Modulation of nigral dopamine signaling mitigates parkinsonian signs of aging: evidence from intervention with calorie restriction or inhibition of dopamine uptake.

Identifying neurobiological mechanisms of aging-related parkinsonism, and lifestyle interventions that mitigate them, remain critical knowledge gaps. No aging study, from rodent to human, has reported loss of any dopamine (DA) signaling marker near the magnitude associated with onset of parkinsonian signs in Parkinson's disease (PD). However, in substantia nigra (SN), similar loss of DA signaling markers in PD or aging coincide with parkinsonian signs. Alleviation of these parkinsonian signs may be possible by interventions such as calorie restriction (CR), which augment DA signaling markers like tyrosine hydroxylase (TH) expression in the SN, but not striatum. Here, we interrogated respective contributions of nigral and striatal DA mechanisms to aging-related parkinsonian signs in aging (18 months old) rats in two studies: by the imposition of CR for 6 months, and inhibition of DA uptake within the SN or striatum by cannula-directed infusion of nomifensine. Parkinsonian signs were mitigated within 12 weeks after CR and maintained until 24 months old, commensurate with increased D1 receptor expression in the SN alone, and increased GDNF family receptor, GFR-α1, in the striatum, suggesting increased GDNF signaling. Nomifensine infusion into the SN or striatum selectively increased extracellular DA. However, only nigral infusion increased locomotor activity. These results indicate mechanisms that increase components of DA signaling in the SN alone mitigate parkinsonian signs in aging, and are modifiable by interventions, like CR, to offset parkinsonian signs, even at advanced age. Moreover, these results give evidence that changes in nigral DA signaling may modulate some parameters of locomotor activity autonomously from striatal DA signaling.

Cardiovascular Metrics Associated With Prevention of Aging-Related Parkinsonian Signs Following Exercise Intervention in Sedentary Older Rats.

Preservation of motor capabilities is vital to maintaining independent daily living throughout a person's lifespan and may mitigate aging-related parkinsonism, a progressive and prevalent motor impairment. Physically active lifestyles can mitigate aging-related motor impairment. However, the metrics of physical activity necessary for mitigating parkinsonian signs are not established. Consistent moderate intensity (~10 m/min) treadmill exercise can reverse aging-related parkinsonian signs by 20 weeks in a 2-week on, 2-week off, regimen in previously sedentary advanced middle-aged rats. In this study, we initiated treadmill exercise in sedentary 18-month-old male rats to address two questions: (1) if a rest period not longer than 1-week off exercise, with 15 exercise sessions per month, could attenuate parkinsonian signs within 2 months after exercise initiation, and the associated impact on heart rate (HR) and mean arterial pressure (MAP) and (2) if continuation of this regimen, up to 20 weeks, will be associated with continual prevention of parkinsonian signs. The intensity and frequency of treadmill exercise attenuated aging-related parkinsonian signs by 8 weeks and were maintained till 23 months old. The exercise regimen increased HR by 25% above baseline and gradually reduced pre-intervention MAP. Together, these studies indicate that a practicable frequency and intensity of exercise reduces parkinsonian sign severity commensurate with a modest increase in HR after exercise. These cardiovascular changes provide a baseline of metrics, easily measured in humans, for predictive validity that practicable exercise intensity and schedule can be initiated in previously sedentary older adults to delay the onset of aging-related parkinsonian signs.

Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency.

Reduced movement frequency or physical activity (bradykinesia) occurs with high prevalence in the elderly. However, loss of striatal tyrosine hydroxylase (TH) in aging humans, non-human primates, or rodents does not reach the ~ 80% loss threshold associated with bradykinesia onset in Parkinson's disease. Moderate striatal dopamine (DA) loss, either following TH inhibition or decreased TH expression, may not affect movement frequency. In contrast, moderate DA or TH loss in the substantia nigra (SN), as occurs in aging, is of similar magnitude (~ 40%) to nigral TH loss at bradykinesia onset in Parkinson's disease. In aged rats, increased TH expression and DA in SN alone increases movement frequency, suggesting aging-related TH and DA loss in the SN contributes to aging-related bradykinesia or decreased physical activity. To test this hypothesis, the SN was targeted with bilateral guide cannula in young (6 months old) rats, in a within-subjects design, to evaluate the impact of nigral TH inhibition on movement frequency and speed. The TH inhibitor, α-methyl-p-tyrosine (AMPT) reduced nigral DA (~ 40%) 45-150 min following infusion, without affecting DA in striatum, nucleus accumbens, or adjacent ventral tegmental area. Locomotor activity in the open-field was recorded up to 3 h following nigral saline or AMPT infusion in each test subject. During the period of nigra-specific DA reduction, movement frequency, but not movement speed, was significantly decreased. These results indicate that DA or TH loss in the SN, as observed in aging, contributes as a central mechanism of reduced movement frequency.

Dissociation of Striatal Dopamine and Tyrosine Hydroxylase Expression from Aging-Related Motor Decline: Evidence from Calorie Restriction Intervention.

The escalating increase in retirees living beyond their eighth decade brings increased prevalence of aging-related impairments, including locomotor impairment (Parkinsonism) that may affect ~50% of those reaching age 80, but has no confirmed neurobiological mechanism. Lifestyle strategies that attenuate motor decline, and its allied mechanisms, must be identified. Aging studies report little to moderate loss of striatal dopamine (DA) or tyrosine hydroxylase (TH) in nigrostriatal terminals, in contrast to ~70%-80% loss associated with bradykinesia onset in Parkinson's disease. These studies evaluated the effect of ~6 months 30% calorie restriction (CR) on nigrostriatal DA regulation and aging-related locomotor decline initiated at 12 months of age in Brown-Norway Fischer F1 hybrid rats. The aging-related decline in locomotor activity was prevented by CR. However, striatal DA or TH expression was decreased in the CR group, but increased in substantia nigra versus the ad libitum group or 12-month-old cohort. In a 4- to 6-month-old cohort, pharmacological TH inhibition reduced striatal DA ~30%, comparable with decreases reported in aged rats and the CR group, without affecting locomotor activity. The dissociation of moderate striatal DA reduction from locomotor activity seen in both studies suggests that aging-related decreases in striatal DA are dissociated from locomotor decline.