A calculation of loss rates is reported for human structural and functional variables from a substantially larger data set than has been previously studied. Data were collected for healthy, nonsmoking human subjects of both sexes from a literature search of cross-sectional, longitudinal, and cross-sequential studies. The number of studies analyzed was 469, and the total number of subjects was 54,274. A linear model provided a fit of the data, for each variable, that was not significantly different from the best polynomial fit. Therefore, linear loss rates (as a percent decline per year from the reference value at age 30) were calculated for 445 variables from 13 organ systems, and additionally for 24 variables even more integrative, such as maximum oxygen consumption and exercise performance, that express effects of multiple contributing variables and systems. The frequency distribution of the 13 individual system linear loss rates (as percent loss per year) for a very healthy population has roughly a unimodal, right-skewed shape, with mean 0.65, median 0.5, and variance 0.32. (The actual underlying distribution could be a truncated Gaussian, an exponential, Poisson, gamma or some other). The linear estimates of loss rates were clustered between 0% and 2% per year for variables from most organ systems, with exceptions being the endocrine, thermoregulatory, and gastrointestinal systems, for which wider ranges (up to approximately 3% per year) of loss rates were found. We suggest that this set of linear losses over time, observed in healthy individuals between ages (approximately) 30 to 70 years, exposes the underlying kinetics of human senescence, independent of effects of substantial disease.

696Dallman & Y ates: Corticosteroid Feedback Path 697 Any i.v. infusions were delivered at 0.0206 ml per minute through a 27-gauge needle inserted into a lateral caudal vein at the start of the experiment. When it was desired to combine the infusion technique with the single-injection technique, the injections were given after the infusion had been established, by either of two routes: (a) into the contralateral caudal vein, or (b) into the ipsilateral vein above the site of the infusion. In some instances, the infusion was stopped while the injection was given and then was restarted within 45 seconds. There was no detectable difference in results within a group from these variations in technique. Preparations in which there was evidence of fluid extravasation in the tail during injection or infusion, or in which any difficulty was encountered in establishing the infusions or injections, were discarded. At the end of each experiment, animals were decapitated, and trunk blood was collected into heparinized test tubes for the subsequent determination of plasma corticosterone concentration by a microfluorometric method.'Substances injected were corticosterone (80 pg), saline, histamine dihydrochloride (230 pg free base), or adrenocorticotropin (ACTH) (4 m u ) . Substances infused were saline or corticosterone (1.8 or 1.9 pg per minute). The corticosterone solutions were prepared by dissolving the steroid in acetone and adding the acetone solution to 0.9% saline. The acetone was then removed by warming the solution at 37' C while nitrogen gas was passed over the surface until the odor of acetone vanished. The ACTH (USP corticotropin standard) solutions were made fresh daily in 0.01 N hydrochloric acid in saline. Histamine was diluted in saline. Saline solutions used as controls for experiments with corticosterone solutions were prepared with acetone in the same manner as were the corticosterone solutions. Data presented as means are accompanied by the standard errors of the means. RESULTS A N D DISCUSSION Connectivity of the Adrenocortical SystemThe block diagram in FIGURE 1 shows the connectivity of the adrenocortical system of vertebrates. The experimental evidence upon which the diagram is based has been discussed e l s e~h e r e ,~.~ and will be only summarized here. The system arrangement shown in FIGURE 1 has also been described elsewhere in greater detaiL7The adrenal glucocorticoid hormones, of which cortisol is the archetype, are secreted into adrenal venous blood and are distributed throughout the plasma and interstitial fluid. In plasma, these hormones are bound to albumin, and in most vertebrate species to a second protein (e.g. transcortin), with the result that only about 5510% of the hormone in plasma is ordinarily free.g The unbound, free moiety enters the interstitial fluid and affects most of the target processes of the adrenocortical system.

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