Sharma and Goodwin physiological states: high or low affinity. Cyclic AMP production is reduced during agonist binding to a low affinity state. The β-receptor density remains unchanged during lifetime, but receptor affinity is reduced (Abrass and Scarface 1982). This reduction in high affinity receptor represents functional uncoupling of the receptor from the adenyl cyclase complex and impaired receptor-mediated adenyl cyclase activity (Feldman et al 1984; Connolly 1993) (Figure 4). Muscarinic receptor The data on age-related changes in pulmonary muscarinic receptor in humans is limited. A study on age-related changes in muscarinic receptors in guinea pigs showed no change in the receptor density but noticed a significant reduction in high affinity agonist binding sites in old tissues compared with young tissues. There was a change in the muscuranic receptor subtypes and receptor coupling to G proteins with senescence (Willis-Karp 1993). Clinical significance of these findings in terms of variation in anticholinergic responsiveness in older adults is yet to be determined. Cysteinyl-Leukotriene (CysLT ) 1 receptor The stimulation of cysteinyl-leukotriene (CysLT1) receptor located on the airway smooth muscles induces bronchoconstriction. CysLT1 antagonists, namely zafrilukast and montelukast, have shown promise in the treatment of asthma in younger adults. There are no in vivo or in vitro studies looking at the effect of age on CysLT1 receptors. Nonetheless, clinical studies of leukotriene receptor antagonist in the treatment of asthma showed minimal improvement in FEV1 in older adults with asthma. Meta- Table 5 Ventilatory response to hypoxia and hypercapnia Young Elderly p-value (22–30 (64–79 years) years) VE (Minute ventilation) in litres/min Kronenberg et al 1973 PaO2 40 mm Hga PaCO2 (L/min/mm Hg)b Peterson et al 1981 SpO2 75%c PaCO2 60 mm Hgd 40.1±4.7 3.4±0.5 10.2±1.2 2.0±0.02 <0.001 <0.025 30.3±2.9 L/min 48.7±4.3 L/min 20.9±2.3 L/min <0.01 34.6±2.9 L/min Note: aChange in minute ventilation from baseline to during hypoxia (arterial oxygen tension of 40 mm of Hg); bChange in minute ventilation per unit change in arterial carbondioxide tension from baseline; cminute ventilation at arterial oxygen saturation of 75%; dminute ventilation at arterial carbondioxide tension of 60 mm Hg. 258 ß-adrenoreceptor + ATP cAMP Phosphorylation Figure 4 Mechanism of action of beta agonist. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate. analysis of five randomized, double-blind studies of over 1900 patients showed treatment with zafrileukast in older adults with asthma showed no improvement in lung function; on the contrary, it increases asthma exacerbations. The latter observation is of particular concern as older adults have reduced perception of dyspnea which may cause delay in getting medical attention (Cuttitta et al 2001). Baseline airway reversibility was similar across all age groups, and the lack of improvement in lung function are unlikely to be explained by “fixed airway disease” secondary to airway remodeling in older adults (Creticos et al 2002). Similar results were noticed in an open label trial of over 3700 patients on zafrileukast (Korenblatt et al 2000). In summary, the clinical significance of age-related β- adrenoreceptor and muscuranic receptor changes are not well studied, but the role of CysLT1 receptor antagonist in older adults remains controversial. Exercise capacity The effect of aging on exercise capacity is highly variable and depends upon individual fitness and regular physical activity. Maximum oxygen consumption (VO2 max), an objective surrogate of fitness, peaks between 20 to 30 years of age, then declines by a rate of about 1% per year depending upon individual level of physical activity (declining more in sedentary compared with physically active adults). McClaran et al (1995) studied the longitudinal effects of aging on lung function at rest and during exercise in healthy older adults and showed an 11% reduction in VO2 max as a group over a 6 year period. All participants were highly trained in aerobic fitness, and their VO2 max was still twice the age predicted maximum. The ventilatory Clinical Interventions in Aging 2006:1(3)