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.”