Aging Takes Its Toll
Authors: Davenport R. John 
Published: August 2003

Like cats pacing a building's perimeter for signs of scuttling vermin, immune cells patrol bodies to stop invading microorganisms before they reach internal organs. But with age, the cells lose the protein tools with which they hunt down trespassers, according to new work. The study is the first to suggest that this frontline defense erodes with time, and it could lead to improved vaccinations for the elderly.
People's ability to fight infections declines with age: Elderly T cells and B cells fail to generate molecules that recognize specific germs, a process known as adaptive immunity. But mammals possess a second protective system--known as innate immunity--that relies on proteins called toll-like receptors (TLRs). These proteins bind sugars, bits of membrane, or nucleic acids found in bacteria and yeast. In response, TLRs coax the cells on which they reside to produce molecules that trigger antimicrobial inflammation. The innate immune system also stimulates the adaptive immune system, in case a more targeted response is needed. Whether passing years impair innate immunity is unclear, but the elderly often suffer from bacterial and fungal infections, the types that this defense system targets.
In the new study, Renshaw and colleagues investigated whether the abundance of TLRs changes with age. The team isolated immune cells called macrophages from the spleens of old (18- to 24-month-old) and young (2- to 4-month-old) mice and purified messenger RNA (mRNA) from the cells. The researchers then measured the amounts of mRNA corresponding to the nine different mouse TLR genes. Macrophages from old animals carried less TLR mRNA than did those from young animals; the extent of decline differed among the TLRs but ranged from an 80% to 90% decrease. The loss of TLR mRNA appears to result in less TLR protein: Old macrophages possessed approximately one-fifth as many molecules of one particular TLR protein as young cells did.
To determine whether the loss of TLRs hinders macrophage function, the scientists tickled the TLRs on macrophages with bits of bacteria and yeast and measured the amount of inflammatory molecules produced in response. Old macrophages pumped out considerably less of the substances than young macrophages did, suggesting that the reduction in TLRs on macrophages results in a curtailed immune response. The next step is to figure out why the amount of TLRs declines with age, says study co-author and vaccine researcher Suryaprakash Sambhara of the Centers for Disease Control and Prevention in Atlanta. He says that the answer could suggest strategies to override the loss of TLRs and improve the response of elderly people to vaccines.
This is the first study to examine TLRs with respect to aging, says immunologist Rita Effros of the University of California, Los Angeles: "It opens up a whole new area that hasn't been looked at before." Because yeast and bacterial infections increase in prevalence with age, loss of TLRs in humans "would explain a lot of problems in the elderly." And that could help scientists figure out ways of encouraging aging immune systems to pounce like feisty felines.
--R. John Davenport

M. Renshaw, J. Rockwell, C. Engleman, A. Gewirtz, J. Katz, S. Sambhara, Cutting edge: Impaired toll-like receptor expression and function in aging.
J. Immunol.
169
, 4697-4701 (2002).
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