The Rodent in Old Age

Everything ages, and everything dies, but the mechanisms behind these processes are anything but clear. Two new papers provide a glimpse of how aging and senescence occur in three species of rodent-kind: rats, mice, and the buck-toothed naked mole-rats of East Africa. Writing in the February 11 Journal of Neuroscience, scientists from Philip Landfield’s group at the University of Kentucky in Lexington describe the maze-solving ability and hippocampal gene expression profiles of rats at five stages of life. The second paper, published online in PNAS February 17, takes a different approach. Viviana Prez, Rochelle Buffenstein, and Asish Chaudhuri, of the University of Texas Health Sciences Center in San Antonio, asked why mice live only a few years, whereas naked mole-rats can survive decades. Both papers call into question the orthodox theory that animals age and die because, over time, they build up so many free radicals and suffer so much oxidative damage that they can no longer survive.

In the Journal of Neuroscience paper, joint first authors Inga Kadish, of the University of Alabama in Birmingham, and Olivier Thibault and Eric Blalock of the University of Kentucky, ran rats through a water maze, and then ran their brains through genetic microarray analysis, to determine what genetic changes are associated with cognitive decline, and when. If we know what the sequence of the changes was, we’d have a much better chance of putting together the jigsaw, Landfield said.

The researchers analyzed 51 animals total, at three, six, nine, 12, and 23 months. They trained the animals to swim to a hidden platform in the Morris water maze, and found during later trials that the 12- and 23-month-old animals were slower to find the platform, often taking 40 seconds or more compared to the younger animals, who escaped the pool in 15 to 20 seconds. They extracted RNA from the hippocampuses of the same animals, once the trials were completed, and used the material for microarray studies.

The genetic changes began early. Between three and six months, the researchers found that the expression levels for several genes involved in metabolism changed. That suggests, Landfield said, that the animals start to age as soon as they have finished growing up. The animals upregulated genes for lipid degradation, and downregulated those for lipid and cholesterol synthesis. As they aged to nine months, the rats expressed more inflammatory and immune genes. Between nine and 12 months, when the rats started to show signs of cognitive decline, the animals upregulated genes associated with myelin production and cholesterol trafficking, including ApoE.

The work, along with two previous gene expression studies by the same group (Blalock et al., 2003; Rowe et al., 2007), completes a trilogy, Landfield said, of analyses of how the rodent brain changes with age. Gene association studies find only correlation, however, so it is not clear what changes are cause and what are effect. The next step is to connect the dots. By knocking out some of the relevant genes in rats, Landfield hopes to determine the cascade of events that is the aging process.

However, the authors did present a speculative model of how the changes they observed could lead to senescence. They suggested that before three months of age, the rats’ metabolism shifted to favor burning of lipids and ketones in the brain. That, in turn, could trigger inflammation that degraded the neurons’ myelin sheaths. The cholesterol-trafficking genes are then upregulated to provide the raw materials for new myelin. Together, these processes could damage neurons or drain their energy supply, resulting in neurodegeneration and ultimately cognitive impairment.

The data suggest that aging is not merely the lifetime accumulation of toxins, but a stepwise, regulated process that begins well before the physical symptoms of senescence appear. These changes in gene expression during aging are not surprising, said George Perry of the University of Texas in San Antonio, who was not involved with the study. I think what he’s found is evidence for something that’s been speculated about for a long time. They’re talking about a whole shift in metabolism throughout the aging process.

The second paper by Prez and colleagues also provides evidence that oxidative stress isn’t a complete answer to the aging question. Unlike the mouse, which manages to survive for approximately 3.5 years in the lab, and 4.5 years in the wild, the naked mole-rat (Heterocephalus glaber) scurries through its underground warren for an astonishing 30 years (Buffenstein and Jarvis, 2002). The two species are nearly the same size, so body mass cannot explain the difference in their longevity. Nor can oxidative damage—the young mole-rat has higher levels of lipid peroxidation, protein carbonylation, and DNA oxidative damage than do young mice (Andziak et al., 2006). Prez and colleagues hypothesized that naked mole-rats might have particularly stable, stress-resistant proteins.

The scientists analyzed the oxidation state of cysteine in liver homogenates from young and old animals of each species. They found that in mice, the levels of oxidized cysteine increased with age. In the mole-rats, while oxidation levels were already high in young animals, they did not go up as the rodents aged. And when the scientists exposed liver protein samples to one molar urea, the mouse proteins unfolded twice as much as the mole-rat proteins, as measured by exposed hydrophobic patches. They also found that the proteasomal enzymes, which degrade misfolded or damaged proteins, were more active in old mole-rats, compared to old mice.

Combined, these results suggest to Chaudhuri that naked mole-rats survive for decades because their proteins are more resistant to damage, and because they speedily destroy any proteins that are beyond repair. Instead of the absolute level of oxidative damage, Chaudhuri suggested, the accumulation of oxidative damage is the determinant for longevity. In mice, the level of damage goes up with time, but in mole-rats, it stays the same. The increase in damage, not the damage itself, is what is correlated with lifespan in these two rodents.

Next, Chaudhuri plans to identify the proteins, perhaps chaperones, that allow mole-rats to maintain their vigor despite a high level of oxidative damage. That understanding could lead to treatments for neurodegenerative diseases such as amyotrophic lateral sclerosis, he said, if there was a way to protect proteins in human cells the same way.

The standard theory that oxidative stress is the sole cause of senescence is pretty much dead, Perry said. It’s all about changes in signaling and metabolism; it’s much more complicated.

Kadish I, Thibault O, Blalock EM, Chen K-C, Gant JC, Porter NM, Landfield PW. Hippocampal and cognitive aging across the lifespan: A bioenergetic shift precedes and increased cholesterol trafficking parallels memory impairment. J Neurosci Febr 11 2009 29(6): 1805-1816. Abstract

Prez VI, Buffenstein R, Masamsetti V, Leonard S, Salmon AB, Mele J, Andziak B, Yang T, Edrey Y, Friguet B, Ward W, Richardson A, Chaudhuri A. Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. PNAS Early Edition Feb 17 2009. Abstract

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