Our aim is to test the common assumption that aging in mammals involves a nonrandom decrease in neuron number and that the decrease is preceded by changes in connections made and received by those neurons. The hypotheses derive from well-established data that at critical periods early in life, the number of neurons is adujsted downward by about 50% in many regions of the nervous system as a normal programmed event, and that axonal innervation of target cells also may be adjusted downward. Do such adjustments occur late in life and what controls them? Our analysis uses two general groups of young adult and aged mice. First, we will examine genetically normal mice of the standard C5BL/6 and BALB/c inbred strains with emphasis on the period from 24 to 30 months of age. Second, we will use old mice bearing single gene mutations that eliminate specific neuron types; resultant changes in connectivity may cause further neuron losses "upstream" or "downstream" in the synaptic chains, not as direct effects of the mutations but representating exaggerated and premature aging effects. The study is made possible by the recent development of computer-assisted quantitative methods applicable at light and electron microscopic levels for scoring the numbers and positions of neurons of defined classes, counting and classifying axons with statistical reliability in central tracts and peripheral nerves, measuring volumes and surface areas of brain regions and of individual cells, estimating area and density of terminal axonal fields and quantifying axosomatic and axodendritic synaptic connections. The measurements that will critically test our hypotheses are 1) retinal ganglion neuron number in normal mice and in mutants that become deficient at various ages in photoreceptor cells or in subclasses of ganglion cell neurons, 2) optic nerve and tract axons and their target territories, 3) sciatic nerve axons, their motor neuron sources, and sensory neuron target fields in normal aged mice, 4) cerebellar Purkinje, granule, and nuclear neurons in normals and mutants, and 5) axosomatic and axodendritic synapse numbers and contract areas in cerebellar deep nuclei of aged normal and Purkinje neuron-deficient mutants.