence of bacterial products on the aging process, scientists at Baylor College of Medicine and Rice University developed a method that uses light to directly control gene expression and metabolite production from bacteria residing in the gut of the laboratory worm Caenorhabditis elegans.
The team reports (“Optogenetic control of gut bacterial metabolism to promote longevity”) in eLife that green-light-induced production of colanic acid by resident Escherichia coli bacteria protected gut cells against stress-induced cellular damage and extended the worm’s lifespan. The researchers indicate that this method can be applied to study other bacteria and propose that it also might provide in the future a new way to fine-tune bacterial metabolism in the host gut to deliver health benefits with minimal side effects.
“Gut microbial metabolism is associated with host longevity. However, because it requires direct manipulation of microbial metabolism in situ, establishing a causal link between these two processes remains challenging. We demonstrate an optogenetic method to control gene expression and metabolite production from bacteria residing in the host gut. We genetically engineer an E. coli strain that secretes colanic acid (CA) under the quantitative control of light,” the investigators wrote.
“Using this optogenetically-controlled strain to induce CA production directly in the C. elegans gut, we reveal the local effect of CA in protecting intestinal mitochondria from stress-induced hyper-fragmentation. We also demonstrate that the lifespan-extending effect of this strain is positively correlated with the intensity of green light, indicating a dose-dependent CA benefit on the host.
“Thus, optogenetics can be used to achieve quantitative and temporal control of [the microbiome] metabolism in order to reveal its local and systemic effects on host health and aging. “We used optogenetics, a method that combines light and genetically engineered light-sensitive proteins to regulate molecular events in a targeted manner in living cells or organisms,” said co-corresponding author Meng Wang, PhD, professor of molecular and human genetics at the Huffington Center on Aging at Baylor.
Unfortunately, we can’t go hard forever. But in the future, that might not be a problem: New research has revealed how to harness the cognitive benefits of a workout — without the actual workout. Scientists think this help slow aging in the brain. A study published Thursday in Science suggests the benefits of exercise run in the blood and may be able to be transferred from one swoll organism to another, less-swoll one.
Researchers report that unexercised, aged mice who received blood plasma donations from exercised mice improved their performance on spatial memory tests and showed fewer markers of inflammation related to aging. The authors suggest that these improvements occurred because exercise releases a series of circulating factors (like proteins) into the bloodstream. Saul Villeda, the study’s senior author and an assistant professor of anatomy at The University of California San Francisco, said that one specific protein abundant in the liver appears to be especially important. It’s called Glpd and it sends a crucial message to the body.
“I think it’s sort of signaling to your body: repair yourself or restore yourself,” Villeda explains.
The study builds upon the larger idea that aging in the brain isn’t inevitable, and that the basic lifestyle tools we have to stave it off can be further honed to keep brains sharp into old age. It’s possibly a step towards an exercise pill that’s intended to keep the brain swole, not the body — though Villeda cautions that this is far in the future.
Numerous studies have suggested that exercise can help slow cognitive decline. The mechanisms for that differ, but a working idea is that exercise triggers a series of changes in the body, including the release of certain blood factors that may confer benefits, the study notes. Villeda calls the blood a “conduit” for all the organs in the body to communicate with one another, which suggests that might help transfer exercise-related benefits from one creature to another. In the study, a group of aged mice (18 months old) was given access to a running wheel all the time. Another group of sedentary mice was provided with nesting materials (to promote more chilling and less running). Then, blood plasma (which is the white-ish part of blood that contains all the circulating cells and proteins) was taken from each group and injected into two additional groups over three weeks.
The mice with their fresh runner-blood injections then performed a water-based maze test — they had to find a platform to get to safety — and a fear conditioning test. These tests are designed to test spatial learning memory. If you’ve ever had a moment when you realize that you can’t find your car in the parking lot anymore, you’ve experienced a lapse in that type of memory, Villeda explains.
“All of a sudden, you might see this older individual using their car alarm to try and find their car because they can’t quite remember where their car was,” he says. “Those are the types of impairments that already are occurring with just normal age before you get dementia or disease.”
The mice who received blood plasma transfusions from the exercised mice were faster to learn the location of the dry platforms in the maze compared to those that got plasma from sedentary mice. In the fear-based test, the mice were quicker to freeze in response to a context clue – suggesting that they were faster to learn what might cause them harm. In mouse-years, you might think of these aged mice as 70-year-olds, Villeda says. The improvements seen in the mice who received plasma donation were the equivalent of turning back the clock decades, he explains:
“We’re reversing it probably back to the late 30s, early 40s. But that’s a significant improvement for these animals.”
This study suggests that these transfusions may help to preserve memory functions that once existed in younger animals, Villeda says — his team found that they were able to reverse some of the animal’s cognitive impairments. What these transfusions can not do is boost memory — the goal is to prevent decline, not add benefits.
Central to a lot of scientific research into aging are tiny caps on the ends of our chromosomes called telomeres. These protective sequences of DNA grow a little shorter each time a cell divides, but by intervening in this process, researchers hope to one day regulate the process of aging and the ill health effects it can bring. A Harvard team is now offering an exciting pathway forward, discovering a set of small molecules capable of restoring telomere length in mice. Telomeres can be thought of like the plastic tips on the end of our shoelaces, preventing the fraying of the DNA code of the genome and playing an important part in a healthy aging process. But each time a cell divides, they grow a little shorter. This sequence repeats over and over until the cell can no longer divide and dies.
This process is linked to aging and disease, including a rare genetic disease called dyskeratosis congenita (DC). This is caused by the premature aging of cells and is where the team focused its attention, hoping to offer alternatives to the current treatment that involves high-risk bone marrow transplants and which offers limited benefits.
One of the ways dyskeratosis congenita comes about is through genetic mutations that disrupt an enzyme called telomerase, which is key to maintaining the structural integrity of the telomere caps. For this reason, researchers have been working to target telomerase for decades, in hopes of finding ways to slow or even reverse the effects of aging and diseases like dyskeratosis congenita.
“Once human telomerase was identified, there were lots of biotech startups, lots of investment,” says Boston Children’s Hospital’s Suneet Agarwal, senior investigator on the new study. “But it didn’t pan out. There are no drugs on the market, and companies have come and gone.”
As we age, our bodies tend to develop diseases like heart failure, kidney failure, diabetes, and obesity, and the presence of any one disease increases the risk of developing others. In traditional drug development, a drug usually only targets one condition, largely ignoring the interconnectedness of age-related diseases, such as obesity, diabetes, and heart failure, and requiring patients to take multiple drugs, which increases the risk of negative side effects.
A new study from the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School (HMS) reports that a single administration of an adeno-associated virus (AAV)-based gene therapy delivering 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 AAV-based gene therapy improved the function of the heart and other organs in mice with various age-related diseases, suggesting that such an approach could help maintain health during aging.
“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, Ph.D., a former Research Scientist at the Wyss Institute and HMS who is now the 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, Ph.D. as part of Davidsohn’s postdoctoral research into the genetics of aging. Davidsohn, Church, and their co-authors honed in on three genes that had previously been shown to confer increased health and lifespan benefits when their expression was modified in genetically engineered mice: FGF21, sTGFβR2, and αKlotho. They hypothesized that providing extra copies of those genes to non-engineered mice via gene therapy would similarly combat age-related diseases and confer 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 II diabetes, heart failure, and renal failure both individually and in combination with the other genes to see if there was a synergistic beneficial effect.
In a small clinical trial, scientists were looking for a means to restore the thymus — the gland that forms and releases key immune cells. By doing so, they actually managed to reverse various aspects of biological aging. The thymus gland, located between the lungs, is the organ within which T cells — a critical population of immune cells — mature. This gland also has a peculiarity. After a person reaches puberty, it begins a process of involution, which means that it becomes less and less active and starts to shrink in size gradually. Studies have shown that thymic involution affects the size of immune cell populations related to it, possibly causing changes to biological mechanisms when people reach their 60s.
Prof. Steve Horvath from the University of California Los Angeles School of Public Health and colleagues initially set out to see if they could restore function in the aging thymus.
“Thymic involution leads to the depletion of critical immune cell populations, […] and is linked to age‐related increases in cancer incidence, infectious disease, autoimmune conditions, generalized inflammation, atherosclerosis, and all‐cause mortalit,” he explains In the study paper recently published in the journal Aging Cell.
For the reasons outlined above, the researchers organized and conducted what they believe is a first-of-its-kind clinical trial: TRIIM (Thymus Regeneration, Immunorestoration, and Insulin Mitigation). The study took place between 2015–2017, and the researchers were pleased with the results they achieved. They found that it was possible to restore thymic function and reduce the risk of age-related conditions and diseases linked to poor immune system reaction.
They also had a pleasant surprise. At the end of the trial, the researchers found that the mix of drugs they used to restore the thymus gland had also reversed other aspects of biological aging. A person’s biological age refers not to how old they are in conventional years, but to how much their biological mechanisms have aged, according to their epigenetic clocks — markers that indicate how changes in various cellular mechanisms have affected gene expression.
For their trial, Prof. Horvath and team recruited 10 healthy adult males aged 51–65. The researchers were able to use and analyze data collected from nine of these individuals. In the first week of the clinical trial, the researchers gave the participants recombinant human growth hormone (rhGH). In its natural state, rhGH supports many different aspects of cellular health, such as cell growth and regeneration. Previous studies — some conducted in animals, and others with the participation of individuals with HIV — have uncovered evidence that rhGH could help restore thymus function, as well as immune system effectiveness.
New research from the USC Viterbi School of Engineering could be key to our understanding of how the aging process works. The findings potentially pave the way for better cancer treatments and revolutionary new drugs that could vastly improve human health in the twilight years. The work, from Assistant Professor of Chemical Engineering and Materials Science Nick Graham and his team in collaboration with Scott Fraser, Provost Professor of Biological Sciences and Biomedical Engineering, and Pin Wang, Zohrab A. Kaprielian Fellow in Engineering, was recently published in the Journal of Biological Chemistry.
LEFT: NON-SENESCENT CELLS WERE SHOWN WITH DIFFERENT COLORS. RIGHT: SENESCENT CELLS APPEARED OFTEN WITH MULTIPLE BLUE NUCLEI AND DID NOT SYNTHESIZE DNA.
“To drink from the fountain of youth, you have to figure out where the fountain of youth is, and understand what the fountain of youth is doing,” Graham said. “We’re doing the opposite; we’re trying to study the reasons cells age, so that we might be able to design treatments for better aging.”
To achieve this, lead author Alireza Delfarah, a graduate student in the Graham lab, focused on senescence, a natural process in which cells permanently stop creating new cells. This process is one of the key causes of age-related decline, manifesting in diseases such as arthritis, osteoporosis and heart disease.
“Senescent cells are effectively the opposite of stem cells, which have an unlimited potential for self-renewal or division,” Delfarah said. “Senescent cells can never divide again. It’s an irreversible state of cell cycle arrest.”
The research team discovered that the aging, senescent cells stopped producing a class of chemicals called nucleotides, which are the building blocks of DNA. When they took young cells and forced them to stop producing nucleotides, they became senescent, or aged. “This means that the production of nucleotides is essential to keep cells young,” Delfarah said. “It also means that if we could prevent cells from losing nucleotide synthesis, the cells might age more slowly.”
Graham’s team examined young cells that were proliferating robustly and fed them molecules labeled with stable isotopes of carbon, in order to trace how the nutrients consumed by a cell were processed into different biochemical pathways.
Scott Fraser and his lab worked with the research team to develop 3D imagery of the results. The images unexpectedly revealed that senescent cells often have two nuclei, and that they do not synthesize DNA. Before now, senescence has primarily been studied in cells known as fibroblasts, the most common cells that comprised the connective tissue in animals. Graham’s team is instead focusing on how senescence occurs in epithelial cells, the cells that line the surfaces of the organs and structures in the body and the type of cells in which most cancers arise. Graham said that senescence is most widely known as the body’s protective barrier against cancer: When cells sustain damage that could be at risk of developing into cancer, they enter into senescence and stop proliferating so that the cancer does not develop and spread.
“Sometimes people talk about senescence as a double-edged sword, that it protects against cancer, and that’s a good thing,” Graham said. “But then it also promotes aging and diseases like diabetes, cardiac dysfunction or atherosclerosis and general tissue dysfunction,” he said. Graham said the goal was not to completely prevent senescence, because that might unleash cancer cells. “But then on the other hand, we would like to find a way to remove senescent cells to promote healthy aging and better function,” he explained.
Graham underscores that the team’s research has applications in the emerging field of senolytics, the development of drugs that may be able to eliminate aging cells. He said that human clinical trials are still in early stages, but studies with mice have shown that by eliminating senescent cells, mice age better, with a more productive life span. “They can take a mouse that’s aging and diminishing in function, treat it with senolytic drugs to eliminate the senescent cells, and the mouse is rejuvenated. If anything, it’s these senolytic drugs that are the fountain of youth,” Graham said. He added that in order for successful senolytic drugs to be designed, it was important to identify what is unique about senescent cells, so that drugs won’t affect the normal, non-senescent cells.
“That’s where we’re coming in–studying senescent cell metabolism and trying to figure out how the senescent cells are unique, so that you could design targeted therapeutics around these metabolic pathways,” Graham added.