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/

Breakthroughs In Anti-Aging Research In Near Future

People 50 and older have a lot to look forward to, according to Juvenescence’s Greg Bailey—mainly that we won’t be aging as fast or poorly as our parents. “Science fiction has become science,” said the UK-based anti-aging biotech’s CEO about the company’s completing its $100 million Series B round of financing last week. “I think the world is going to be shocked,” he said in an interview. In total, Juvenescence has now raised $165 million in just 18 months to fund longevity projects with the lofty goal of extending human lifespans to 150 years. Bailey said the money will allow the company “to progress all of our products.” And there’s quite a list of potential therapies.

We have 12 programs based on hard, rigorous science, to try to modify aging. From stem cell research to senolytics to modifying or preventing Alzheimer’s and Parkinson’s diseases,” he said. It’s no secret that anti-aging is big business. According to Endpoints News, “Bank of America has forecast the market will balloon to $610 billion by 2025, from an estimated $110 billion currently.”  “I think there’s a huge amount of skepticism. There’s an enormous number of charlatans…I understand why they would be thinking you know, is this real?” Bailey told Endpoints. “Walk into your local drugstore, you’re going to see about 50 products that claim to be anti-aging, and I can assure you that none of them are.

Bailey said creams that claim everything and do nothing and vitamins that basically give users “expensive urine” are the reason for that skepticism. And investors are not as quick to step up as he would like. Bailey told Endpoints: “We’re dramatically being underserved…it’s not getting the exposure that tech gets, considering the size of the market.” He said he believes there is “a disconnect” on how investors and institutions are viewing anti-aging technology. “I don’t think they quite grasp how fast this is going to happen, and how big it’s going to be.”

Source: https://www.forbes.com/

New Cause Of Cell Aging Discovered: Findings Have Huge Implications

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.

Source: https://viterbischool.usc.edu/
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https://eurekalert.org/