The Obesity Paradox and Mortality in Older Adults: A Systematic Review

“Obesity paradox” describes the counterintuitive finding that aged overweight and obese people with a particular disease may have better outcomes than their normal weight or underweight counterparts. This systematic review was performed to summarize the publications related to the obesity paradox in older adults, to gain an in-depth understanding of this phenomenon. PubMed©, Embase©, and Scopus© were used to perform literature search for all publications up to 20 March 2022. Studies were included if they reported data from older adults on the relation between BMI and mortality. The following article types were excluded from the study: reviews, editorials, correspondence, and case reports and case series. Publication year, study setting, medical condition, study design, sample size, age, and outcome(s) were extracted. This review has been registered with PROSPERO (no. CRD42021289015). Overall, 2226 studies were identified, of which 58 were included in this systematic review. In all, 20 of the 58 studies included in this review did not find any evidence of an obesity paradox. Of these 20 studies, 16 involved patients with no specific medical condition, 1 involved patients with chronic diseases, and 2 involved patients with type 2 diabetes mellitus. Seven out of the nine studies that looked at short-term mortality found evidence of the obesity paradox. Of the 28 studies that examined longer-term mortality, 15 found evidence of the obesity paradox. In the studies that were conducted in people with a particular medical condition (n = 24), the obesity paradox appeared in 18 cases. Our work supports the existence of an obesity paradox, especially when comorbidities or acute medical problems are present. These findings should help guide strategies for nutritional counselling in older populations.


Introduction
Obesity, usually defined by the body mass index (BMI), is considered a public health problem, and is associated with many diseases [1][2][3]. The prevalence of obesity is high in younger adults but also in older people [4], and evidence suggests that prevalence of obesity will continue to increase [5]. The term "obesity paradox" is used to describe the counterintuitive finding that aged overweight and obese people with a particular disease may have better outcomes than their normal weight or underweight counterparts. However, there is wide heterogeneity between studies regarding the association between obesity and mortality in older adults, depending on the diseases concerned, the presence or absence of a particular disease, or the BMI level considered [6][7][8]. In aged people, body composition tends to change, and body weight tends to decrease, and some authors have suggested that fatness could be healthy [9]. Thus, it is important to confirm whether an "obesity paradox" truly exists, with a view to adapting management policies for overweight or obese old people.
(2 points), and outcome assessment (3 points). This gives a total of between 0 and 9 points. Scores of 7 or more are considered high quality studies, scores of 5-6 as moderate quality, and scores below 5 as low quality. Disagreements in scoring were resolved by a joint review of the manuscript to reach consensus.
Where possible and appropriate, some parameters were calculated from available data (e.g., mean age and/or standard deviation, rate ratio, odds ratio, etc.).
The quality of the included studies, as assessed using the NOS, was considered high for all 58 studies (Table 3). Table 3. Quality assessment of the different studies included in this systematic review, using the Newcastle-Ottawa scale (NOS).
Nearly two-thirds of the studies included in this work report better survival in overweight or obese older people. Several factors may influence the relationship between obesity and survival in the older population, including age, degree of obesity, presence or absence of comorbidities, and occurrence of an acute event.
Regarding age, the studies in this review that failed to show better survival in overweight or obese individuals included populations that were, on average, younger than those demonstrating an obesity paradox. Wu et al. [25], in their study of the impact of age on the association between BMI and all-cause mortality in patients with atrial fibrillation, found better survival in overweight or obese patients aged 75 years or older but not in patients aged between 65 and 74 years. Observations made in older populations must therefore take into account the intrinsic characteristics of the survivors. For the same BMI, patient profiles can be different, and this profile can influence survival. For instance, body composition may differ due to ethnicity, sex, or advancing age [71,72]. BMI does not provide information on body composition, and is less correlated with percentage of body mass or fat mass index, especially in younger people [72]. Abdominal obesity has direct metabolic consequences (adipose tissue inflammation, dysglycaemia, alteration of blood pressure regulation, etc.). Conversely, subcutaneous fat accumulation in the hips, for example, appears to have benign effects on cardiovascular risk. Other indicators, such as waist circumference or waist-to-hip ratio, are strongly associated with higher mortality risk [73,74]. Taking only BMI into account does not make it possible to differentiate between these situations [9]. In all studies included in this work, BMI was defined as an obesity index. If obesity is defined by "body adiposity", BMI level is probably not the best criterion [75]. The term "BMI paradox" may be more appropriate than "obesity paradox", as suggested by Antonopoulos et al. [9].
Obesity is a factor associated with higher mortality in younger populations [76][77][78], but it is also associated with an increased risk of developing and dying from a number of diseases [3], such as cancer [79,80], Some authors point to the obesity-related cellular and immune changes that make obese people more vulnerable, including an increased risk of infections [1]. Older obese people could be considered constitutionally more robust as they have survived the risk factor of obesity into adulthood. The degree of obesity could also be a factor. In this review, not all authors differentiated between different classes of obesity. However, the positive effect on survival in cases of overweight and obesity was not found for morbid obesity (BMI ≥ 35.0 kg/m 2 ) in 5 studies [11,32,57,58,66]. Furthermore, weight is not a reflection of body composition, in particular the muscle mass/fat mass ratio. Loss of muscle mass and strength (sarcopenia) is a factor associated with an increased risk of death. Tian et al. reported that obese people with sarcopenia have a higher risk of death than obese people without sarcopenia [81]. Obese people may be less frequently sarcopenic than non-obese people. In 1493 subjects aged 65 years or more (median age 74 ± 11 years), Sousa-Santos et al. [82] found a prevalence of 0.8% of obese sarcopenic individuals versus 11.6% of sarcopenic individuals of all BMI status.
The presence of a chronic pathology or an acute event may also influence survival. In this review, 20 studies [11,12,14,16,18,19,21,[24][25][26]37,40,44,52,54,55,58,60,64,66] of the 38 which found a favourable effect of overweight or obesity on survival involved patients with a particular chronic condition or facing a specific medical event. This finding suggests that even moderately overweight older individuals with chronic disease or acute medical events have better survival. Obesity in older people with a chronic disease could be a sign of greater robustness or higher reserves (better appetite, less risk of undernutrition).
Overweight or obese older subjects would be less undernourished than the general older population. Cereda et al. [83], in their meta-analysis of the prevalence of undernutrition in an older population, found a prevalence of undernutrition ranging from 3.1 to 29.4%, depending on the setting. Sousa-Santos et al. [84] showed that 6% of obese elderly subjects (BMI ≥ 30 kg/m 2 ) were also undernourished or at risk of undernutrition. In the event of an acute event, obese elderly people may have a better chance of survival, particularly because of their greater functional reserves. This observation is also made in younger obese or overweight subjects. Akinnusi et al. [85] show in their meta-analysis of patients admitted to intensive care that obese subjects have a similar mortality to non-obese subjects. In 2013, the meta-analysis by Flegal et al. [76] confirmed in a population without any particular pathology that overweight people (BMI > 25 kg/m 2 ) (all types of obesity and all ages) had a higher overall mortality rate, whatever the cause. However, mildly overweight people (BMI ≥ 25 and <30 kg/m 2 ) had lower all-cause mortality than normal weight people (BMI < 25 kg/m 2 ). Thus, this advantage was found regardless of age.
Several mechanisms could explain "obesity paradox". Probably, there are "good adipose tissues" in elderly subjects. In the literature, overweight or obesity, defined by high level of BMI, is shown to have positive influence on prothrombotic factors, production of certain cytokines, or NT-proBNP levels. Adipokine produced by adipose tissue seems to be cardioprotective [86]. Obesity could have a protective effect against progression or consequences of some chronic diseases. High BMI could also reflect better nutritional status and adequate muscle reserves. Casas-Vara et al. [87] showed better nutritional status in overweight or obese elderly people with heart failure.
Our systematic review has limitations. Although the WHO has proposed thresholds for BMI, the authors used different thresholds in their respective studies. In addition, the outcomes were also different between the studies. This made it difficult to compare the studies, and precluded meta-analysis. The age variable was missing in 14.0% of cases (8/57).
However, this work covers a large number of studies, totalling more than 1,120,000 people aged 65 years or over, with varying medical conditions and in different settings. The followup time of the studies ranged from 30 days to 156 months (even though the majority of studies have a long-term follow-up). These differences in follow-up time may make comparison difficult. In addition, there is no information on BMI variation over time, especially for studies with long-term follow-up. Weight loss or gain between baseline measurement and death could have a significant impact. The fact that only studies conducted in subjects aged 65 years or older were selected gives a certain homogeneity to this systematic review in terms of population. Finally, all studies were evaluated for methodological quality using the NOS, and were found to be of high quality.

Conclusions
The findings of this systematic review are in favour of the existence of an obesity paradox, which could more specifically concern older subjects with a comorbidity and/or experiencing an acute event. Nevertheless, because BMI does not reflect body composition, the term "BMI paradox" would be more appropriate. The influence of the level of BMI remains unclear. These findings should help guide strategies for nutritional counselling in the older population.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/nu15071780/s1, Table S1: Outcome and results of association between body mass index groups and mortality in aged adults (detailed information).
Author Contributions: L.G. and M.D. conceived and designed the study, prepared the material, collected the data, and performed the analysis. They wrote the first draft of the manuscript, and approved the final manuscript. All authors have read and agreed to the published version of the manuscript.

Funding:
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The APC was funded by tht University Hospitals of Martinique.

Informed Consent Statement: Not applicable.
Data Availability Statement: Data could be made available on reasonable request at moustapha.drame@chu-martinique.fr.