We have discovered two different, but related, biological markers of aging in the peripheral sensory nervous system of rats, that we can also produce in young adults by a specific antibody treatment. These findings arose from our recent demonstration in rats and mice that the collateral sprouting of undamaged nerves which occurs in partially denervated skin of mammals, including humans, is evoked by endogenous nerve growth factor (NGF). We now find that daily anti-NGF treatment not only prevents such sprouting, but in rats causes a progressive shrinkage of the behaviorally measured heat-nociceptive fields, by almost 50% in one month. There is an even more dramatic attenuation of the entire sensory C fiber fields as revealed by a quite different technique, the extravasation of Evans blue. These observations, plus electron microscopic ones, suggest that endogenous NGF normally regulates a continuous turnover of these endings, which regress if they are chronically deprived of NGF. A potential link between these observations and aging came from a consideration of the brains of Alzheimer patients, and aged normal people and rats; here there is a progressive degeneration of certain cholinergic projections, hypothesized to result from a NGF deficiency in their target regions. Could a NGF deficiency also exist in aged skin, revealing itself by an analogous regression of the NGF-sensitive nerve projections there? Our first results are promising; in 4 out of 4 rats aged 2-21/2 years we found a marked shrinkage of the heat nociceptive fields, and an even more striking attenuation of the """"""""Evans blue fields""""""""; the NGF- insensitive touch fields however were of normal size. We will now characterise these aging effects further, including mice in our studies, and ask: (1) are the field shrinkages due to regression of sensory terminals in the skin? (2) will exogenous NGF cause an expansion of the fields? (experimentally shrunken fields in young adults re-expand after anti-NGF treatment is stopped). (3) will regenerating sensory nerves restore normal or even enlarged fields? (in young adults, even an augmented anti-NGF treatment fails entirely to prevent sensory recovery by nerves regenerating after a crush); (4) (in collaboration with Dr. . Reichardt's group) will these sensory markers of aging, i.e. the shrunken heat fields and the almost obliterated Evans blue fields, which we hypothesis are due to a NGF deficiency, be correlated with reduced levels of mRNA for NGF in skin?
| Diamond, J (1994) Nerve-skin interactions in adult and aged animals. Prog Clin Biol Res 390:21-44 |
| Van der Zee, C E; Fawcett, J; Diamond, J (1992) Antibody to NGF inhibits collateral sprouting of septohippocampal fibers following entorhinal cortex lesion in adult rats. J Comp Neurol 326:91-100 |
| Diamond, J; Foerster, A (1992) Recovery of sensory function in skin deprived of its innervation by lesion of the peripheral nerve. Exp Neurol 115:100-3 |
