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K. Kinoshita1,2, R. Otsuka3, C. Tange3, Y. Nishita1, M. Tomida3, F. Ando3,4, H. Shimokata3,5, H. Arai6
1. Department of Epidemiology of Aging, Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Aichi Japan; 2. Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, Aichi, Japan; 3. Section of NILS-LSA, Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Aichi, Japan; 4. Faculty of Health and Medical Sciences, Aichi Shukutoku University, Aichi, Japan; 5. Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Aichi, Japan; 6. National Center for Geriatrics and Gerontology, Aichi, Japan
Corresponding author: Rei Otsuka, Section of NILS-LSA, Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan, Tel: +81-562-46-2311; FAX: +81-562-46-2373; E-mail: otsuka@ncgg.go.jp

J Frailty Aging 2020;in press
Published online December 22, 2020, http://dx.doi.org/10.14283/jfa.2020.67



Polyunsaturated fatty acids help maintain insulin sensitivity, mitochondrial function, and anti-inflammation. It is well known that deterioration in these areas can cause frailty. However, little is known about the differences in serum polyunsaturated fatty acid levels among frailty components. We investigated the cross-sectional relationship between frailty and serum fatty acids in 1,033 community-dwelling older adults aged 60–88 years. Polyunsaturated fatty acid concentrations were measured from fasting blood samples. The modified phenotype criteria defined frailty. Polyunsaturated fatty acid levels were compared among each component using general linear modeling after controlling for sex, age, body mass index, smoking status, household income, and medical history. Lower polyunsaturated fatty acid levels were associated with the modified frailty criteria, including shrinking and weakness (p < 0.05). Our findings suggest that serum polyunsaturated fatty acid levels differ depending on the frailty status of older adults.

Key words: Cross-sectional study, polyunsaturated fatty acids, n-3 polyunsaturated fatty acids.



Fatty acids, especially polyunsaturated fatty acids (PUFA), have gained attention from many researchers and clinicians because they may have beneficial effects on the health of older adults (1). Besides being produced from food intake, some fatty acids are synthesized in the body. Previous studies have reported that the serum levels of fatty acids are affected by age and are independent of their intake (2).
PUFA can help maintain insulin sensitivity, mitochondrial function, and anti-inflammation (1). This is significant, since deterioration in these areas is known to cause frailty (3). Thus, frail older adults may have lower PUFA serum levels than healthy older adults. However, little is known about differences in fatty acid serum levels associated with frailty in community-dwelling older adults.
Investigating the relationship between serum fatty acids and frailty signs could be useful for future research and medical treatments, especially towards maintaining the health of older adults. Therefore, we aimed to verify the differences of fatty acid serum levels associated with frailty components in community-dwelling older adults.



Study participants

This study was conducted as a part of the National Institute for Longevity Sciences – Longitudinal Study of Aging (NILS-LSA) (4). Participants were recruited using a stratified random sampling method, by age (≥ 40 years) and sex, from the community-dwelling population of Obu City and Higashiura Town in Aichi Prefecture, Japan (4).
We cross-sectionally analyzed the fifth study wave data (between July 2006 and July 2008). Of the 2,419 participants in the fifth study, we excluded participants who: were aged < 60 years (n = 1,140), had incomplete frailty diagnoses (n = 178), had missing data for serum samples (n = 38), and had missing data for covariates (n = 30). Finally, 1,033 participants (males, n = 513, 49.7%) were analyzed in this study.
All participants provided written informed consent before participation. This study protocol was approved by the Ethics Committee of Human Research of the National Center for Geriatrics and Gerontology, Japan (No. 1115-3).

Blood sampling and fatty acid measurement

Blood samples were collected in the morning after fasting at least 12 hours. The NILS-LSA measurement details for fatty acids have been reported elsewhere (2). This study assessed total fatty acids (TFA), saturated fatty acids (SFA), monosaturated fatty acids (MUFA), and PUFA. Regarding PUFA, the n-3 series PUFA (n-3 PUFA) including alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA); and the n-6 series PUFA (n-6 PUFA) including gamma-linoleic acid (GLA), linoleic acid (LA), arachidonic acid (AA) were also assessed.

Physical frailty assessment

Frailty was assessed using frailty phenotype modified for Japanese, based on the original criteria outlined by Fried (5, 6). Frailty was indicated if participants met three or more components; meeting one or two components indicated pre-frailty. Shrinking was defined by ≥ 5% weight loss in the prior two years, since the NILS-LSA survey is biennial (4, 6). Weakness was defined by a maximum grip strength of < 26 kg in males and < 18 kg in females (6). Slowness was defined by a 10-m general gait speed of < 1.0 m/sec (6). Low activity was defined as scoring in the lower 20% for physical activity on a modified Minnesota Leisure-time Physical Activity Questionnaire (6). Exhaustion was assessed by determining whether participants experienced either of the following conditions: “I felt that everything I did was an effort” and “I could not get ‘going,’” The responses, with regard to the previous week, were: “less than 1 day,” “1-2 days,” “3-4 days,” and “5-7 days.” Participants were defined as exhausted if they did not answer “less than 1 day” for either of these questions (6).


Body mass index (BMI, kg/m2) was calculated from anthropometric data. Smoking status (current smoker or not), annual household income (less than 5.5 million yen or more), and medical history (hypertension, ischemic heart disease, dyslipidemia, diabetes mellitus, and stroke) were assessed using self-report questionnaires.

Statistical analysis

Serum fatty acid levels were estimated with logarithmic conversion. Mean and standard deviations were calculated for continuous variables.
Participant characteristics, according to frailty status, were analyzed using the Chi-squared test and analysis of variance.
Using general linear modeling after controlling for covariates, we compared serum fatty acid levels between participants in three categories according to frailty phenotype (i.e., robust, pre-frail, and frail), and in participants with or without each of the five frailty components.
In the additional analysis, we included the overall energy intake (kcal/day) as covariates. The energy intake was assessed using a three-day dietary record that has been reported in detail elsewhere (7).
All analyses were performed using the Statistical Analysis System version 9.3 (SAS Institute, Cary, NC, USA); a two-sided p-value < 0.05 indicated statistical significance.



Table 1 shows participant characteristics. Participant age ranged from 60 to 88 years. There were 68 (6.6%) frail, 561 (54.3%) pre-frail, and 404 (39.1%) robust participants.

Table 1
Characteristics of participants according to physical frailty (n=1,033)

*Chi-squared test for proportion variables and ANOVA for continuous variables; †5.5 million yen = $51,882.32 USD, which was calculated according to the mean conversion rate during the study period (i.e., July 2006 to July 2008); SD, standard deviation; BMI, body mass index; ANOVA, analysis of variance.


In comparing fatty acid serum levels in robust, pre-frail, and frail participants, PUFA levels (μg/ml) were highest in the robust group and lowest in the frail group (least squares mean ± standard error; 1416.1 ± 1.0, 1378.1 ± 1.0, and 1341.5 ± 1.0; in respectively, p = 0.020 for between-group difference, p = 0.026 for trend).
Table 2 shows fatty acid serum levels according to the five frailty components. Participants with shrinking had significantly lower levels of TFA, SFA, MUFA, and PUFA than those without (p < 0.01 in all). Those with weakness had significantly lower EPA and DHA levels, than those without (p < 0.05 in all). Those with slowness had significantly lower EPA levels (p = 0.032); those with low activity had significantly lower DHA levels (p = 0.048). However, we found no significant differences in fatty acid serum levels for participants with and without exhaustion.

Table 2
Serum levels of fatty acids according to the five components of physical frailty (n=1,033)

Values are least squares mean (standard error). General linear modeling was performed after controlling for sex, age, BMI, current smoker, annual household income (< 5.5 million yen), and history of stroke, ischemic heart disease, hypertension, dyslipidemia, diabetes mellitus. Serum fatty acids levels were estimated after logarithmic conversion. TFA, total fatty acids; SFA, saturated fatty acids; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; ALA, alpha-linoleic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid, GLA, gamma-linoleic acid; LA, linoleic acid; AA, arachidic acid.



This study investigated the serum fatty acid levels according to frailty components in community-dwelling older adults. Our findings suggest that serum fatty acid concentrations, especially PUFA levels, differ depending on the frailty signs in older adults.
Both PUFA and MUFA are suggested to be effective in preventing muscle loss through suppressing reductions in insulin sensitivity (1). This may be because insulin accelerates muscle synthesis by activating the mammalian target of rapamycin complex 1 (8). PUFA is believed to prevent muscle atrophy and physical dysfunction by improving mitochondrial function and anti-inflammatory effects (1, 9). Mitochondrial dysfunction overproduces reactive oxygen species, leading to muscle atrophy due to induced protein degradation through the accelerated ubiquitin-proteasome system (10). Inflammation is suggested to be associated with components of frailty; however, this needs to be further explored in future studies (9, 3).
Participants with shrinking had significantly lower serum SFA levels. SFA may have an association with muscle loss (1). However, participants with shrinking also showed significantly lower TFA levels. Previous research observed that TFA serum levels were significantly lower in thin people compared with obese people (11). To account for the effect of consumption on shrinking, we additionally analyzed and controlled participants’ energy intake (kcal/day); however, this association remained even after the adjustment (data not shown).
We determined that lower PUFA levels, especially n-3 PUFA, were associated with signs of frailty. Based on a review article, randomized controlled trials (RCTs) of n-3 PUFA supplementation for muscle function were conducted with healthy older adults. However, the beneficial effects were shown only during sufficient supplementation (12). Intriguingly, Guerville and colleagues conducted an RCT in community-dwelling older adults with regard to slow gait speeds or any limitations in the activities of daily living; they reported that the n-3 PUFA supplementation and lifestyle intervention resulted in a lower frailty incidence than the placebo group, when they excluded participants who became frail within one year (13). They suggested that earlier intervention may be crucial (13). Considering our findings together, PUFA requirements might vary according to the conditions of frailty.
There are several limitations to this study. First, the participants may have been healthier than those in other cohorts because the mean frailty prevalence is 11.2% in Japan, as reported from seven community-based studies (14). However, our study participants were younger than in those seven studies. Second, although shrinking status was measured as the change after two years, whether these weight losses were intentional was not clarified. The original criteria measured the weight change during one year (5). Thus, it is possible that some participants with shrinking displayed more gradual weight loss than the original criteria accounted for, or they lost weight intentionally (5). Third, we repeated the analysis for each component; thus, the possibility of an alpha error cannot be ruled out. However, we judged this according to the statistical results, and our interpretation coincides with the view of the American Statistical Association (15).
In conclusion, our findings suggest that older adults with frailty components show lower serum levels of PUFA, especially EPA and DHA. PUFA may prevent frailty signs, such as skeletal muscle catabolism and physical dysfunction, through the beneficial effects of suppressing insulin resistance, maintaining the mitochondrial function, and anti-inflammation. These results can be useful for designing studies and treatment strategies regarding the improvement of physical frailty in older age.


Acknowledgments: We truly appreciate all participants and staff of the NILS-LSA for their cooperation and contributions to this study. We would like to thank Editage (www.editage.com) for English language editing.
Funding: This study was supported in part by the Food Science Institute Foundation, and Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology, Japan (19-10 to R.O.); and the Japanese Ministry of Education, Culture, Sports, Science and Technology (20H04114 to H.S.).
Author contributions: Kaori Kinoshita conceived the study design, performed the data analysis, interpreted the results, and drafted the initial manuscript; Rei Otsuka collected data, conceived the study design, performed the data analysis, interpreted the results, and contributed to discussions; Chikako Tange collected data, interpreted the results and contributed to discussions; Yukiko Nishita collected data, interpreted the results, and contributed to discussions; Makiko Tomida collected data, interpreted the results, and contributed to discussions; Fujiko Ando designed the NILS-LSA, collected data, interpreted the results, and contributed to discussions; Hiroshi Shimokata designed the NILS-LSA, collected data, interpreted the results, and contributed to discussions; and Hidenori Arai supervised the study, conceived the study design, interpreted the results, and contributed to discussions.
Conflict of Interest: None declared by the authors.
Ethical standards: This study was carried out in accordance with the ethical standards.



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