Variations in a gene that regulates dopamine levels in the brain may influence the mobility of elderly and frail adults, according to new research from the University of Pittsburgh Graduate School of Public Health.
These results, published today in the Journal of The American Geriatrics Society, add to a growing body of evidence hinting that lower dopamine levels could contribute to the slower, often disabling walking patterns seen in some elderly populations.
“Most people think about dopamine’s role in mobility in the context of Parkinson’s disease, but not in normal aging,” said senior author Caterina Rosano, M.D., M.P.H., professor of epidemiology at Pitt Public Health.
“We were curious to see if a genetic predisposition to produce more or less dopamine was related to mobility in individuals who had some level of frailty, yet did not have dementia, parkinsonism or any other neurological condition.”
While several genetic elements control dopamine signaling, Rosano and her team focused on a gene called COMT, which breaks down dopamine to control its levels within the brain.
They also considered the frailty status of participants, which is a common consequence of aging marked by a decline in physiological function, poor adjustment to stressors and a susceptibility toward adverse health outcomes.
The researchers suspected that frail participants could be particularly vulnerable to COMT-driven differences in dopamine levels.
Rosano and her collaborators examined this gene in more than 500 adults above the age of 65 in Pennsylvania, North Carolina, California and Maryland, excluding any participants taking dopamine-related medications or diagnosed with Parkinson’s disease. The researchers then looked for potential links between genotype, frailty and speed.
“We found that in older, frail adults, those who have a high-dopamine genotype are more likely to maintain a faster gait and may be more resilient to mobility disablement as they age,” said Rosano.
The team discovered that frail participants with a high-dopamine COMT genotype had a 10% faster walking speed compared with participants with the low-dopamine COMT genotype.
“This 10% difference may seem small, but it could make a big difference for a person walking across a busy street while negotiating traffic,” said Rosano.
“This difference is even more striking when you consider just how many complex genes influence walking.”
Rosano and study co-author Nicolaas Bohnen, M.D., Ph.D., professor of neurology and radiology at the University of Michigan School of Medicine, are working with a team of scientists at Pitt to quantify what level of dopamine could give elders greater resilience to gait-slowing and mobility disablement.
Their hope is that older adults with low dopamine levels could one day receive pharmacologic supplements of dopamine to help preserve their mobility.
“There are a lot of individuals living in the community who have dopamine levels toward the lower end of normal who don’t have Parkinson’s disease or psychiatric conditions,” said Rosano.
“If we give dopamine to these people, could we make them more resilient? That’s what we don’t know yet.”
In the meantime, she suggests that there are actions that seniors can take today to keep moving. She recommends that elders focus on physical activities that are enjoyable and involve both the body and the brain, especially multi-sensory activities, such as dancing or walking with a loved one.
“I love to see grandparents walking around holding hands with their grandchildren because they have to look where they are going, where the child is going, keep an eye on the surroundings and pay attention to what the grandchild is saying, all at the same time,” said Rosano. “They get an amazing multi-sensory rehab, and it’s fantastic.”
There is clear scientific evidence of the beneficial effects of physical activity and the negative consequences of sedentary behaviour on numerous health outcomes, as well as premature death [1, 2].
Regular physical activity can help maintain independence and increase the quality of life and well-being in later life [2, 3]. Older adults are therefore recommended to spend at least 150 min per week in physical activities at moderate-to-vigorous intensity [3, 4].
However, epidemiological data show that many older adults do not reach the recommended amount of physical activity and spend on average 70% of their waking hours being sedentary [5–7].
Understanding why people are physically active or not can contribute to planning of targeted evidence-based interventions to increase physical activity and reduce sedentary time. There are several known factors of importance for physical activity [8–10] and sedentary behaviour [11, 12] in older adults, such as social interaction, feeling of meaningfulness and joy, belief in health benefits, and exercise self-efficacy.
All these factors are related to motivational and reward processes, which are associated with the dopaminergic system . For example, animal data show that blocking dopamine receptors results in less engagement in voluntary exercise [14, 15].
In humans, dopamine receptor density as well as a dopamine-related genetic variation have been related to self-reported physical activity [16, 17] and measured changes in physical activity levels during intervention , suggesting that dopamine receptor expression might result in differences in physical activity engagement.
Dopamine has also a well-established role in motor functioning [19, 20], which may influence an individual’s ability to engage in physical activity. The relationship between dopamine and cognitive performance is characterized by a well-established inverted u-shaped function , which likely generalizes to other domains, such as physical activity [14–16].
Aging is associated with losses in dopamine receptors and transmitter content , which may exacerbate the influence of dopamine-related genetic variations on physical functioning even further in a non-linear way, increasing between-person differences in performance. Our hypothesis was that higher age may exacerbate the impact of dopamine-related genetic variations on physical activity (Fig. 1).
Moreover, the current evidence on the dopamine-physical activity link is mainly based on self-reported data [16, 17, 22], which are prone to reporting bias and have limited ability to identify light-intensity physical activity, such as household chores or slow walking, and sedentary time [23, 24].
With recent technological advancements, small lightweight movement sensors (accelerometers) have become available, allowing objective assessments of physical activity [25, 26]. These devices provide a more accurate investigation of physical activity across the whole intensity spectrum.
Our aim was to use the candidate gene approach to investigate individual differences in dopaminergic modulation, focusing on three dopamine receptor-related polymorphisms (DRD1, DRD2, and DRD3), and their association to objective measures of physical activity and sedentary time in a population-based sample of older adults.
We focus on D1 and D2-like receptor genes (i.e., D2 and D3), given that both have been involved in reward and motivational processes  as well as physical activity [16, 28, 29]. Moreover, by considering the effects of D2 and D3 receptors, which also function as autoreceptors [30, 31], regulating release of the neurotransmitter, we take into account the balance between pre-and postsynaptic components, which is crucial for optimal dopamine signaling .
Further, we aimed to verify whether advanced age may exacerbate the impact of dopamine-related genetic variations on physical activity.
Sample characteristics by age are presented in Table 1. In Table 2, the main results from the analyses involving DRD1 are presented for Model 1 (adjusting for age, sex and physical function) and Model 2 (additionally adjusting for main and interactive effects of SNPs). Analyses revealed only an association between DRD1 and moderate-to-vigorous physical activity in the total sample trending toward statistically significant, F(2,492) = 3.004, p = 0.051, partial-eta squared = 0.012 (Model 1), but not for DRD2, F(2,492) = 0.023, p = 0.977, partial-eta squared = 0.000, and DRD3, F(2,492) = 2.093, p = 0.124, partial-eta squared = 0.008. Moreover, there were no interactions between cohort and DRD1, F(2,492) = 1.716, p = 0.181, partial-eta squared = 0.007, DRD2, F(2,492) = 0.591, p = 0.544, partial-eta squared = 0.002, or DRD3, F(2,492) = 0.099, p = 0.906, partial-eta squared = 0.000. Non-significant associations between SNPs and sedentary behavioral and light-intensity physical activity are presented in Table S1 in the supplementary. The association between DRD1 and moderate-to-vigorous physical activity became even more evident in the second model, when taking into account the other two polymorphisms and their interaction effects in the analyses, F(2,474) = 6.531, p = 0.002, partial-eta squared = 0.027. More specifically, C-homozygotes were significantly more active than T-homozygotes, t(1, 261) = 3.28, p = 0.001, and heterozygotes, t(1,309) = 3.29, p = 0.001. The latter two groups did not differ from each other (Model 2 for total sample). Moreover, none of the gene-gene interactions were significant.
Sample characteristics stratified by age group
|66 years (n = 357)||81–87 years (n = 147)|
|Female, n (%)||212 (59.4)||101 (68.7)|
|Married/living together, n (%)||233 (65.3)||73 (49.6)|
|Body mass index, M (SD)||26.0 (3.8)||25.8 (3.9)|
|Use walking aid, n (%)||5 (1.4)||33 (22.4)|
|5 times sit to stand, not able, n (%)||6 (1.7)||27 (18.4)|
|One-leg stance, < 5 s, n (%)||25 (7.0)||75 (51.0)|
|Sitting, min/day, M (SD)||506.13 (96.8)||521.1 (82.8)|
|Light-intensity PA, min/day, M (SD)||319.3 (93.6)||291.1 (80.1)|
|Moderate-to-vigorous PA, min/day, (SD)||39.6 (24.5)||20.6 (20.5)|
|Accelerometer wear time, min/day, M (SD)||866.6 (61.3)||832.7 (63.2)|
|DRD1 (T/T; C/T; C/C), n||137/171/49||55/71/21|
|DRD2 (A2/A2; A2/A1; A1/A1), n||229/113/15||100/40/7|
|DRD3 (T/T; T/C; C/C), n||151/171/35||57/77/13|
Estimated marginal means (standard error) and p-values for pairwise comparisons of moderate-to-vigorous physical activity in min/day, as a function of DRD1 genotype, in the total sample and stratified by age
|Total sample||66 years||81–87 years|
|DRD1 genotype||Model 1||Model 2||Model 1||Model 2||Model 1||Model 2|
|TT (lower efficacy)||32.7 (26.6, 38.7)||30.5 (23.3, 37.7)||38.8 (34.7, 42.9)||36.6 (28.4, 44.9)||14.8 (10.1, 19.6)||15.2 (8.2, 22.1)|
|CT (intermediate efficacy)||37.7 (31.6, 43.8)||32.7 (27.9, 37.5)||39.8 (36.1, 43.5)||32.1 (24.1, 40.2)||23.1 (18.9, 27.3)||24.5 (17.7, 31.3)|
|CC (higher efficacy)||39.8 (32.4, 47.2)||49.9 (40.8, 59.0)||40.8 (33.9, 47.8)||52.1 (40.3, 63.8)||27.2 (19.5, 34.9)||35.8 (26.8, 44.8)|
|TT vs. CC (p-value)||0.043||0.001||0.626||0.036||0.007||0.000|
|TT vs. CT (p-value)||0.041||0.618||0.727||0.442||0.012||0.064|
|CT vs. CC (p-value)||0.538||0.001||0.798||0.007||0.354||0.049|
Model 1 was adjusted for age, sex and physical function (5 STS and OLS) and included cohort as a factor in the total sample. Main effects of the two other SNPs are not included in Model 1. In Model 2, additional adjustments were made for main (i.e., DRD1, DRD2, DRD3) and interactive effects between the other SNPs (i.e., DRD1 x DRD2, DRD1 x DRD3, DRD2 x DRD3, and DRD1 x DRD2 x DRD3)
Stratifying the sample in relatively younger (age = 66) and older adults (age = 81–87) revealed more pronounced effect sizes in the older age cohort (Model 2).
Notably, the association in relatively younger adults was not significant in the first model, F(1,349) = 0.135, p = 0.874, partial-eta squared = 0.001. However, in relatively older adults the association was marginally significant, F(1,140) = 5.019, p = 0.008, partial-eta squared = 0.067.
When taking into account the other dopamine SNPs and interaction effects in the analyses, the association between DRD1 and moderate-to-vigorous physical activity became marginally significant also in the relatively younger adults, with DRD1 explaining 2.7% of variance in moderate-to-vigorous physical activity, F(1,329) = 4.553, p = 0.011, partial-eta squared = 0.027.
The effect of DRD1 on moderate-to-vigorous physical activity was even more pronounced in relatively older adults, F(1,122) = 6.886, p = 0.001, partial-eta squared = 0.101, accounting for about 10% of variance.
We investigated the associations between predispositions in dopamine-related genetic variations and physical activity and sedentary time in older adults. Our findings suggest that higher dopamine receptor efficacy (DRD1 C-homozygotes) is related to more moderate-to-vigorous physical activity.
We did not observe this to be the case for light-intensity physical activity or sedentary time.
Importantly, the effects remained when adjusted for individual differences in physical functions. Further, we found that the impact of dopaminergic SNPs on moderate-to-vigorous physical activity was more pronounced among people aged 80 years and older.
Thus, our findings suggest that individual differences in dopaminergic modulation may influence motivation and reward-processes relevant for engaging in more intense physical activity especially among the oldest-old.
The fact that a D1-receptor polymorphism was associated with higher levels of moderate-to-vigorous physical activity is in line with the classical view of a crucial role of D1 receptors in positive reinforcement and reward . It should be noted that D2-receptor mediated mechanisms also contribute to motivational behaviour , for instance, though their role as autoreceptors regulating transmitter levels.
However, these effects may be more difficult to reveal, given the low expression of auto- relative to post-synaptic receptors [30, 31]. A recent study showed that higher dopamine signalling supports changes in physical activity during an intervention, but not at baseline .
This study investigated another genetic variation in the DRD2 gene, associated with differences in endogenous dopamine, but not receptor density. A physical exercise intervention study in older adults, measuring D2 receptor density in the reward system, documented decreased D2 receptor availability, which is likely due to increased endogenous dopamine .
Accordingly, increased dopamine release may be a consequence of a physical activity intervention and support motivational or reward processes though D2-related mechanisms. The stronger genetic effect in older age is in line with the inverted U-shaped function (Fig. 1), which describes the relationship between dopaminergic modulation and performance, such as cognitive  and physical function . To the best of our knowledge, this pattern has not previously been reported for physical activity.
Small effects sizes are very common in behaviour-genetic studies, typically explaining around 1% of variance. In this study, the observed effects size estimates were particularly high in individuals over 80 years. The differences in daily moderate-to-vigorous physical activity between individuals with more advantageous genotype and those with a disadvantageous genotype were around 20 min per day, which clearly could contribute to better health and well-being [2, 3].
The finding that individuals with higher dopamine D1 receptor efficacy actively engage in more intense physical activities supports the results from a previous study, showing that self-reported intensity of physical activity was associated with higher receptor density in the dopamine system .
Moreover, our findings are in line with the results from den Hoed and colleagues , who used objective assessment of physical activity in a twin study to investigate the role of genetic factors in physical activity regulation. They found that heritability explained 47% of the variance in time spent in moderate-to-vigorous physical activity.
In contrast to our results, they also found a genetic component for time spent in sedentary behaviour. Still, the lack of associations with sedentary time and genetic differences in dopamine in this study is not surprising, given that the dopamine system seems to play a bigger role in more intense physical activity.
Sedentary time and light-intensity physical activity are highly correlated, and older adults who spend less time sitting do not necessary spend more time in moderate-to-vigorous physical activity, but rather in activities with light-intensity [57, 58]. Hence, the associations with sedentary behaviour found by den Hoed and colleagues  may be related to other genes than those involved in the dopamine system.
In addition, as noted above, exercise intervention studies have documented both increased dopamine transmitter as well as receptor availability after intervention [28, 29]. Consequently, individuals with a stronger dopaminergic tone may be more likely to engage in physical activity.
Environmental exposure, such as being more physically active may, in turn, enhance expression of a particular gene via epigenetic mechanisms, thereby resulting in stronger genetic effects, which are further exacerbated with aging. Such feedback-loops are likely related to intensity, which may also be the reason why we did not see any association between dopamine SNPs and light-intensity physical activity.
An important strength of our study is that we used objective assessment of physical activity and thereby reduced the likelihood of misclassification compared to self-reports. Our study focuses on well-described candidate genes in the literature, which have been related to inter-individual differences in brain and performance measures and which, according to theory, are related to the dopaminergic reward and motivational system.
However, Rosso et al. who investigated the link between a genetic variation in the DRD1 gene and physical activity did not find any association . The missing link is very likely due to fact that the investigated DRD1 polymorphisms may not result in strong functionally relevant interindividual differences with respect to receptor efficacy, as it has not been related to other functional outcomes in previous studies. Moreover, although our sample size may be small for genetic studies aiming at discovering new gene-phenotype links, it is reasonably powered for theory-driven candidate genes studies as in the present case [18, 54].
That said, our sample is not suitable to reveal gene-gene interactions. It should also be acknowledged that other dopamine SNPs likely contribute to physical activity, but their effects may not be picked up in such small samples and may, therefore, not be useful as biomarkers for individual differences in physical activity.
From our data, it is evident that the investigated genetic variations in DRD2 and DRD3 influenced the effects of DRD1 on physical activity, although they were not directly associated with physical activity. Optimally, a polygenic score, considering many SNPs, should be created to reflect individual differences in dopamine signaling.
Another strength of this study is the population-based sample, but as in any study, participants may be healthier and more physically active than the general population. Due to the physical activity assessment method, we did not include participants with severe cognitive impairment or those who could not move indoors without assistance.
The fact that our study sample was positively selected and healthier than older adults in general, may have attenuated the genetic effect on physical activity. Independent replication studies in other populations are needed to confirm the observed association.
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Journal information:Journal of the American Geriatrics Society