prevalence of activity-related breathlessness increases with age, particularly in women, but the specific underlying mechanisms have not been studied. This novel cross-sectional study was undertaken to examine the effects of age and sex, and their interaction, on the perceptual and ventilatory responses to incremental treadmill exercise in 73 healthy participants (age range 40 -80 yr old) with normal pulmonary function. Age-related changes at a standardized oxygen uptake (V O2) during exercise included significant increases in breathlessness ratings (Borg scale), ventilation (V E), ventilatory equivalent for carbon dioxide, and the ratio of tidal volume (VT) to dynamic inspiratory capacity (IC) (all P Ͻ 0.05). These changes were quantitatively similar in women (n ϭ 39) and in men (n ϭ 34). For the group as a whole, exertional breathlessness ratings increased as resting static inspiratory muscle strength diminished (P ϭ 0.05), as exercise ventilation increased relative to capacity (P ϭ 0.013) and as the VT/IC ratio increased (P ϭ 0.003) during exercise. Older women (60 -80 yr old, n ϭ 23) reported greater (P Ͻ 0.05) intensity of exertional breathlessness at a standardized V O2 and V E than age-matched men (n ϭ 16), despite similar age-related changes in ventilatory demand and dynamic ventilatory mechanics. These increases in breathlessness ratings in older women disappeared when sex differences in baseline maximal ventilatory capacity were accounted for. In conclusion, although increased exertional breathlessness with advancing age is multifactorial, contributory factors included higher ventilatory requirements during exercise, progressive inspiratory muscle weakness, and restrictive mechanical constraints on VT expansion related to reduced IC. The sensory consequences of this age-related respiratory impairment were more pronounced in women, who, by nature, have relatively reduced maximal ventilatory reserve. dyspnea; aging; inspiratory capacity CARDIOVASCULAR FACTORS are widely accepted as a proximate limit to maximal oxygen uptake (V O 2 ) during weight-bearing exercise in healthy humans (42,48). By contrast, the respiratory system is regarded as relatively "overbuilt" and less likely to contribute to exercise limitation except in elite athletes at very high power outputs (15, 21). However, it is recognized that in sedentary older individuals, intolerable exertional breathlessness may contribute to exercise limitation even before physiological maxima are attained (39). A number of studies have reported that more than 30% of the elderly (Ͼ65 yr) experience breathlessness during activities of daily living (23,24,30,47). The nature and mechanisms of exertional breathlessness in older healthy humans are poorly understood.While the physiological effects of aging on the respiratory system are well established (14,25,40), the interaction between these changes in respiratory system compliance, muscle function, and ventilation/perfusion (V /Q ) matching and the perceptual responses to physical exertion is largely unknow...