SCIENCE ADVANCES.
In 1997, when Japanese researchers accidentally discovered a gene variant that appeared to speed up aging in lab mice — which they stumbled upon while conducting an unrelated study on high blood pressure — they named it Klotho.
The figure in Greek mythology, one of Zeus’ many daughters, was said to spin the thread of life, determining when one is born and when one dies.
The klotho protein, which is produced in the kidney and brain and circulates throughout the body, has since been widely studied by researchers all over the world. One of them is Dr. Dena Dubal of UCSF, a neuroscientist and neurologist who treats patients with strokes, seizures, dementia and other cognitive problems, who believes the protein has the potential to help mankind lead longer, healthier lives.
Injections of klotho into the bellies of lab mice have resulted in measurable improvements in brain functions like learning and memory, sometimes as quickly as four hours later, according to recent published findings from Dubal’s lab.
The procedure has yet to be tested in humans. But scientists know that people can tolerate a wide range of naturally produced klotho already inside their bodies — raising the prospect that klotho could be used as a therapeutic to boost brain function, especially for aging patients with cognitive decline.
“What would be an important endgame is to know whether this could be useful to humans,” Dubal said. “That’s where our science is leading us. That’s for the future.”
Dubal’s lab runs one of dozens of research initiatives under way at Bay Area universities, institutions and biotech firms — some funded by a new influx of venture capital — that show promise that modern medicine may be able to eradicate or prevent diseases for which aging is the biggest risk factor. These include neurodegenerative diseases that have no known cure, like Alzheimer’s and other forms of dementia, as well as other prevalent diseases of aging, such as osteoarthritis and glaucoma.
Such a future is within reach as soon as a decade from now, some experts say, as scientists are developing therapies that can slow, reverse or prevent the diseases by targeting their greatest risk factor — aging itself.
“When I started my lab several years ago, I asked a very simple, naive but ambitious question,” Dubal said. “If aging itself is one of the biggest risk factors for decline in the brain, what if we just blocked aging in the brain?”
The objective is not to extend life span but to extend “health span” — the period of life during which people are healthy and active — and shorten the amount of time, often during one’s final years, when agingrelated ailments render many bedridden or disabled.
“The last two decades of our lives are beginning to get filled up with disability,” Dubal said. “Brain aging, bone aging, heart aging, kidney aging — if we could shorten that time of problems from 20 years to maybe just the last few years of life, it would be a huge boon for society, for caregivers, for the trillions of dollars spent on treatment and caring for dementia.”
Dementia is the costliest disease to care for in the United States, according to a 2013 Rand Corp. study published in the New England Journal of Medicine that is the most recent comprehensive study on the topic. The economic cost of dementia in the United States is between $159 billion and $215 billion a year, which is more than cancer or heart disease because the associated costs of institutional and home-based long-term care are so high.
Veteran researchers say we are turning a corner in terms of interest, public awareness and funding to find a cure for neurodegenerative diseases, which have lagged behind cancer in terms of progress in diagnostics and treatments. Better technology such as improved imaging techniques to diagnose Alzheimer’s and other forms of dementia have been perfected just in the last few years. And more funding is making the race for a cure seem winnable: Congress this year boosted the National Institutes of Health budget for research on Alzheimer’s and related dementias nearly 30 percent to $1.8 billion.
“I’m optimistic that in the next five years, we’ll have effective therapies,” said Dr. Bruce Miller, director of UCSF’s Memory and Aging Center, one of the largest memory centers in the country that conducts research and treats patients with aging-related brain diseases. “I was very pessimistic about therapies. In the last 10 years, I’ve started to become really excited about therapies.”
Miller says progress is happening faster than he once expected. He believes it’s possible to wipe out neurodegenerative diseases within our lifetime, much like the polio vaccine eliminated the oncewidespread disease in most parts of the world.
The strategies of the future, he said, will be highly individualized. For instance, people will be able to get their entire genome sequenced to screen for genetic variants that increase the risk of developing Alzheimer’s and other types of dementia.
Other out-of-the-box strategies that once seemed relegated to science fiction are becoming a reality, and may be poised to help future generations age with fewer debilitating impairments.
Researchers at Stanford University Medical School in October announced the conclusion of a small clinical trial that found that infusions of blood plasma from young adults to older patients with mild Alzheimer’s improved the patients’ ability to perform daily activities, like grocery shopping and cooking for themselves. The study garnered much interest and excitement because its approach is a departure from most research on Alzheimer’s and dementia, which focuses on the accumulation of two types of proteins in the brain, the amyloid and the tau, that researchers have long believed trigger the diseases.
There’s also the pop-culture buzz around transfusion therapies after HBO featured a socalled “blood boy” pumping youth into an aging tech mogul on its “Silicon Valley” show — though the reality is far less outlandish.
The results of the Stanford trial, funded by the San Carlos biotech startup Alkahest, were surprising because the study was actually designed to show whether the transfusions were safe, not necessarily to prove their effectiveness. Researchers have yet to pinpoint what exactly is in plasma — the liquid part of blood — that may have improved the behavioral functions in Alzheimer’s patients. Lead investigator Dr. Sharon Sha said the hope is to conduct a larger trial to determine whether the transfusions can improve memory as well and, if so, re-create or “bottle” the proteins or other factors in plasma so it wouldn’t have to come from human donors.
The concept of using transfusions to combat aging stems from Stanford neurologist Tony Wyss-Coray, one of the founders of Alkahest who published a 2014 study that found that injecting old mice with the plasma of young mice appeared to improve the older rodents’ memory.
“There’s something in plasma of young mice that benefits learning and memory,” said Joe McCracken, vice president of business development for Alkahest. “That’s nice for mice. But the real question is, can that be translated in any way that would benefit humans? Alkahest was established to answer that question.”
The pursuit has already piqued the interest of the Spanish company Grifols, the world’s leading producer of plasma products, which invested $37.5 million for a 45 percent stake in Alkahest in 2015. Alkahest is now gearing up for another fundraising round in early 2018 with more traditional venture investors.
Financing for aging-related research is also pouring in from venture firms and tech investors. Brisbane’s Unity Biotechnology, which is experimenting with removing senescent cells — which accumulate with age and cause inflammation, arthritic joints and cataracts — has raised $152 million since its 2011 debut, closing its most recent round in June. Its backers are a mix of venture funds, mutual funds and tech investors including Venrock, Fidelity, Jeff Bezos’ Bezos Expeditions and Paul Allen’s Vulcan Capital.
The company was created in 2011 after a Mayo Clinic study found that removing some senescent cells from aging lab mice led to the mice living longer and preventing some diseases of aging from taking hold. Mice that received the drug to remove the cells had better bone density and kidney function, moved more nimbly, and had fuller, healthier coats. There is evidence that removing senescent cells from animals can actually halt or reverse osteoarthritis by clearing out senescent cells at sites of disease like the joints, thus eliminating osteoarthritis at its root, said Unity’s chief medical officer Jamie Dananberg.
Unity is developing drugs that company executives hope will achieve similar effects in humans. Human clinical trials for osteoarthritis are slated to start next year.
In eight to 10 years, Dananberg predicted, patients could walk into the doctor’s office and ask for a drug — an injection, pill or inhalable medicine — to remove senescent cells from their body.
“This isn’t just symptomatic, this is improving the actual joint, the cartilage, making it better,” Dananberg said. “To be able to do that in humans would be phenomenal. It would change everything in terms of how we think about getting older.”
“If aging itself is one of the biggest risk factors for decline in the brain, what if we just blocked aging in the brain?” Dr. Dena Dubal, UCSF neuroscientist