We are very pleased to announce the addition of two new Mprize competitors, Alan Cash & Holly Brown Borg. Here are their stories.
Alan Cash learned about aging the hard way. Although he hadn’t turned 50 yet he experienced a rare and extremely painful side effect of aging. At the time Alan wasn’t aware that our veins and arteries lengthen as we age until an artery pushed into a major nerve bundle and caused excruciating pain in his neck. “I’ve often been accused of being a pain in the neck,” quips Alan, “I guess this was just payback.” A six-hour brain surgery separated the nerve from artery with the help of a Teflon pad.
Although the pain was completely gone, the experience left Alan with “the intense feeling that Aging was bad.” So he decided to do something about it. A lengthy recuperation gave him the opportunity to read about aging. He became fascinated by the work involving Calorie Restriction (CR) by such notable researchers as Leonard Guarente and David Sinclair, because CR was a proven method to slow aging.
He learned that CR leads to changes in metabolism and gene expression that result in increased lifespan and the reduction of the incidence of heart disease, kidney disease, Alzheimer’s disease, type-2 diabetes and cancer. Alan realized that three molecular pathways that extend life as a result of CR had been identified:
1. Increasing the NAD+/NADH ratio in the cells,
2. Chronically activating AMPK and
3. Increasing the NAD+ levels in the mitochondria.
All of these could be achieved by supplementing the diet with the metabolite oxaloacetate. Oxaloacetate is a human metabolite, and is consumed in the foods we eat on a daily basis, such as apples, chicken, and potatoes, but these foods do not contain enough oxaloacetate to continually activate AMPK, the AMP-activated protein kinase that regulates metabolism.
Working with scientists at UCSD and UCLA schools of medicine, Alan showed that animals given supplements of oxaloacetate have increased lifespan, just like animals under CR. And equally important, others have already shown that oxaloacetate provides many of the same health benefits as CR, including mitochondrial DNA protection, and protection of retinal, neural and pancreatic tissues. Human studies indicate a substantial reduction in fasting glucose levels and improvement in insulin resistance.
With his training as a physicist, Alan strove to take the complex biology of aging and reduce it to a simple idea to slow aging and extend life— mainly to supplement the diet with higher amounts of oxaloacetate. When Alan presented his ideas to a molecular biologist at University of California San Diego, the biologist immediately cleared space and invited him to test his theory! Together they did tests on worms, flies and mice, and the initial data was very promising, leading to journal articles in “Aging Cell”, “Open Longevity Science” and “Anti-Aging Therapeutics.” A simple solution for aging with a human metabolite had extended lifespan!
To publicize the discovery, Alan saw that the Mprize might be the best route, but additional data was required. Various long-term tests of oxaloacetate are underway at UC Riverside, LSU Baton Rouge, and, through the National Institute on Aging Interventions Testing Program, at UT Austin, UM Ann Arbor and the Jackson Laboratory in Bar Harbor. Concurrently, after submitting extensive safety information, Alan received approval to market the new dietary supplement in Canada, Europe and the USA for human use, under the trade name “benaGene”.
Holly Brown Borg
Holly’s acquaintance with Ames dwarf mice led her to aging research. While she was in a postdoctoral position she began working with these small but long-lived mice to do studies on immunology. At that time she was working with Andrzej Bartke, he holds the Mprize for Longevity for a mouse that lived almost 5 years, double the normal lifespan.
After heading to North Dakota, where she became an Assistant Professor in Pharmacology, Physiology & Therapeutics, Holly continued to follow the progress of the mice. Their long life intrigued her. What was it that caused them to live so much longer than other mice?
Holly began exploring so she could understand what it was about these mice, lacking growth hormone, which allowed them to live so long. She explains her hypothesis, “A lack of growth hormone means there is no demand to make protein and turn amino acid into muscle; this frees the mice, metabolically, to fight off internal and external stresses.”
The human nutrition center on campus suggested that Holly turn her attention to methionine metabolism. This essential amino acid is critical for protein synthesis and growth, and is also integral to metabolism. To go a bit deeper, glutathione, an important antioxidant, is generated by the methionine (MET) pathway. Glutathione is made up of three amino acids, the key one in these studies is cysteine. The essential amino acids, MET and cysteine, can be easily modified in the diet.
The Ames mice have highly active methionine metabolism but when they are given growth hormone, this activity goes down. This was the proof Holly needed that methionine metabolism is regulated by growth hormone.
Calorie restriction (CR) is well known to extend lifespan in multiple species. It has also been shown that restricting MET intake (without CR) extends the lifespan of rats and mice. There are similarities in mice subjected to CR and the dwarf mice which suggests there are common underlying factors that lead to slower aging.
According to Holly, “The mechanisms leading to this potential “˜slower’ aging and lifespan extension are unknown. Our lab is interested in pursuing studies altering the level of essential amino acids in the diet and following modifications to key metabolic pathways involved in aging processes and lifespan. The beauty of these studies lies in their simplicity and potential therapeutic value.”
Just today on the radio I heard a woman talk about the agony of waiting for someone to die so she can live ““ she needs a transplant. Everything she said about her situation, and the hopelessness of many, many others waiting for organs, demonstrated the challenges and limitations of the current system of organ replacement.
We believe it’s time for dramatic change. You already know Methuselah doesn’t accept the idea that “everyone falls apart.” (I have a harder time accepting that each year as I get closer to senior status.) Our vision is a long, healthy life for you, me and everyone on the waiting list for an organ.
This year we are focusing our efforts on tissue engineering and organ replacement. We are looking ahead 10 years and projecting that, with our help, everyone who needs an organ will get an organ. To realize our vision we are advocating nothing short of a whole new system. We call it Organomics. It is the science of organ regeneration combined with the economic means to make it possible.
The promise of Organomics is to provide a new organ to any patient in need, not from a donor or from the black market but from their own cells. NewOrgan Prize was created to reach this ambitious goal.
Methuselah Foundation has been working for years to find causes and solutions of deteriorating health and productivity. I’m glad to be part of an organization that drives science to find solutions that will work for all of us.
I challenge you to be Organomical!
Now that you know the science of NewOrganomics, be part of the economics that make it happen. Join a community of supporters and fundraisers who make the NewOrgan Prize possible and help us invest in the science of tissue and organ regeneration. Please join me in making a contribution today.
Silverstone Solutions is one of the Methuselah Foundation’s strategic investments made in support of the recently launched NewOrgan Prize. Silverstone’s Matchmaker product was recently featured in an ABC7 article and video:
Technology developed in the Bay Area could soon have a dramatic impact on kidney transplants. It is designed to help patients who need a matching donor and a new version may be able to pair up thousands of patients in a fraction of the time.
Maggie Ervin recently started a chain reaction. After listening to a documentary on organ donation, she decided to donate one of her two kidneys to a stranger, as an altruistic donor.
Rather than helping just one person, Maggie’s kidney was the first of a chain donation at California Pacific Medical Center in San Francisco. Over the course of the day, surgeons removed and transplanted kidneys among half a dozen people.
“It’s exciting. A lot of people are getting transplanted that otherwise wouldn’t have an opportunity to get a transplant,” said.
They are known as unmatched donors. Maggie’s kidney went to Fernando Rico whose friend Guadalupe Ramirez was not compatible. Instead, Guadalupe donated her kidney in Fernando’s name to a different recipient, whose sister then donated to another stranger.
Identifying and arranging these donation chains in time and space – a very challenging problem – is the benefit provided by Silverstone’s work.
Methuselah Foundation co-founder and CEO David Gobel was recently featured in an interview on the Morning radio program for the Australian Broadcasting Corporation in Canberra. You can download an MP3 copy of the interview and listen at your leisure.
Wired is running a photo essay on organ-printing startup company Organovo. Generous Methuselah Foundation donors provided the funds for the Foundation to invest in the growth of Organovo, an investment that is a part of the Foundation’s long-term strategy to support and nurture important research:
“Right now we’re really good at printing blood vessels,” says Ben Shepherd, senior research scientist at regenerative-medicine company Organovo. “We printed 10 this week. We’re still learning how to best condition them to be good, strong blood vessels.”
Most organs in the body are filled with veins, so the ability to print vascular tissue is a critical building block for complete organs. The printed veins are about to start testing in animal trials, and eventually go through human clinical trials. If all goes well, in a few years you may be able to replace a vein that has deteriorated (due to frequent injections of chemo treatment, for example) with custom-printed tissue grown from your own cells.
The photos are good, but the article mistakenly suggests that hundreds of millions of dollars will be needed to develop the organ printing system. In fact, Organovo’s devices are already on sale to research groups – the large expenditures of the future will be spread amongst researchers who are working on moving from printing blood vessels to printing entire complex human organs.