10 Sep 2005

Clearly, the greatest risk factor for AD is advanced age, but a satisfying explanation of the link between aging and AD remains uncertain. To understand this connection, it is argued that a better understanding of "normal" aging is needed.

An emerging area of overlap between aging and AD lies in synaptic atrophy. Loss of synapses is generally accepted as an underlying process of AD, but it also may explain a more general drop in people's cognitive ability with age. One theory is that chronic, mild inflammatory activation of glial cells may lead to synaptic atrophy with aging. Inflammatory processes increase with advancing age, and conversely, anti-inflammatory drugs reduce amyloid load in transgenic mouse models. Epidemiologic evidence in humans also supports this theory.

To study neuronal aging, a recent study compared gene expression of normal humans ranging from people in their twenties to centenarians. Gene expression changes that correlated with age revealed a group of genes whose expression starts to drop around age 40. More precisely, this group of genes showed a uniformly high expression level in young people and a uniformly lower expression level in most very old people, but great variability from person to person in the middle decades of life, perhaps yielding clues as to why some people age "better" than others. Among these down-regulated genes were genes that function in mitochondria, synaptic plasticity, and vesicle transport. A cell-based assay revealed that these down-regulated genes sustained high levels of DNA damage in their promoter regions when exposed to mild oxidative stress and were less able to repair that damage. In essence, DNA damage results in transcriptional silencing of a subset of genes important for cognition (Lu et al, 2004). This study was recently confirmed and extended (Fraser et al., 2005).

The reasons why particular promoters are more susceptible to oxidative damage, and the connection of this phenomenon to AD pathology are unclear. It remains an open question whether similar expression changes could be detected in peripheral cells around mid-life, yielding perhaps a biomarker for elevated risk. Broadly, DNA sequence determinants as well as epigenetic changes during life should be analyzed for how they affect expression of these genes. For now, it appears as if aging processes are heterogeneous. Different people may be impacted by different genetic and epigenetic factors, some combinations of which will be more likely to result in AD.

The link between oxidative stress and AD and Parkinson's pathology has inspired tests of antioxidants as therapeutic agents. The free radical scavenger coenzyme Q10 has shown some promise in the clinic and is expected to enter a phase 3 trial of Parkinson's in 2006. Preclinical CoQ10 tests in APP transgenic mice also show promise. That said, as a group, antioxidants have disappointed in the clinic so far. Their weak effect may be partly due to the BBB, which makes it difficult to achieve effective concentrations in brain while keeping levels safe in the rest of the body.

Caloric restriction has been shown to increase longevity in multiple systems from yeast through worms and flies to rodents. Molecular biological approaches to the study of aging have focused on the genetic programs that become active under conditions of caloric restriction. The biochemical function of some of these genes, called sirtuins, is to remove acetyl groups from components of the DNA-packing material chromatin. When that happens, certain genes become silenced. Intriguingly, the sirtuins require a cofactor, NAD, whose supply rises and falls with an organism's nutritional state. This makes certain sirtuin genes a nexus between diet and gene expression, and it suggests that sirtuins might relate a person's metabolism to his or her pace of aging. Sirtuins are one player in a web of molecular pathways, and though it grows rapidly, this field has to date gained little more than a toehold into a complex area of metabolic regulation. Scientists need a much larger body of knowledge about exactly how diet and other epigenetic factors that drive gene expression can influence the molecular processes of aging and age-related diseases.

—Gabrielle Strobel

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References

Paper Citations

1. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. Gene regulation and DNA damage in the ageing human brain. Nature. 2004 Jun 24;429(6994):883-91. PubMed.
2. Fraser HB, Khaitovich P, Plotkin JB, Pääbo S, Eisen MB. Aging and gene expression in the primate brain. PLoS Biol. 2005 Sep;3(9):e274. PubMed.

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