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In addition to their extended lifespans, slow-aging growth hormone receptor/binding protein gene-disrupted (knockout) (GHR-KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR-KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic β-cells by expressing Igf-1 under the rat insulin promoter 1 (RIP::IGF-1). The RIP::IGF-1 transgene increased circulating insulin content in GHR-KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non-β-cell cell types. Multiple (nonsurvivorship) longevity-associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR-KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated., (© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Presbycusis can be considered a slow age-related peripheral and central deterioration of auditory function which manifests itself as deficits in speech comprehension, especially in noisy environments. The present study examined neural correlates of a simple broadband noise stimulus in primary auditory cortex (A1) of young and aged Fischer-Brown Norway (FBN) rats. Age-related changes in unit responses to broadband noise bursts and spontaneous activity were simultaneously recorded across A1 layers using a single shank, 16-channel electrode. Noise bursts were presented contralateral to the left A1 at 80 dB SPL. Aged A1 units displayed increased spontaneous (29%), peak (24%), and steady state response rates (38%) than did young A1 units. This was true across all A1 layers, although age-related differences were significantly greater for layers I-III (43% vs 18%) than lower layers. There was a significant age-related difference in the depth and duration of post-onset suppression between young and aged upper layer A1 units. The present functional differences across layers were consistent with studies showing greatest losses of gamma-aminobutyric acid (GABA) markers in superficial layers of A1 and with anatomic studies showing highest levels of inhibitory neurons located in superficial cortical layers. The present findings were also consistent with aging studies suggesting loss of functional inhibition in other cortical sensory systems., (Copyright 2009 Elsevier B.V. All rights reserved.)

Aging and acoustic trauma may result in partial peripheral deafferentation in the central auditory pathway of the mammalian brain. In accord with homeostatic plasticity, loss of sensory input results in a change in pre- and postsynaptic GABAergic and glycinergic inhibitory neurotransmission. As seen in development, age-related changes may be activity dependent. Age-related presynaptic changes in the cochlear nucleus include reduced glycine levels, while in the auditory midbrain and cortex, GABA synthesis and release are altered. Presumably, in response to age-related decreases in presynaptic release of inhibitory neurotransmitters, there are age-related postsynaptic subunit changes in the composition of the glycine (GlyR) and GABA(A) (GABA(A)R) receptors. Age-related changes in the subunit makeup of inhibitory pentameric receptor constructs result in altered pharmacological and physiological responses consistent with a net down-regulation of functional inhibition. Age-related functional changes associated with glycine neurotransmission in dorsal cochlear nucleus (DCN) include altered intensity and temporal coding by DCN projection neurons. Loss of synaptic inhibition in the superior olivary complex (SOC) and the inferior colliculus (IC) likely affect the ability of aged animals to localize sounds in their natural environment. Age-related postsynaptic GABA(A)R changes in IC and primary auditory cortex (A1) involve changes in the subunit makeup of GABA(A)Rs. In turn, these changes cause age-related changes in the pharmacology and response properties of neurons in IC and A1 circuits, which collectively may affect temporal processing and response reliability. Findings of age-related inhibitory changes within mammalian auditory circuits are similar to age and deafferentation plasticity changes observed in other sensory systems. Although few studies have examined sensory aging in the wild, these age-related changes would likely compromise an animal's ability to avoid predation or to be a successful predator in their natural environment.

The fusiform cell and deep layers of the dorsal cochlear nucleus (DCN) show neurotransmitter and functional age-related changes suggestive of a downregulation of inhibitory efficacy onto DCN output neurons. Inhibitory circuits implicated in these changes include vertical and D-multipolar cells. Cartwheel cells comprise a large additional population of DCN inhibitory neurons. Cartwheel cells receive excitatory inputs from granule cell parallel fibers and provide a source of glycinergic inhibitory input onto apical dendrites of DCN fusiform cells. The present study compared the response properties from young and aged units meeting cartwheel-cell criteria in anesthetized rats. Single unit recordings from aged cartwheel cells revealed significantly higher thresholds, increased spontaneous activity and significantly altered rate-level functions characterized by hyperexcitability at higher intensities. Aged cartwheel cells showed a significant reduction in off-set suppression. Collectively, these findings suggest a loss of tonic and perhaps response inhibition onto aged DCN cartwheel neurons. These changes likely reflect a compensatory downregulation of synaptic inhibition in response to a loss of excitatory drive from auditory and non-auditory excitatory inputs via granule cells. The impact of increased excitability of cartwheel cells on DCN output neurons is likely to be complex, influenced by loss of glycinergic release and/or subunit receptor changes which would only partially off-set age-related loss of inhibition onto the somata and basal dendrites of fusiform cells.

Advanced age is commonly associated with progressive cochlear pathology and central auditory deficits, collectively known as presbycusis. The present study examined central correlates of presbycusis by measuring response properties of primary auditory cortex (AI) layer V neurons in the Fischer Brown Norway rat model. Layer V neurons represent the major output of AI to other cortical and subcortical regions (primarily the inferior colliculus). In vivo single-unit extracellular recordings were obtained from 114 neurons in aged animals (29-33 mo) and compared with 105 layer V neurons in young-adult rats (4-6 mo). Three consecutive repetitions of a pure-tone receptive field map were run for each neuron. Age was associated with fewer neurons exhibiting classic V/U-shaped receptive fields and a greater percentage of neurons with more Complex receptive fields. Receptive fields from neurons in aged rats were also less reliable on successive repetitions of the same stimulus set. Aging was also associated with less firing during the stimulus in V/U-shaped receptive field neurons and more firing during the stimulus in Complex neurons, which were generally associated with inhibited firing in young controls. Finally, neurons in aged rats with Complex receptive fields were more easily driven by current pulses delivered to the soma. Collectively, these findings provide support for the notion that age is associated with diminished signal-to-noise coding by AI layer V neurons and are consistent with other research suggesting that GABAergic neurotransmission in AI may be compromised by aging.