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Decreased receptor activation with age. Can it be explained by desensitization?
1GRECC, VA Medical Center, Gainesville, FL 32602.
Abstract:
In the three endocrine/neuroendocrine systems discussed, there are demonstrable declines in post-maturational responsiveness. Parathyroid hormone stimulation of 1,25-dihydroxyvitamin D production declines with age in the kidney as does calcium absorption in the intestine. Chronotropic and inotropic responsiveness to beta-adrenergic agonists decreases with age in the myocardium, and performance on passive avoidance tasks related to memory dysfunction declines with age in rodents. In each case there is a corresponding decrease in receptor activation with age. Parathyroid hormone receptors are less able to activate adenylate cyclase in older rat kidneys; beta-adrenergic receptors have reduced density in some tissues, demonstrate reduced agonist affinity (are uncoupled), and are less able to activate adenylate cyclase in most tissues with age; and muscarinic receptors demonstrate mixed agonist affinity (are uncoupled) with age in rat hippocampal cells. This reduction in receptor activation can be attributed to desensitization to increased agonist concentrations. Parathyroid hormone receptor activation is restored by parathyroidectomy, beta-adrenergic agonists no longer desensitize in older animals, and muscarinic receptors from senescent rats pharmacologically mimic desensitized receptors. However, desensitization of receptor activation cannot fully account for the reduced hormonal responsiveness in any of these systems. Parathyroidectomy does not restore 1,25-dihydroxyvitamin D production or intestinal calcium absorption. There are age-related post receptor deficits in beta-adrenergic pathway that are not mediated by changes in serum catecholamines. In conclusion, there are significant changes in receptor and post-receptor biochemistry with age. The overall decreases in hormonal responsiveness are not due to a single biochemical defect in the system and are probably multiple in nature.
Insights
Aging reduces the body's response to hormones, affecting systems like the heart and kidneys. This decline involves receptor changes and post-receptor issues, indicating multiple age-related biochemical defects.
Area of Science:
- Endocrinology
- Neuroendocrinology
- Gerontology
Background:
- With aging, endocrine and neuroendocrine systems show reduced responsiveness.
- Key examples include declines in parathyroid hormone (PTH) stimulation of vitamin D, cardiac response to beta-adrenergic agonists, and memory function in rodents.
Purpose of the Study:
- To investigate age-related changes in receptor activation and post-receptor signaling pathways.
- To determine the extent to which receptor desensitization contributes to diminished hormonal responsiveness in aging.
Main Methods:
- Examined age-related changes in parathyroid hormone (PTH) and beta-adrenergic receptor function in rat kidneys and myocardium.
- Assessed muscarinic receptor function in senescent rat hippocampal cells.
- Investigated the impact of interventions like parathyroidectomy and pharmacological agents on receptor desensitization and hormonal response.
Main Results:
- Receptor activation declines with age, evidenced by reduced adenylate cyclase activity in response to PTH and beta-adrenergic agonists.
- Beta-adrenergic receptors show decreased density and affinity, while muscarinic receptors exhibit altered agonist affinity.
- While desensitization plays a role, it does not fully explain the reduced hormonal responsiveness, indicating significant post-receptor deficits.
Conclusions:
- Aging leads to significant alterations in receptor and post-receptor biochemistry.
- The observed decrease in hormonal responsiveness is multifactorial, involving both receptor-level and post-receptor defects.
- These age-related biochemical changes contribute to functional declines in multiple physiological systems.