Reprogramming Aging Bodies Back to Youth

A little over 15 years ago, scientists at Kyoto University in Japan made a remarkable discovery. When they added just four proteins to a skin cell and waited about two weeks, some of the cells underwent an unexpected and astounding transformation: they became young again. They turned into stem cells almost identical to the kind found in a days-old embryo, just beginning life’s journey.
At least in a petri dish, researchers using the procedure can take withered skin cells from a 101-year-old and rewind them so they act as if they’d never aged at all.

You must be logged in to view this content.

Anti-inflammatory Molecules Decline in the Aging Brain

Aging involves complicated plot twists and a large cast of characters: inflammation, stress, metabolism changes, and many others.

Now, a team of Salk Institute and UC San Diego scientists reveal another factor implicated in the aging process—a class of lipids called SGDGs (3-sulfogalactosyl diacylglycerols) that decline in the brain with age and may have anti-inflammatory effects.

 

The research, published in Nature Chemical Biology, helps unravel the molecular basis of brain aging, reveals new mechanisms underlying age-related neurological diseases, and offers future opportunities for therapeutic intervention.

You must be logged in to view this content.

How to Boost DNA Repair in Aging Cells

Scientists have long wondered why cells lose their ability to repair themselves as they age. New research by scientists has uncovered two intriguing cluesDNA strands in human cells routinely break and repair themselves, Seluanov and Gorbunova from University of Rochester explained, but as cells age, the system for repair becomes less efficient and flaws in the process lead to a decline in the functionality of tissue and an increase in the incidence of tumors. Their team wanted to determine why this occurs, and establish whether the process could be slowed, or even reversed.
Seluanov and his colleagues found that the decline in a cell's ability to repair DNA during aging coincided with a global reduction in the levels of proteins involved in the repair process. Seluanov's group tried to reverse the age-related decline in DNA repair efficiency by restoring the proteins to their original levels and found only one protein, SIRT6, did the trick. Gorbunova said the results build on a paper by Haim Cohen, a staff scientist investigating aging at Bar-Ilan University in Israel, and others published in the journal Nature this summer.

"That work showed that overexpressing the SIRT6 protein extended the lifespans of mice," said Gorbunova, "Our research looked at DNA repair and found a reason for the increased longevity, and that is SIRT6's role in promoting more efficient DNA repair."

The next step for Seluanov and his team is to study the factors that regulate SIRT6, in an effort to learn more about the early stages of the DNA repair process. Seluanov said that multiple groups are trying to develop drugs that activate SIRT6, and he hopes that this research will one day lead to therapies that help extend a person's lifespan and treat cancer.

You must be logged in to view this content.

Saudi Arabia to Spend $1 billion a Year to Slow Aging

Anyone who has more money than they know what to do with eventually tries to cure aging. Google founder Larry Page has tried it. Jeff Bezos has tried it. Tech billionaires Larry Ellison and Peter Thiel have tried it. Now the kingdom of Saudi Arabia, which has about as much money as all of them put together, is going to try it. The Saudi royal family has started a not-for-profit organization called the Hevolution Foundation that plans to spend up to $1 billion a year of its oil wealth supporting basic research on the biology of aging and finding ways to extend the number of years people live in good health, a concept known as “health span.”

The sum, if the Saudis can spend it, could make the Gulf state the largest single sponsor of researchers attempting to understand the underlying causes of aging—and how it might be slowed down with drugs. The foundation hasn’t yet made a formal announcement, but the scope of its effort has been outlined at scientific meetings and is the subject of excited chatter among aging researchers, who hope it will underwrite large human studies of potential anti-aging drugs. The fund is managed by Mehmood Khan, a former Mayo Clinic endocrinologist and the onetime chief scientist at PespsiCo, who was recruited to the CEO job in 2020. ““Our primary goal is to extend the period of healthy lifespan,” Khan said in an interview. “There is not a bigger medical problem on the planet than this one.

The idea, popular among some longevity scientists, is that if you can slow the body’s aging process, you can delay the onset of multiple diseases and extend the healthy years people are able to enjoy as they grow older. Khan says the fund is going to give grants for basic scientific research on what causes aging, just as others have done, but it also plans to go a step further by supporting drug studies, including trials of “treatments that are patent expired or never got commercialized.”

We need to translate that biology to progress towards human clinical research. Ultimately, it won’t make a difference until something appears in the market that actually benefits patients,” Khan says.

Khan says the fund is authorized to spend up to $1 billion per year indefinitely, and will be able to take financial stakes in biotech companies. By comparison, the division of the US National Institute on Aging that supports basic research on the biology of aging spends about $325 million a year.

Hevolution hasn’t announced what projects it will back, but people familiar with the group say it looked at funding a $100 million X Prize for age reversal technology and has reached a preliminary agreement to fund a test of the diabetes drug metformin in several thousand elderly people.

That trial, known as “TAME” (for “Targeting Aging with Metformin”), has been touted as the first major test of any drug to postpone aging in humans, but the study has languished for years without anyone willing to pay for it.

Source: https://www.technologyreview.com/

Memory Problems Common in Old Age Can Be Reversed

While immortality might forever be out of reach, a long, healthy retirement is the stuff dreams are made of. To that end, a recent study suggests that the kinds of memory problems common in old age can be reversed, and all it takes is some cerebrospinal fluid (CSF) harvested from the young. In mice, at least.

If this is sounding a little familiar, you might be thinking of a similar series of studies done back in the mid-2010s, which found that older mice could be generally ‘rejuvenated‘ with the blood of younger animals – both from humans and from mice. The FDA even had to warn people to stop doing it. This new study instead examined the links between memory and cerebrospinal fluid  (CSF), and the results show considerable promise, even providing a mechanism for how it works, and highlighting a potential growth factor that could mimic the results.

“We know that CSF composition changes with age, and, in fact, these changes are used routinely in the clinic to assess brain health and disease biomarkers,” Stanford University neurologist Tal Iram said. “However, we don’t know well how these changes affect the function of the cells in the aging brain.

To investigate, the researchers, led by Iram, took older mice (between 18–22 months old) and gave them light shocks on the foot, at the same time as a tone and flashing light were activated. The mice were then split into groups, and either given young mouse CSF (from animals 10 weeks old) or artificial CSF. In experiments like this, if the mice ‘freeze’ when they see the tone and light, it means they’re remembering the foot shock, and are preparing for it to happen again. In this study, three weeks after the foot shocks were conducted (which the team called “memory acquisition“), the researchers tested the mice, finding that the animals that had been given the CSF from young mice showed higher-than-average freezing rates, suggesting they had better memory. This was followed up by a battery of other experiments to test the theory, which revealed that certain genes (that are different in young-versus-old CSF) could be used to get the same response. In other words, without needing to extract someone’s brain fluid.

When we took a deeper look into gene changes that occurred in the hippocampus (a region associated with memory and aging-related cognitive decline), we found, to our surprise, a strong signature of genes that belong to oligodendrocytes,” Iram explained. “Oligodendrocytes are unique because their progenitors are still present in vast numbers in the aged brain, but they are very slow in responding to cues that promote their differentiation. We found that when they are re-exposed to young CSF, they proliferate and produce more myelin in the hippocampus.” Oligodendrocytes are particularly helpful because they produce myelin, a material that covers and insulates neuron fibers.

New Drug Could Protect Against Aging

Senolytics are an emerging class of drugs designed to target zombie-like cells that have stopped dividing and build up in the body as we age, and the past few years have seen some exciting discoveries that demonstrate their potential. Adding another to the list are Mayo Clinic researchers, who have shown that these drugs can protect against aging and its related diseases, by acting on a protein long associated with longevity. The zombie-like cells involved in this research are known as senescent cells, and their accumulation during aging is associated with a range of diseases. Recent studies have shown that using senolytics to clear them out could serve as new and effective treatments for dementia and diabetes, and also improve health and lifespan more broadly.

The Mayo Clinic team were exploring how senolytics can influence levels of a protein called a-klotho, known to help protect older people from the effects of aging. The role of this protein in the aging process is well established and has placed it at the center of much research in this space, with studies demonstrating how it could help reverse osteoarthritis and regenerate old musclesLevels of a-klotho are also known to decrease with age, and studies have shown these declines shorten the lifespan of mice. Conversely, inserting genes that encode for the protein has been shown to increase the lifespan of mice by 30 percent. Boosting its levels in humans has been problematic, however, as its larger size would require it to be administered intravenously. But now the Mayo Clinic scientists believe they have found another route, as senolytic drugs can be administered orally.

They first showed that senescent cells reduce levels of a-klotho in human cells. They then demonstrated that using a combination of senolytic drugs on three different types of mice could counter this and increase levels of a-klotho. This effect was then observed in follow-up experiments on patients with idiopathic pulmonary fibrosis, a lung disease that can cause breathing difficulty, frailty and death.

“We show that there is an avenue for an orally active, small-molecule approach to increase this beneficial protein and also to amplify the action of senolytic drugs,” says James Kirkland, M.D., Ph.D., a Mayo Clinic internist and senior author of the study.

Source: https://www.thelancet.com/

The Fountain of Youth

A step toward discovering the fountain of youth could involve protecting against the inevitable accumulation of “senescentcells associated with aging and age-related diseases. Now, researchers from Japan have identified the MondoA protein as key to protecting against the accumulation of senescent cells.

In a study published this month in Cell Reports, researchers led by Osaka University have shown that MondoA delays cellular senescence, and therefore promotes longevity, by activating . Autophagy is a process whereby cells undergo controlled breakdown and recycling of their components, which is important for maintaining stable conditions in the cellular environment and for enabling adaptation to stress. Activation of autophagy by MondoA partly involves suppressing a protein called Rubicon, which is a negative regulator of autophagy. Rubicon can increase with aging in various tissues and model organisms, which can cause the decline in autophagy seen with aging.

Furthermore, MondoA is also essential to maintaining stable conditions of parts of the cell called mitochondria, which are responsible for energy production. MondoA does this by regulating another molecule, Prdx3, which is involved in mitochondrial turnover. Mitochondria are constantly fusing and dividing, which is important for maintaining their health. Prdx3 is part of the process by which autophagy occurs in mitochondria, preventing senescence. The research team led by Osaka University concluded that MondoA plays a key role in the regulation of Prdx3 and therefore in maintaining mitochondrial stability.

Particularly dense accumulation of senescent cells has been observed in the kidney. The researchers therefore looked at ischemic acute kidney injury (AKI) in mice.

Mice with ischemic AKI and reduced levels of MondoA showed increased senescence,” explains lead author Hitomi Yamamoto-Imoto. “We also found that decreased MondoA in the nucleus correlated with human aging and ischemic AKI. MondoA therefore counteracts cellular  in aging and ischemic AKI in both mice and humans.”

Drugs that eliminate senescent cells, called senolytics, are currently being considered as treatment for age-associated diseases. However, senescent  play important roles, and their complete removal may have considerable side effects. “Our work shows that the transcriptional activation of MondoA can protect against , kidney injury associated with aging, and organismal aging,” explains senior author Tamotsu Yoshimori. “Activation of MondoA and therefore autophagy could be a potentially safe therapeutic strategy.” This work could well open new and safer avenues for the treatment of aging and age-related diseases.

Source: https://phys.org/

How to Reverse Muscle Loss Due to Aging

An international team led by uOttawa Faculty of Medicine researchers have published findings that could contribute to future therapeutics for muscle degeneration due to old age, and diseases such as cancer and muscular dystrophyIn a study appearing in the Journal of Cell Biology, which publishes peer-reviewed research on cellular structure and function, the authors said their work demonstrates the importance of the enzyme GCN5 in maintaining the expression of key structural proteins in skeletal muscle. Those are the muscles attached to bone that breathing, posture and locomotion all rely on.

We found that if you delete GCN5 expression from muscle it will no longer be able to handle extreme physical stress,” says Dr. Keir Menzies, a molecular biologist at the Faculty of Medicine’s Biochemistry, Microbiology and Immunology department and cross-appointed as an associate professor at the Interdisciplinary School of Health Sciences.

Over the span of roughly five years, the uOttawa-led international collaboration painstakingly experimented with a muscle-specific mouse knockout” of GCN5, a well-studied enzyme which regulates multiple cellular processes such as metabolism and inflammation. Through a series of manipulations, scientists produce lab mice in which specific genes are disrupted, or knocked out, to unveil animal models of human disease and better understand how genes work.

In this case, multiple experiments were done to examine the role the GCN5 enzyme plays in muscle fiber. What they found with this line of muscle-specific mouse knockouts was a notable decline in muscle health during physical stress, such as downhill treadmill running, a type of exercise known by athletes to cause micro-tears in muscle fibres to stimulate muscle growth. The lab animals’ muscle fibers became dramatically weaker as they scurried downhill, like those of old mice, while wild-type mice were not similarly impacted

Dr. Menzies, the senior author of the study, says the findings are akin to what is observed in advanced aging, or myopathies and muscular dystrophy, a group of genetic diseases that result in progressive weakness and loss of muscle mass. It was supported by human data, including an observed negative correlation between muscle fiber diameter and Yin Yang 1, a highly multifunctional protein that is pivotal to a slew of cellular processes and found by the Menzies lab to be a target of GCN5. Ultimately, the team’s research found that GCN5 boosts the expression of key structural muscle proteins, notably dystrophin, and a lack of it will reduce them.

Source: https://rupress.org/
AND
https://www.thebrighterside.news

Rejuvenation by Controlled Reprogramming

On 19 January 2022, co-founders Rick Klausner and Hans Bishop publicly launched an aging research initiative called Altos Labs, with $3 billion in initial investment from backers including tech investor Yuri Milner and Amazon founder Jeff Bezos. This is the latest in a recent surge of investment in ventures seeking to build anti-aging interventions on the back of basic research programs looking at epigenetic reprogramming. In December, cryptocurrency company Coinbase’s cofounder Brian Armstrong and venture capitalist Blake Byers founded NewLimit, an aging-focused biotech backed by an initial $105 million investment, with the University of California, San Francisco’s Alex Marson and Stanford’s Mark Davis as advisors.

The discovery of the Yamanaka factors’ — four transcription factors (Oct3/4, Sox2, c-Myc and Klf4) that can reprogram a differentiated somatic cell into a pluripotent embryonic-like state — earned Kyoto University researcher Shinya Yamanaka a share of the Nobel prize in 2012. The finding, described in 2006, transformed stem cell research by providing a new source of embryonic stem cell (ESC)-like cells, induced pluripotent stem cell (iPSCs), that do not require human embryos for their derivation. But in recent years, Yamanaka factors have also become the focus for another burgeoning area: aging research.

So-called partial reprogramming consists in applying Yamanaka factors to cells for long enough to roll back cellular aging and repair tissues but without returning to pluripotency. Several groups, including those headed by Stanford University’s Vittorio Sebastiano, the Salk Institute’s Juan Carlos Izpisúa Belmonte and Harvard Medical School’s David Sinclair, have shown that partial reprogramming can dramatically reverse age-related phenotypes in the eye, muscle and other tissues in cultured mammalian cells and even rodent models by countering epigenetic changes associated with aging. These results have spurred interest in translating insights from animal models into anti-aging interventions. “This is a pursuit that has now become a race,” says Daniel Ives, CEO and founder of Cambridge, UK-based Shift Bioscience.

The Yamanaka factors that can reprogram cells into their embryonic-like state are at the heart of longevity research

We’re investing in this area [because] it is one of the few interventions we know of that can restore youthful function in a diverse set of cell types,” explains Jacob Kimmel, a principal investigator at Alphabet subsidiary Calico Life Sciences in South San Francisco, California. The zeal is shared by Joan Mannick, head of R&D at Life Biosciences, who says partial reprogramming could be potentially “transformative” when it comes to treating or even preventing age-related diseases. Life Biosciences, a startup co-founded by David Sinclair, is exploring the regenerative capacity of three Yamanaka factors (Oct4, Sox2 and Klf4).

Source: https://www.nature.com/

Flexible device could treat hearing loss without batteries

Some people are born with hearing loss, while others acquire it with age, infections or long-term noise exposures. In many instances, the tiny hairs in the inner ear’s cochlea that allow the brain to recognize electrical pulses as sound are damaged. As a step toward an advanced artificial cochlea, researchers in ACS Nano report a conductive membrane, which translated sound waves into matching electrical signals when implanted inside a model ear, without requiring external power.

An electrically conductive membrane implanted inside a model ear simulates cochlear hairs by converting sound waves into electrical pulses; wiring connects the prototype to a device that collects the output current signal.

When the hair cells inside the inner ear stop working, there’s no way to reverse the damage. Currently, treatment is limited to hearing aids or cochlear implants. But these devices require external power sources and can have difficulty amplifying speech correctly so that it’s understood by the user. One possible solution is to simulate healthy cochlear hairs, converting noise into the electrical signals processed by the brain as recognizable sounds. To accomplish this, previous researchers have tried self-powered piezoelectric materials, which become charged when they’re compressed by the pressure that accompanies sound waves, and triboelectric materials, which produce friction and static electricity when moved by these waves. However, the devices aren’t easy to make and don’t produce enough signal across the frequencies involved in human speech. So, Yunming Wang and colleagues from the University of Wuhan wanted a simple way to fabricate a material that used both compression and friction for an acoustic sensing device with high efficiency and sensitivity across a broad range of audio frequencies.

To create a piezo-triboelectric material, the researchers mixed barium titanate nanoparticles coated with silicon dioxide into a conductive polymer, which they dried into a thin, flexible film. Next, they removed the silicon dioxide shells with an alkaline solution. This step left behind a sponge-like membrane with spaces around the nanoparticles, allowing them to jostle around when hit by sound waves. In tests, the researchers showed that contact between the nanoparticles and polymer increased the membrane’s electrical output by 55% compared to the pristine polymer. When they sandwiched the membrane between two thin metal grids, the acoustic sensing device produced a maximum electrical signal at 170 hertz, a frequency within the range of most adult’s voices. Finally, the researchers implanted the device inside a model ear and played a music file. They recorded the electrical output and converted it into a new audio file, which displayed a strong similarity to the original version. The researchers say their self-powered device is sensitive to the wide acoustic range needed to hear most sounds and voices.

Source: https://www.acs.org/
AND
https://pubmed.ncbi.nlm.nih.gov/