Expert on Cellular and Organ Aging: “The Body’s Ability to Dispose of Cell Debris Could Extend Life.”

One of the main goals of my blog is to keep readers aware of important research and discoveries in the field of life extension, longevity and anti-aging. To that end, we have been following the work of Dr. Ana Maria Cuervo (www.einstein.yu.edu/cuervo), a molecular biology professor at the Albert Einstein College of Medicine and would like to provide some details into her important research and recent findings.
According to Cuervo, “the current challenges in the field of aging are two-fold: To continue and complete the molecular dissection of the factors that contribute to aging and to promote the translation of these novel findings into interventions to improve the health-span of the aging human population”.

Dr. Cuervo identified certain defects that lead to decreased activity of Chaperone-Mediated Autophagy (CMA) (www.einstein.yu.edu/cuervo/chaperone.htm) with age and how to correct and improve cellular function. Dr. Cuervo theorized that the decrease of Autophagy could be a determining factor in why some older organisms are unable to fight off cell abnormalities. Her research looked at the breakdown of the various autophagic pathways as the body ages and if restoring these pathways would jumpstart normal cellular activity. CMA is involved in at least 30% of the body’s cell degradation processes and upon studying this pathway, Cuervo determined that the LAMP-2A protein acts as a vital receptor in the pathway.

In recent experiments, livers in genetically modified mice 22 to 26 months old (the equivalent of octogenarians in human years), that were injected with the LAMP-2A protein, cleaned blood as efficiently as those in animals a quarter their age! By contrast, the livers of normal mice in a control group began to fail. While her paper didn’t show increased survival rates among the mice, Dr. David le Couteur (http://ichal06.longevity-international.com/cms/details.asp?NewsID=281), a leading Australian ageing researcher and Professor of Geriatric Medicine at the University of Sydney, says the paper was a major breakthrough and that Cuervo’s data definitely demonstrated improved survival rates. “She has single-handedly shown that lysosome function is a crucial part of the ageing process,” he says. Cuervo has also shown, he says, the critical role the lysosomal receptor molecules play in keeping the liver clean of damaged proteins.

Cuervo’s findings suggest that therapies for boosting protein clearance might help stave off some of the declines in function that accompany old age. This is especially positive news for those suffering from Alzheimer’s, Parkinson’s and Huntington’s disease as Dr. Cuervo has linked these diseases to a toxic buildup from mutated proteins possibly due to a breakdown in autophagy.

Dr. Cuervo is also working with pharmaceutical companies to identify drugs that will turn receptors on, or make them more active. Cuervo believes maintaining efficient protein clearance may improve longevity and function in all the body’s tissues. “The benefits of restoring the cleaning mechanisms found inside all cells could extend far beyond a single organ”, says Cuervo. “If the body’s ability to dispose of cell debris within the cell were enhanced across a wider range of tissues, she says, it could extend life as well”.

Read more about chaperone-mediated autophagy and the published research findings of Dr. Ana Maria Cuervo:http://www.nature.com/nm/journal/v14/n9/full/nm.1851.html

Maria Konovalenko
SCIENCE FOR LIFE EXTENSION FOUNDATION
http:/mariakonovalenko.wordpress.com/
maria.konovalenko@gmail.com

Scientists Discover New Way to Detect and Fix DNA Damage

Researchers at Vanderbilt University, Pennsylvania State University and the University of Pittsburgh have discovered a new mechanism that detects and repairs a more common form of DNA damage called alkylation.
In a typical day, about one million bases in the DNA of a human cell are damaged. These lesions are caused by a combination of normal chemical activity within the cell and exposure to radiation and toxins coming from environmental sources including cigarette smoke, grilled foods, UV rays and industrial waste. These lesions cause structural damage to the DNA molecule, and can dramatically alter the cell’s way of reading the information encoded in its genes. Luckily, repairing damage and maintaining the integrity of its DNA is one of the cell’s highest priorities. 

As cells age however, the DNA repair process can no longer keep up with ongoing DNA damage. The cell then suffers one of three possible outcomes:
* An irreversible state of dormancy, known as senescence (http://en.wikipedia.org/wiki/Senescence)
* Cell suicide, also known as apoptosis (http://en.wikipedia.org/wiki/Apoptosis) or programmed cell death
* Cancer
When cells become senescent, alterations in their gene regulation cause them to function less efficiently, which inevitably causes disease. The DNA repair ability of a cell is vital to its normal functioning and to the health and longevity of the organism. Many genes that are shown to influence lifespan are associated with DNA damage repair and protection.

“There is a general belief that DNA is ‘rock solid’ – extremely stable,” said Brandt Eichman (http://structbio.vanderbilt.edu/faculty/eichman.php), associate professor of biological sciences at Vanderbilt, who directed the project. “Actually DNA is highly reactive,” he was quoted as saying.
According to the Vanderbilt study, when a DNA base becomes alkylated, it forms a lesion that distorts the shape of the molecule enough to prevent successful replication. Human cells contain a single glycosylase (http://en.wikipedia.org/wiki/DNA_glycosylase), named AAG that repairs alkylated bases. It’s specialized to detect and delete “ethenoadenine” bases, which have been deformed by combining with highly reactive, oxidized lipids in the body.

“It’s hard to figure out how glycosylases recognize different types of alkylation damage from studying AAG since it recognizes so many. So we have been studying bacterial glycosylases to get additional insights into the detection and repair process,” said Eichman.
That is how they discovered the bacterial glycosylase AlkD with its unique detection and deletion scheme. “All the known glycosylases work in basically the same fashion: hey flip out the deformed base and hold it in a special pocket while they excise it. AlkD, by contrast, forces both the deformed base and the base it is paired with to flip to the outside of the double helix.”

“Understanding protein-DNA interactions at the atomic level is important because it provides a clear starting point for designing drugs that enhance or disrupt these interactions in very specific ways,” says Eichman. “So it could lead to improved treatments for a variety of diseases, including cancer.”

So there is a vast body of evidence that correlates DNA damage to death and disease. As indicated by the findings of the Vanderbilt study, increasing the activity of some DNA repair enzymes could cause a decrease in the rate of cell damage which would result in adding many healthy and disease-free years to our aging population.
Read about the DNA Repair study: (http://news.vanderbilt.edu/2010/10/newly-discovered-dna-repair-mechanism/)

Maria Konovalenko 
SCIENCE FOR LIFE EXTENSION FOUNDATION 
http:/mariakonovalenko.wordpress.com/ 
maria.konovalenko@gmail.com