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Published in final edited form as: J Appl Gerontol. 2024 Jun 5;43(12):1939–1949. doi: 10.1177/07334648241257995

Exercise: Just What the Doctor Ordered, But Why? Elucidating Mechanisms for Women’s Increased High-Density Lipoprotein Benefit From Exercise and for the Health ABC Study

Rachel A Bernier 1,2, Erin E Sundermann 1, Steven D Edland 1, Kacie D Deters 3, Alyx L Shepherd 1, Alexandra L Clark 4,5, Eric J Shiroma 6, Sarah J Banks 1
PMCID: PMC12984035  NIHMSID: NIHMS2142412  PMID: 38835249

Abstract

High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: β = 0.09, p = .013; exercise on HDL in women: β = 0.07, p = .015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer’s disease risk, findings have implications for sex differences in AD risk factors.

Keywords: exercise, women, cognition, high-density lipoprotein, tumor necrosis factor, aging, inflammation

Introduction

High-density lipoprotein (HDL) is protective against cardiovascular disease (Di Angelantonio et al., 2009). There is a growing body of evidence implicating cardiovascular disease in the pathogenesis and clinical expression of Alzheimer ‘s disease (AD) (Brickman et al., 2015). Therefore, increased HDL levels may represent an intervention point for AD by reducing cardiovascular disease risk. Aerobic exercise is a modifiable risk factor for AD and has been linked to HDL whereby higher levels of aerobic activity relate to increased HDL concentration (Hsu et al., 2019). Women may receive a greater boost in HDL levels from exercise compared to men (Warner et al., 1995). Given that women have an increased prevalence of AD (Alzheimer’s Association, 2017) and show a steeper cognitive decline in later stages of AD (Lin et al., 2015), it is prudent to examine sex-specific influences on outcomes that may elucidate preventive measures and interventions that are tailored to women. Much remains unknown regarding the intersection between sex and race on cardiovascular risk factors. Fundamental group differences in social determinants of health (SDOH) due to structural inequities may influence the way exercise relates to HDL among Black and White individuals. There is evidence that HDL levels and their relationship to cardiovascular risk may differ between Black and White individuals. Black men have higher HDL compared to White men, but Black and White women show no differences in mean HDL (Hutchinson et al., 1997). Higher HDL levels have been associated with lower stroke risk in Black individuals but not White, Hispanic, or Native American individuals (Reina et al., 2015). Higher HDL relates to lower risk of coronary heart disease in non-Black participants but not Black participants (Chandra et al., 2015). In contrast, evidence suggests that the relationship between exercise and HDL is independent of race (e.g., Leon et al., 2000). We aim to establish whether exercise relates to HDL in a sex-dependent manner, and to separately examine whether this relationship exists within Black individuals and White individuals.

Given known sex differences in immune response (Hanamsagar & Bilbo, 2016), anti-inflammatory effects of exercise may represent a potential mechanism to improve women’s HDL levels. Reduced inflammatory markers relate to higher levels of HDL (Feingold & Grunfeld, 2016) and exercise (Woods et al., 2011). Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine and soluble tumor necrosis factor receptor-2 (sTNFR2) is a transmembrane TNFα receptor expressed in immune cells and activated brain endothelial cells that is cleaved from endothelial cell membranes under inflammatory conditions (Akassoglou et al., 2003). Circulating sTNFR2 is elevated in biological fluids of participants with inflammatory disease and is considered a biomarker for inflammation (Mizoguchi et al., 2021). With regard to HDL, higher levels of HDL are correlated with decreased levels of serum TNFα (Memon et al., 1997; Yamagishi et al., 2009) and sTNFR2 (Figarska et al., 2018). Both annual time spent completing physical activity and higher levels of exercise have been linked to lower levels of serum TNFα in older adults (Colbert et al., 2004). Furthermore, an exercise training program in women aged 41–69 years resulted in decreased serum TNFα and sTNFR2 (Tsukui et al., 2000), and aerobic training was associated with decreased serum sTNFR2 in older women with osteoarthritis (Gomes et al., 2012).

Establishing mechanisms of sex differences in health outcomes holds the potential to elucidate pathways for targeted treatments. Inflammation is one such potential mechanism. Women tend to mount a stronger immune response to insult and injury (Cannon & St Pierre, 1997) and account for 80% of autoimmune disease diagnoses (Kivity & Ehrenfeld, 2010). This pro-inflammatory immune response is critical for clearing pathogens and mitigating tissue damage after insult and injury (Lyman et al., 2014). However, prolonged inflammation can lead to increased tissue damage (Libby, 2012) and is associated with several diseases, including AD (King et al., 2018). Women may be more responsive to mechanisms that inhibit or relate to reduced immune responses. CSF-TNFα has been linked with tau, the AD biomarker most strongly correlated to clinical functioning, with CSF-TNFα negatively correlated with p-tau and t-tau in cognitively unimpaired older adults (Clark et al., 2021). There is also evidence of a sex-specific association between CSF-TNFα and cognition, where TNFα was negatively correlated with cognition, mediated by p-tau (Bernier et al., 2022). Therefore, we selected TNFα and sTNFR2, both related to the TNF system, as potential mediating pathways.

There is no strong evidence of differences between Black and White Americans in levels of serum sTNFR2 (Leng et al., 2015) or TNFα (Deswal et al., 2001), but research to date has largely been comprised racially homogenous and non-representative samples. One study of 10 Black women and 11 White women found that Black women showed higher increases in serum TNFα after eating compared to White women (Pearson et al., 2021). While preliminary, this suggests differences in Black versus White women in the inflammatory response to a lifestyle factor.

We sought to test whether there is a stronger exercise-HDL link in older adult women versus men and examine peripheral inflammatory marker levels (serum levels of TNFα and sTNFR2) as potential mediators in older adults from the Health, Aging and Body Composition study. We hypothesized a sex-by-exercise interaction on HDL, whereby women would show a stronger positive relationship between exercise and HDL level compared to men. We also hypothesized that structural equation modeling (SEM) would reveal that serum levels of TNFα and sTNFR2 would mediate the relationship between exercise and HDL level in women. Given known racial health disparities due to systemic racism, we replicated analyses within Black and White participants separately to examine whether the pattern of results remained.

Material and Methods

Participants and Data Source

Baseline data were extracted from the Health, Aging and Body Composition (Health ABC) study, a prospective study that included community-dwelling older adults living in Memphis, TN, or Pittsburgh, PA, between 1997 and 1998. General enrollment inclusion and exclusion criteria are described in detail elsewhere (Simonsick et al., 2001). Health ABC data and further information are available at healthabc.nia.nih.gov. This specific study was limited to participants with baseline data for (1) fasting plasma HDL and (2) exercise level. This study included 2,957 community-dwelling participants who underwent a blood draw for biomarker analysis of HDL. All participants were aged 68–80 years. TNFα data were missing for 164 participants and sTNFR2 data were missing for 1,563 participants; therefore, these participants were excluded from respective analyses examining their mediating roles. See Table 1 for sample characteristics.

Table 1.

Sample Characteristics by Sex and Race.

Total sample range (n = 2,957) Women (n = 1,520) Men (n = 1,437) p value Black Women (n = 689) Black Men (n = 521) p value White Women (n = 831) White Men (n = 916) p value Black (n = 1,210) White (n = 1,747) p value
Age (years), M (SD) 73.5 (2.9) 73.8 (2.9) .018 73.4 (3.0) 74.5 (2.8) .525 73.6 (2.8) 73.9 (2.9) .027 73.4 (2.9) 73.8 (2.9) .003
Education levela (n)   68, 80 1 = 354  1 = 394  <.001 1 = 268  1 = 263  <.001 1 = 86  1 = 131  <.001 1 = 531  1 = 217  <.001
2 = 601  2 = 369  2 = 240  2 = 127  2 = 361  2 = 242  2 = 367  2 = 603 
3 = 565  3 = 674  3 = 181  3 = 131  3 = 384  3 = 543  3 = 312  3 = 927 
Memphis Site (n) 770 (50.7) 731 (50.9) .938 322 (46.7) 263 (50.5) .218 448 (53.9) 468 (51.1) .258 585 (48.3) 916 (52.4) .032
BMI (kg/m2), M (SD)  14.60, 51.99 27.7 (5.5) 27.1 (4.0) <.001 29.7 (5.9) 27.3 (4.4) <.001 26.0 (4.5) 27.0 (3.7) <.001 28.7 (5.4) 26.5 (4.1) <.001
Exercise level, M (SD)b 0, 28,375.76  705.8 (1299.3) 1415.9 (2310.8) <.001 985.6 (2005.2) 523.3 (924.3) <.001 857.1 (1526.8) 1660.6 (2434.6) <.001 722.4 (1506.0) 1278.4 (2091.7) <.001
HDL (mg/dL), M (SD) 13, 163   60.1 (17.4) 47.9 (13.8) <.001 61.4 (18.2) 51.6 (14.8) <.001 59.1 (16.6) 45.1 (12.6) <.001 57.2 (17.5) 51.7 (16.2) <.001
sTNFR2 (pg/mL), M (SD)c 1,795.3, 47,193.00 3,475.6 (826.4) 3,697.3 (2,281.7) .018 3,421.7 (876.5) 3,477.1 (882.3) .454 3,519.2 (781.9) 3,830.5 (2,800.9) .029 3,446.1 (878.7) 3679.0 (2,084.4) .004
TNFα (pg/mL), M (SD) 0.566, 29.55 3.4 (1.6) 3.6 (1.9) .003 3.3 (1.7) 3.3 (1.9) .509 3.5 (1.5) 3.7 (1.8) .004 3.3 (1.8) 3.6 (1.7) <.001
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Note. Table displays raw means, standard deviations and percentages. Sample characteristics by sex alone, race and sex, and race alone were assessed using independent t-tests for continuous variables and chi-square tests for categorical variables. Abbreviations: BMI = body mass index. HDL = high-density lipoprotein. TNFα = tumor necrosis factor α. sTNFR2 = soluble tumor necrosis factor receptor 2.

a

Education levels: 1 = less than high school; 2 = high school graduate; 3 = postsecondary.

b

Exercise levels = kilocalories/week.

c

sTNFR2 sample included 322 Black women, 398 White women, 254 Black men, and 420 White men.

Measures

Sex.

Sex was defined as either “male” or “female” based on self-reported choice between these options.

Exercise.

Exercise level was defined as the number of kilocalories per week multiplied by the person’s weight in kilograms using data from a self-reported standardized physical activity questionnaire (https://healthabc.nia.nih.gov/sites/default/files/Y1_Documentation.pdf). The raw exercise data were positively skewed (5.62) and had a high level of kurtosis (52.16) (Komsta & Novomestky, 2022). We performed a log-transformation of exercise level to normalize the distribution and examined exercise level continuously. To include individuals whose level of exercise was equal to 0 kilocalories per week, a value of 1 was added to all values prior to performing the log-transformation. Following transformation, kurtosis was 2.8 and skewness was −0.96. No outliers were identified using the interquartile range method of detection (Rousseeuw & Leroy, 2005).

High-density lipoprotein.

Our main outcome of interest was fasting plasma HDL (mg/dL) based on a Vitros 950 analyzer after an overnight fast.

Inflammatory Markers.

We examined serum levels of sTNFR2 and TNFα. Data collection details can be found elsewhere (Colbert et al., 2004). Levels were quantified by enzyme-linked immunosorbent assay.

Race.

Analyses were repeated within Black and White individuals. Race was defined as either “Black” or “White” based on self-reported choice between these options. Ethnicity data were not available.

Covariates.

Covariates included site, age, education level, race, and body mass index (BMI). Site was the participant’s study location, either Pittsburgh or Memphis.

Statistical Analyses

Sex differences in sample characteristics were assessed using independent t-tests for continuous variables and chi-square tests for categorical variables.

Cross-sectional linear regression analyses examined the relationship between log-transformed exercise level and HDL. We examined sex differences in this relationship by testing a sex-by-exercise level interaction in the overall sample and by conducting sex-stratified analyses. Men served as the reference group. If non-significant (p > .05), the sex-by-exercise interaction term was removed from the model to assess main effects of sex and exercise on HDL level.

If the association between exercise level and HDL level was significant (either across sex or sex-specific), we examined TNFα and sTNFR2 as potential mediators using a multiple mediation SEM approach with bootstrapping techniques using the lavaan package (Rosseel, 2012) in R. A 95% bias-corrected confidence interval of the indirect effect (a × b) was generated. The a-path represented the path from exercise level to the mediator, and the b-path represented the impact of the mediator on HDL level. The product of a × b represents the indirect effect. This mediational analysis cannot confirm causality because of the cross-sectional nature of the data (Chmura Kraemer et al., 2008).

All analyses were performed with R version 3.5.0 (https://cran.r-project.org/). Significance was defined as α = .05 (two-sided).

Results

See Table 1 for sample characteristics. In the largest sample of 2,957 participants, women were significantly younger, less educated, less likely to be White, had higher BMI, lower exercise levels, higher HDL levels, and lower levels of sTNFR2 and TNFα relative to men.

Sex by Exercise Level Interactions on HDL Level

We assessed how exercise level relates to HDL level and whether this relationship is moderated by sex. Covariates included site, age, education, race, and BMI. When characterizing effect size, β of 0.10–0.29 was considered small, 0.30–0.49 was considered medium, and 0.50 or greater was considered large to the nearest tenth (Cohen, 2013; Fey et al., 2023). In line with hypotheses, there was a significant sex-by-exercise level interaction on HDL level (Table 2), whereby there was a small effect of higher exercise level relating to higher HDL level in women but not men (Table 3, Figure 1). There was also a significant main effect of sex within the whole sample, (Table 2), whereby being a woman was associated with higher HDL level, although the effect size was small. There was no significant main effect of exercise level on HDL level.

Table 2.

Results of Multivariable Linear Regression Modeling Sex x Exercise Level on HDL.

HDL (mg/dL) Main effects of sex and exercise level
 Sex-by-log-transformed exercise level interaction
Sex (male vs. female)a
 Exercise level
B, β SE 95% CI p value B, β SE 95% CI p value B, β SE 95% CI p value
Whole sample 10.18, 0.10 1.30 7.61, 12.75 <.001 −0.14, −0.02 0.17 −0.47, 0.20 .421 0.53, 0.90 0.22 0.10, 0.97 .015
Black individuals 12.08, 0.34 0.99 10.13, 14.03 <.001 0.07, 0.10 0.19 −0.31, 0.33 .724 0.68, 0.11 0.36 −0.02, 1.38 .058
White individuals 13.82, 0.43 0.71 12.43, 15.21 <.001 0.26, 0.04 0.15 −0.04, 0.55 .016 0.41, 0.08 0.29 −0.15. 0.98 .228
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Abbreviations: HDL = high-density lipoprotein. B = unstandardized beta. β = standardized beta. SE = standard error. CI = confidence interval. Log-transformed exercise levels: estimated kilocalories/week.

a

Men served as the reference group.

Table 3.

Results of Sex- and Race-Stratified Multivariable Linear Regression Modeling Exercise Level on HDL.

Log-transformed exercise level
Women
 Men
B, β SE 95% CI p value B, β SE 95% CI p value
Total 0.44, 0.07 0.18 0.09, 0.79 .015 −0.13, −0.02 0.15 −0.42, 0.17 .400
Black individuals 0.42, 0.06 0.28 −0.13, 0.97 .131 −0.20, −0.04 0.25 −0.69, 0.29 .418
White individuals 0.50, 0.07 0.24 0.03, 0.96 .035 0.02, 0.004 0.18 −0.34, 0.39 .901
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Abbreviations: HDL = high-density lipoprotein. B = unstandardized beta. β = standardized beta. CI = confidence interval. Log-transformed exercise levels: estimated kilocalories/week.

Figure 1.

Figure 1.

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Sex-Specific Relationship Between Exercise HDL Level in Older Adults. Note. A positive association between exercise level and HDL level, whereby higher levels of exercise related to higher levels of HDL in women but not men. Abbreviations: HDL = high-density lipoprotein. Exercise levels: log-transformed estimated kilocalories/week. The shaded areas around fitted lines indicate standard error.

Analyses were repeated within Black individuals and White individuals. We observed consistent directions of association to the pooled analysis, although not all associations maintained statistical significance. Among Black individuals, there was a marginally significant sex-by-exercise level interaction on HDL (Table 2). There was no main effect of exercise on HDL level in among Black individuals (Table 2). There was no significant or marginally significant exercise-HDL link within Black women or men (Table 3, Figure 2). Among White individuals, there was a small effect of exercise on HDL level, where higher exercise levels related to higher HDL (Table 2), but the sex-by-exercise level interaction on HDL level was not significant (Table 2). However, when stratified by sex, the positive association only survived among White women (although the effect size was small) and was not present in White men (Table 3, Figure 3). There was a medium effect size of sex where being a woman was associated with higher HDL level for both Black and White individuals (Table 2).

Figure 2.

Figure 2.

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Sex-Specific Relationship Between Exercise HDL Level in Black Older Adults. Note. A positive, though not statistically significant, association between exercise level and HDL level, whereby higher levels of exercise related to higher levels of HDL in Black women but not Black men. Abbreviations: HDL = high-density lipoprotein. Exercise levels: log-transformed estimated kilocalories/week. The shaded areas around fitted lines indicate standard error.

Figure 3.

Figure 3.

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Sex-Specific Relationship Between Exercise HDL Level in White Older Adults. Note. A positive association between exercise level and HDL level, whereby higher levels of exercise related to higher levels of HDL in White women but not White men. Abbreviations: HDL = high-density lipoprotein. Exercise levels: log-transformed estimated kilocalories/week. The shaded areas around fitted lines indicate standard error.

Mediating Role of Plasma Inflammatory Marker Level in the Link Between Exercise Level and HDL

We examined the mediating role of serum levels of TNFα and sTNFR2 in the significant, female-specific positive relationship between exercise level and HDL. Using a multiple mediation SEM approach to examine the mediating role of TNFα level and sTNFR2 level in the relationship between exercise level and HDL level among women, we found a significant indirect effect of exercise through TNFα on HDL level, suggesting a mediating effect of TNFα in the female-specific relationship between exercise level and HDL level (Figure 4). We found a non-significant indirect effect of exercise through sTNFR2 on HDL level, suggesting no mediating effect of sTNFR2 in the female-specific relationship between exercise level and HDL level.

Figure 4.

Figure 4.

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Inflammatory Marker Mediators of the Exercise Level Link with HDL Level Among Women. Note. Mediation of relationship between exercise level and HDL level through TNFα and sTNFR2. A significant mediation through TNFα in all women. Standardized coefficients are reported for each path.

Abbreviations: HDL = high-density lipoprotein. TNFα = tumor necrosis factor α. sTFR2 = soluble tumor necrosis factor receptor 2. A significant aXb estimate suggests mediation, denoted by zero falling outside the CI. * denotes significance p < .05. ** denotes significance p < .01. *** denotes significance p < .001.

Discussion

There was a sex-by-exercise level interaction on HDL, whereby exercise was associated with increased HDL level in women but not men. The female-specific positive association was significantly mediated by TNFα and not mediated by sTNFR2. The mediation of the exercise-HDL link suggests that it is possible that exercise may benefit HDL in women by affecting the TNFα pathway.

Given the potential for racial disparities in this relationship due to systemic racism, analyses were repeated within Black and White individuals separately. Within Black individuals, the sex-by-exercise interaction on HDL was marginally significant. Although the positive association between exercise and HDL levels within Black women was non-significant (p = .131), the beta coefficient for this relationship (β = 0.06) was similar to the beta coefficient among all women (β = 0.07). Therefore, the null result in Black women may be reflective of insufficient power rather than a difference in the strength of the relationship across racial groups. Among White individuals, there was a positive main effect of exercise on HDL. However, sex-stratified analyses revealed that this was driven by a significant exercise-HDL link within White women. Therefore, the overall pattern was consistent within Black women and within White women. The generalizability of study samples is important to consider. This sample of Black individuals had higher levels of HDL compared to White individuals, consistent with prior work reporting higher levels of HDL in Black men compared to White men (Hutchinson et al., 1997). Black individuals also showed lower levels of inflammatory markers compared to White individuals. Whether this sample is representative of Black individuals in these communities is unclear. Findings suggest that the protective factors of higher HDL levels and, relatedly, lower inflammation, may be more common among Black individuals; furthermore, the sex difference in the exercise-HDL link is generalizable by race.

Overall, findings underscore the importance of exercise as a mitigator of vascular risk and, in turn, AD risk, particularly in women. The female-specific benefit of exercise on HDL level extends previous work that found that women’s HDL levels were significantly higher each year for the duration of an up to 5-year cardiac rehabilitation exercise program, but this benefit was not observed in men. In contrast, however, they found that HDL levels among both adult men and women benefitted from exercise at one year. The authors posited that women’s protracted boost in HDL from exercise may have resulted from higher baseline body fat and lower estimated metabolic equivalents (MET), that is, the amount of energy consumed at rest, compared to men and, therefore, had more opportunity for gain from the intervention (Warner et al., 1995). Furthermore, they note that although women’s baseline HDL levels were higher than men’s, as in the present study, evidence suggests that the HDL threshold for women to be at risk for cardiovascular disease is higher in women compared to men (Bass et al., 1993). Thus, even though higher HDL levels are associated with reduced cardiovascular risk, a woman can have a higher level of HDL compared to a man, but still be at equal or higher risk. Overall, results from this study align with findings from the present study and may inform findings that physical activity has stronger protective effects on brain outcomes in women (Barha et al., 2017, 2020; Colcombe & Kramer, 2003). As we did not have measurements of body fat or MET, we are unable to examine whether men and women differed in measurements at baseline. Nevertheless, we posit that sex differences in immune functioning, such as women’s more reactive immune response, likely contributes to sex differences in the relationship between exercise and HDL level.

Our results lend credence to the relevance of inflammation in the effects of exercise on cardiovascular health in women and highlight the potential importance of peripheral markers of TNFα and sTNFR2 in studies of brain health. Neuro-inflammation relates to increases in the hallmark pathological processes of AD: tau aggregation (Laurent et al., 2018; Vogels et al., 2019) and amyloid burden (Blasko et al., 1999). Our results suggest that peripheral measures of inflammation, such as serum TNFα and sTNFR2, may relate to indices of heart health, such as HDL, which has downstream consequences on AD risk, especially given that both TNFα and sTNFR2 show associations with cognition (de Pablo-Bernal et al., 2016; Gomes et al., 2012; Windham et al., 2014; Yaffe et al., 2003) and decline in individuals on the AD continuum (Akiyama et al., 2000; Holmes et al., 2009; Kester et al., 2015; Shen et al., 2020).

Limitations

Our study has limitations. To address the difference in sample sizes for TNFα and sTNFR2, we conducted post-hoc sensitivity power analyses to determine the necessary effect size for detecting a true effect (Faul et al., 2007). While there is reduced power for the sTNFR2 mediation compared to the TNFα mediation analysis, the effect size of the TNFα mediation analysis would have been sufficient for detection even with a sample size of 1,394 (the sTNFR2 sample size), reducing concern that the absence of a significant sTNFR2 mediation reflects Type II error. A limitation of our dataset is our ability to characterize how other aspects of identity, such as whether someone is foreign-born, interacts with race and its relationship to HDL and exercise. With regard to cardiovascular health and inflammatory markers, there is evidence that factors such as whether a Black individual in the United States is foreign-born and level of acculturation can impact allostatic load (defined in this case as the composite of systolic blood pressure, diastolic blood pressure, 60-second pulse, c-reactive protein, HDL, total cholesterol, creatinine clearance, and serum albumin), whereby U.S. born non-Hispanic Black individuals bear a higher allostatic load compared to non-U.S. born non-Hispanic Black individuals (Doamekpor & Dinwiddie, 2015). However, this difference does not remain after accounting for sociodemographic variables. Furthermore, in our study, race was coded as either Black or White, and there was no information on ethnicity, limiting our ability to examine how this facet of identity relates to findings. This study focused on sex-specific associations between exercise and HDL, and explored possible mediators of this link. Given evidence that Black individuals have a higher preponderance of vascular risk factors (Centers for Disease Control and Prevention, 2020), future studies should examine whether exercise relates to certain vascular factors more than other vascular factors in Black women versus men. In general, the effect size of exercise on HDL was small. The study design is cross-sectional and observational, limiting our ability to determine causality. It is possible that HDL mediates the relationship between exercise and inflammation or that the relationship is bidirectional. Indeed, chronic inflammation may alter the structure of HDL resulting in impeded anti-arteriosclerotic and anti-inflammatory functioning (Ahn & Kim, 2016), which suggests a bidirectional relationship. The exercise measure was based upon self-report, which is susceptible to inaccuracy and may contribute noise to the data. Despite this potential for increased noise in the data, we found support for our hypotheses. Furthermore, available measures of inflammation were derived from serum samples and are not direct measures of neuroinflammation which may be more relevant for understanding the pathogenesis and cognitive trajectory of AD. Our study examined HDL due to its prominent sex-specific characteristics (Katan et al., 1994) and its relationship with exercise (Hsu et al., 2019). Future studies should examine whether exercise has sex-specific relationships with other measures of vascular health (e.g., blood pressure) possibly mediated by inflammatory marker levels.

Our study also contains a number of strengths. This is the first study to our knowledge that demonstrates a potential pathway by which women derive an HDL boost from exercise. This is particularly relevant given the established relationship between inflammatory markers and cognition using data from this study (Yaffe et al., 2003). Our sample also contained 42% Black individuals and 58% White individuals from two cities in the U.S., enabling us to generalize beyond a strictly White U.S. sample. However, it is critical to continue to work toward recruitment and inclusion of participants who reflect the racial, ethnic, and socioeconomic statuses of the U.S. population. Future studies should examine these interrelationships longitudinally and across the AD spectrum and examine measures of SDOH that may be driving relationship with health outcomes that drive health disparities.

Conclusions

Our results suggest that women may derive more benefit from exercise on HDL level, integral to cardiovascular health, than men via a TNF mechanism. We are the first to show that the female-specific exercise-HDL link is generalizable by race and lower levels of peripheral pro-inflammatory markers may be the pathway by which women derive a benefit from exercise on HDL level. Given the role of cardiovascular health in AD risk, findings have implications for sex differences in AD risk factors including evidence of a stronger effect of exercise on cognitive outcomes in women versus men (Barha et al., 2020). These findings highlight potential therapeutic targets for women specifically. If replicated, our findings suggest that women may benefit more from treatments targeting inflammation, including exercise.

What this paper adds

  • Higher levels of exercise related to higher HDL levels in older women but not men.

  • The effect size was consistent in Black and White older women.

  • The exercise-HDL link was mediated by TNFα in women.

Applications of study findings

  • Test HDL levels in women.

  • Encourage women to exercise.

  • Encourage recruitment and inclusion of diverse populations in future research efforts.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the California Department of Public Health (19-10613). Dr. Bernier’s effort was supported by the Alzheimer’s Association (AARG-20-644036) and the Shiley-Marcos ADRC (P30AG062429). This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was funded in part by the Intramural Research Program of the NIH, National Institute on Aging. This study used preexisting data from the multi-site Health ABC study, IRB protocols were approved at each site.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Bernier reports no conflicts. Dr. Sundermann reports no conflicts. Dr. Edland reports no conflicts. Dr. Deters reports no conflicts. Ms. Shepherd reports no conflicts. Dr. Clark reports no conflicts. Dr. Shiroma reports no conflicts. Dr. Banks reports no conflicts.

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