Human ageing and the sympathoadrenal system

Abstract

Over the past three decades the changes in sympathoadrenal function that occur with age in healthy adult humans have been systematically studied using a combination of neurochemical, neurophysiological and haemodynamic experimental approaches. The available experimental evidence indicates that tonic whole-body sympathetic nervous system (SNS) activity increases with age. The elevations in SNS activity appear to be region specific, targeting skeletal muscle and the gut, but not obviously the kidney. The SNS tone of the heart is increased, although this appears to be due in part to reduced neuronal reuptake of noradrenaline (norepinephrine). In contrast to SNS activity, tonic adrenaline (epinephrine) secretion from the adrenal medulla is markedly reduced with age. This is not reflected in plasma adrenaline concentrations because of reduced plasma clearance. Despite widely held beliefs to the contrary, sympathoadrenal responsiveness to acute stress is not exaggerated with age in healthy adults. Indeed, adrenaline release in response to acute stress is substantially attenuated in older men. The mechanisms underlying the age-associated increases in SNS activity have not been established, but our preliminary data are consistent with increased subcortical central nervous system (CNS) sympathetic drive. These changes in sympathoadrenal function with advancing age may have a number of important physiological and pathophysiological consequences for human health and disease.

Figure 1. Age-associated increases in muscle sympathetic nerve activity

A, integrated peroneal neurograms of muscle sympathetic nerve activity (MSNA) from 4 healthy adult humans under supine resting conditions (top to bottom): young female, young male, older female, older male. MSNA burst frequency (BF; bursts min⁻¹) and burst incidence (BI; bursts (100 heart beats)⁻¹) are higher in the neurograms of the older adults in both sexes. However, the female subjects demonstrate lower MSNA than the males at each age. AP, arterial blood pressure. B, mean ±s.e.m. values for peroneal MSNA in 4 groups of subjects: young women (YW), young men (YM), older women (OW) and older men (OM). MSNA was at least twice as great in the older compared with the young subjects of the same sex. At each age, however, MSNA was significantly lower in the women. These age and sex differences in MSNA were not reflected in the corresponding antecubital venous plasma noradrenaline concentrations. PNA, plasma noradrenaline concentration; *P < 0·05 vs. all other groups.

Figure 2. Influence of ageing on noradrenaline (NA) kinetics in the heart and hepatomesenteric circulation, and on secretion of adrenaline

Cardiac noradrenaline spillover was higher in older men (upper left panel). This appeared to be due in part to reduced neuronal reuptake of noradrenaline, evident in reduced transcardiac extraction of plasma tritiated noradrenaline (upper right panel); removal of noradrenaline from plasma by the heart is largely by uptake into the cardiac sympathetic nerves. Noradrenaline spillover into the hepatomesenteric circulation was also higher in the older men (lower left panel), but unlike in the heart, this was most probably due exclusively to increased sympathetic nerve firing rates, as plasma tritiated noradrenaline extraction across the gut and liver (not shown) was normal. In contrast to the augmentation of sympathetic tone in the heart and hepatomesenteric circulation, adrenaline secretion rates were reduced in the older men (lower right panel). Mean +s.e.m. values are indicated in the histograms. *P < 0·05 vs. young men.

Figure 3. Regional changes in the sympathoadrenal system with primary (healthy) human ageing

Augmentation of sympathetic activity, evident in increased noradrenaline (NA) spillover rates or sympathetic nerve firing measured with microneurography, occurs with ageing in the sympathetic outflows of the heart, hepatomesenteric circulation and skeletal muscle vasculature. In contrast, ageing produced no obvious change in sympathetic nervous activity in the kidney, and a reduction in adrenaline secretion by the adrenal medulla. Symbols in parentheses indicate an increase, decrease or no change in activity.

Figure 4. The influence of ageing on increases in (top to bottom) adrenaline secretion and the spillover of noradrenaline to plasma from the whole body and from the heart during the application of laboratory stress

The increases in total noradrenaline spillover rates with the stimuli were not affected by ageing. Contrasting effects of ageing were observed for stimulation of adrenaline secretion (lower in older men) and cardiac noradrenaline spillover (higher in older men). Reprinted (from Esler et al. 1995a) with permission. *P < 0·05 and **P < 0·01 indicate significance of differences between younger and older men. Mean ±s.e.m. values are shown.