After randomization, ASPREE trial participants were contacted quarterly by telephone and visited in person annually. At these annual visits, body weight, height at baseline, WC, and laboratory test measurements were recorded, and other health-related data were collected.

Prespecified ASPREE end points ie, cancer, clinically significant bleeding, dementia, depression, hospitalization for heart failure, myocardial infarction, and stroke and hospitalizations were recorded at 6-month intervals by in-person interview or by a 6-month telephone call.

All end point data were adjudicated by expert panels. Change in WC was measured in a similar manner. Mortality events were identified during routine follow-up by a review of health records when participants could not be contacted or when the next of kin or a close contact notified the trial center.

In Australia, the trial staff performed weekly linkage with the Ryerson Index, a community-maintained register that monitors death notices and obituaries. The names of all Australian and US participants who had withdrawn or were lost to follow-up were linked to the National Death Index.

Cause of death was established by an adjudication panel determining the single disease that was most likely to have initiated the trajectory toward death. Where relevant records could not be obtained, the underlying cause of death was based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes recorded on the death certificate or on the results of a search of the National Death Index.

The present study analyzed change in body size between study entry and annual visit 2 and mortality that occurred after annual visit 2. Statistical analysis was performed from April to September The characteristics of the participants were compared for continuous variables using analysis of variance and for categorical variables using χ 2 tests, according to the weight change categories and WC change categories.

Thereafter, we examined the 5 categories of WC change with mortality in a similar manner. All analyses were repeated in the same way for the individual end points of all-cause mortality, cancer-specific mortality, CVD-specific mortality, and noncancer non-CVD—specific mortality.

There was a significant interaction between change in body size categories and sex that persisted in the fully adjusted models. There was no similar interaction between change in body size and age; analyses were therefore stratified by sex.

Sensitivity analyses were performed excluding the US population predominantly comprising the US racial and ethnic minority population , excluding participants with a cognitive impairment at baseline, 8 and restricting the analysis of outcomes to those occurring after annual visit 3 to reduce the association with outcomes of illness progressing during years 1 and 2.

Stata MP, version 17 StataCorp LLC , was used for analysis. Among these participants, mortality events were recorded. The participants were followed up for a mean SD of 4. Conversely, participants Those who had a decrease in weight were mainly women, from the US, and prefrail or frail.

The characteristics of participants according to change in WC are shown in eTable 1 in Supplement 1. Table 2 shows the association between percentage change in BMI and subsequent all-cause and cause-specific mortality.

The lowest risk of all-cause mortality was observed for the stable weight group Figure 2. A total of of mortality events were recorded among men with stable weight 8.

Hazard ratios were only modestly changed after adjustment for age, frailty status, country of birth, smoking status, alcohol intake, educational level, hypertension, chronic kidney disease, diabetes, and interim hospitalization.

A total of mortality events were recorded among women with stable weight 5. Increase in weight was not associated with cancer mortality. Increase in weight was not associated with CVD mortality.

However, this association was not seen for women HR, 1. The associations of change in WC with all-cause and cause-specific mortality are presented in Table 3. Change in WC was not associated with CVD mortality. Change in WC was not associated with noncancer non-CVD mortality among women.

The associations persisted when we excluded participants from the US and participants who had any evidence of cognitive impairment at baseline and after restricting the analysis to outcomes occurring after annual visit 3 eTables 2, 3, and 4 in Supplement 1. Similar associations of change in body weight with all-cause mortality and cause-specific mortality were observed among participants with or without obesity, as well as participants who were younger than 75 years at recruitment or those 75 years or older at recruitment eTable 5 and eTable 6 in Supplement 1.

The associations of change in BMI with all-cause and cause-specific mortality also remained similar when the analyses were stratified by interim hospitalization status eTable 7 in Supplement 1. The associations of change in WC with all-cause mortality and cause-specific mortality remained similar to our main analyses in all the sensitivity analyses eTables in Supplement 1.

The association was more pronounced among men, for whom, in absolute terms, subsequent all-cause mortality was 8. A decrease in WC was also associated with increased mortality. Weight gain, however, was not significantly associated with mortality, with the possible exception of noncancer non-CVD mortality for women.

However, based on the small number of events in that category, this result should be interpreted cautiously.

Previous studies have reported an association between weight loss and subsequent mortality, but these studies included only a small number of older adults, typically with multiple comorbidities eTable 14 in Supplement 1.

The results also showed that weight loss was more associated with mortality among men than women. Two previous longitudinal studies examined the association of weight loss with CVD and cancer mortality and yielded conflicting results.

The Enquête de Santé Psychologique-Risques, Incidence et Traitement ESPRIT study showed that weight loss was associated with higher CVD mortality but not cancer mortality. In addition, our study showed that these results persisted even after adjustment for age, frailty status, baseline BMI, country of birth, smoking, hypertension, diabetes, and hospitalization in the previous 24 months.

Adjustment for recent hospitalization is important because hospitalization is often followed by weight loss due to acute conditions.

In addition, our study has clarified the lesser implications of weight gain. Compared with previous reports, the present study is based on individual measures of weight rather than self-report and adjudicated assessments of the cause of death.

The observation that weight loss was associated with mortality among men may be the result of the different body composition characteristics of men and women. Something similar might be at work to explain why weight loss, rather than decrease of WC, is more associated with mortality.

A likely explanation for these findings is that weight loss can be an early prodromal indicator of the presence of various life-shortening diseases. The latter may include deaths from trauma, dementia, Parkinson disease, and other less common causes.

In this age group, weight loss was largely associated with a reduction of appetite, leading to reduced food intake. Appetite is a complex process, governed by both the central nervous system and various circulating hormones. Several proposals have been put forward to explain why appetite might be suppressed in the early stages of chronic illness, ranging from increases in resistance to appetite-stimulating hormones, 28 increased levels of inflammatory cytokines, 29 and high levels of other mediators such as growth differentiation factor This study has some strengths.

The combination of the large cohort, the focus on the population older than 70 years, and the extensive amount of hospitalization data, coupled with the regular and objective measures of body size and expert adjudication of cause of death, makes this the most comprehensive and detailed study of weight loss in this age group yet published, to our knowledge.

This study also has some limitations. The principal limitation is the inability to differentiate intended vs unintended weight loss, although bariatric surgery, the only likely intervention proven capable of intended long-term sustained weight loss, 32 is rarely undertaken in this age group.

Furthermore, exploring whether change in activity level and diet quality between baseline and annual visit 2 had any association with outcomes was not possible because they were not recorded in this study.

Residual confounding, such as intended weight loss or change in activity or diet, cannot be excluded. The risk extends beyond an increased risk of cancer, extending to CVD and a range of other life-limiting conditions.

Further research will be needed to determine more precisely the association between weight loss and the onset of fatal diseases and whether clinical or laboratory investigations can identify individuals for whom early intervention may be effective. Published: April 10, Open Access: This is an open access article distributed under the terms of the CC-BY License.

JAMA Network Open. Corresponding Author: Sultana Monira Hussain, PhD, School of Public Health and Preventive Medicine, Monash University, St Kilda Rd, Melbourne, VIC , Australia monira. hussain monash. Author Contributions: Drs Hussain and McNeil had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Hussain, Newman, Beilin, Woods, Reid, Owen, Cicuttini, Tran, McNeil. Acquisition, analysis, or interpretation of data: Hussain, Newman, Tonkin, Woods, Neumann, Nelson, Carr, Reid, Owen, Ball, Wang, Ernst, McNeil.

Critical revision of the manuscript for important intellectual content: Hussain, Newman, Beilin, Tonkin, Woods, Neumann, Nelson, Carr, Reid, Owen, Ball, Cicuttini, Tran, Wang, Ernst. Administrative, technical, or material support: Hussain, Newman, Tonkin, Owen, Ernst, McNeil.

Conflict of Interest Disclosures: None reported. The Aspirin in Reducing Events in the Elderly study was supported by grant U01AG from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, grants and from the NHMRC of Australia, Monash University, and the Victorian Cancer Agency.

Data Sharing Statement: See Supplement 2. Additional Contributions: We thank the patients who participated in this trial. full text icon Full Text. Download PDF Comment.

Top of Article Key Points Abstract Introduction Methods Results Discussion Conclusions Article Information References. Figure 1. Percent Body Mass Index Changes and Mortality Ascertainment Timeline Among the Aspirin in Reducing Events in the Elderly ASPREE Trial Participants.

View Large Download. Figure 2. Associations of Changes in Body Size and All-Cause Mortality in the Aspirin in Reducing Events in the Elderly Trial. Table 1. Baseline Characteristics of Aspirin in Reducing Events in the Elderly Trial Participants Who Remained Free of Mortality Through the Second Annual Visit.

Table 2. Association Between Body Weight Change Categories and Risk of Mortality in Men and Women a. Table 3. Association Between WC Change Categories and Risk of Mortality in Men and Women a.

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Sign up now and get a FREE copy of the Best Diets for Cognitive Fitness. Shared decision-making and goals of care should guide diagnostic evaluation. Initial workup for most patients should include laboratory studies and imaging.

Laboratory tests include complete blood count, basic metabolic panel, liver function tests, thyroid function tests, C-reactive protein level, erythrocyte sedimentation rate, glucose measurement, lactate dehydrogenase measurement, protein electrophoresis, ferritin, urinalysis, and fecal occult blood testing.

Initial imaging should include chest radiography. Low albumin and elevated total white blood cell count, platelets, calcium, or inflammatory markers are most associated with cancer. Although normal laboratory test results may be reassuring, they do not effectively rule out cancer, and further workup should be based on each patient's presentation and evaluation.

Appropriate follow-up of patients with unexplained, unintentional weight loss is needed if the initial evaluation is unclear. Studies suggested that if the initial evaluation was normal and screening tests were negative, no further workup is needed, and a three- to six-month observation period is warranted.

The length and frequency of follow-up should be specific to the clinician and patient. Follow-up at least annually is prudent if the initial evaluation does not determine a cause for the unintentional weight loss. Treatment should focus on the underlying cause and often involves a multidisciplinary team, including dentists; dietitians; speech, occupational, or physical therapists; and social service workers.

Common strategies to address unintentional weight loss in older adults are dietary changes, environmental modifications, nutritional supplements, flavor enhancers, and appetite stimulants.

Decreased saliva production, ill-fitting dentures, periodontal disease, and weakened mastication muscles can lead to poor dentition and impaired chewing. Having fewer teeth is associated with more insufficient nutritional intake because of the decreased variety of foods consumed.

According to the Choosing Wisely campaign by the American Geriatrics Society, appetite stimulants and high-calorie supplements should be avoided secondary to lack of evidence on long-term survival and quality of life.

The authors concluded that more studies were needed to assess the effects of supplementation in this population. Despite the lack of evidence of benefits and potential harms, appetite stimulants such as megestrol Megace and mirtazapine Remeron are prescribed.

Adverse effects of megestrol include gastrointestinal upset, insomnia, impotence, hypertension, thromboembolic events, and adrenal insufficiency. However, no literature exists solely looking at mirtazapine use for unintentional weight loss.

Adverse effects of mirtazapine include dizziness, fatigue, nausea, and somnolence, which can increase fall risk in older adults. This article updates previous articles on this topic by Huffman 39 and the authors. Data Sources: A PubMed search was completed in clinical queries.

The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Also searched were Agency for Healthcare Research and Quality Effective Healthcare Reports, the Cochrane database, Dynamed, and Essential Evidence Plus.

Search dates: December 13, and April 12, The contents of this article are solely the views of the authors and do not necessarily represent the official views of the Uniformed Services University of the Health Sciences, the U.

Air Force, the U. Army, the U. Navy, the U. military at large, the U. Department of Defense, or the U. Nicholson BD, Hamilton W, O'Sullivan J, et al. Weight loss as a predictor of cancer in primary care: a systematic review and meta-analysis.

Br J Gen Pract. Bosch X, Monclús E, Escoda O, et al. Unintentional weight loss: clinical characteristics and outcomes in a prospective cohort of patients.

PLoS One. Marton KI, Sox HC, Krupp JR. Involuntary weight loss: diagnostic and prognostic significance. Ann Intern Med. Evans WJ, Morley JE, Argilés J, et al. Cachexia: a new definition. Clin Nutr. Atalayer D, Astbury NM.

Anorexia of aging and gut hormones. Aging Dis. Mondello P, Mian M, Aloisi C, et al. Cancer cachexia syndrome: pathogenesis, diagnosis, and new therapeutic options. Nutr Cancer.

Le Thuc O, Stobbe K, Cansell C, et al. Hypothalamic inflammation and energy balance disruptions: spotlight on chemokines. Front Endocrinol Lausanne. Wallace JI, Schwartz RS. Epidemiology of weight loss in humans with special reference to wasting in the elderly.

Int J Cardiol. National Cancer Institute. Age and cancer risk. Updated March 5, Accessed April 12, Bulut EA, Khoury R, Lee H, et al. Eating disturbances in the elderly: a geriatric-psychiatric perspective.

Nutr Healthy Aging. McMinn J, Steel C, Bowman A. Investigation and management of unintentional weight loss in older adults. Lankisch P, Gerzmann M, Gerzmann JF, et al. Unintentional weight loss: diagnosis and prognosis.

The first prospective follow-up study from a secondary referral centre. J Intern Med. Metalidis C, Knockaert DC, Bobbaers H, et al. Involuntary weight loss.

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Table of Contents. Initial workup for most patients should include laboratory studies and imaging. Laboratory tests include complete blood count, basic metabolic panel, liver function tests, thyroid function tests, C-reactive protein level, erythrocyte sedimentation rate, glucose measurement, lactate dehydrogenase measurement, protein electrophoresis, ferritin, urinalysis, and fecal occult blood testing.

Initial imaging should include chest radiography. Low albumin and elevated total white blood cell count, platelets, calcium, or inflammatory markers are most associated with cancer. Although normal laboratory test results may be reassuring, they do not effectively rule out cancer, and further workup should be based on each patient's presentation and evaluation.

Appropriate follow-up of patients with unexplained, unintentional weight loss is needed if the initial evaluation is unclear. Studies suggested that if the initial evaluation was normal and screening tests were negative, no further workup is needed, and a three- to six-month observation period is warranted.

The length and frequency of follow-up should be specific to the clinician and patient. Follow-up at least annually is prudent if the initial evaluation does not determine a cause for the unintentional weight loss.

Treatment should focus on the underlying cause and often involves a multidisciplinary team, including dentists; dietitians; speech, occupational, or physical therapists; and social service workers.

Common strategies to address unintentional weight loss in older adults are dietary changes, environmental modifications, nutritional supplements, flavor enhancers, and appetite stimulants. Decreased saliva production, ill-fitting dentures, periodontal disease, and weakened mastication muscles can lead to poor dentition and impaired chewing.

Having fewer teeth is associated with more insufficient nutritional intake because of the decreased variety of foods consumed. According to the Choosing Wisely campaign by the American Geriatrics Society, appetite stimulants and high-calorie supplements should be avoided secondary to lack of evidence on long-term survival and quality of life.

The authors concluded that more studies were needed to assess the effects of supplementation in this population. Despite the lack of evidence of benefits and potential harms, appetite stimulants such as megestrol Megace and mirtazapine Remeron are prescribed.

Adverse effects of megestrol include gastrointestinal upset, insomnia, impotence, hypertension, thromboembolic events, and adrenal insufficiency. However, no literature exists solely looking at mirtazapine use for unintentional weight loss.

Adverse effects of mirtazapine include dizziness, fatigue, nausea, and somnolence, which can increase fall risk in older adults.

This article updates previous articles on this topic by Huffman 39 and the authors. Data Sources: A PubMed search was completed in clinical queries.

The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Also searched were Agency for Healthcare Research and Quality Effective Healthcare Reports, the Cochrane database, Dynamed, and Essential Evidence Plus. Search dates: December 13, and April 12, The contents of this article are solely the views of the authors and do not necessarily represent the official views of the Uniformed Services University of the Health Sciences, the U.

Air Force, the U. Army, the U. Navy, the U. military at large, the U. Department of Defense, or the U. Nicholson BD, Hamilton W, O'Sullivan J, et al. Weight loss as a predictor of cancer in primary care: a systematic review and meta-analysis.

Br J Gen Pract. Bosch X, Monclús E, Escoda O, et al. Unintentional weight loss: clinical characteristics and outcomes in a prospective cohort of patients. PLoS One. Marton KI, Sox HC, Krupp JR. Involuntary weight loss: diagnostic and prognostic significance.

Ann Intern Med. Evans WJ, Morley JE, Argilés J, et al. Cachexia: a new definition. Clin Nutr. Atalayer D, Astbury NM. Anorexia of aging and gut hormones. Aging Dis. Mondello P, Mian M, Aloisi C, et al. Cancer cachexia syndrome: pathogenesis, diagnosis, and new therapeutic options.

Nutr Cancer. Le Thuc O, Stobbe K, Cansell C, et al. Hypothalamic inflammation and energy balance disruptions: spotlight on chemokines. Front Endocrinol Lausanne. Wallace JI, Schwartz RS. Epidemiology of weight loss in humans with special reference to wasting in the elderly.

Int J Cardiol. National Cancer Institute. Age and cancer risk. Updated March 5, Accessed April 12, Bulut EA, Khoury R, Lee H, et al. Eating disturbances in the elderly: a geriatric-psychiatric perspective. Nutr Healthy Aging. McMinn J, Steel C, Bowman A.

Investigation and management of unintentional weight loss in older adults. Lankisch P, Gerzmann M, Gerzmann JF, et al. Unintentional weight loss: diagnosis and prognosis. The first prospective follow-up study from a secondary referral centre. J Intern Med. Metalidis C, Knockaert DC, Bobbaers H, et al.

Involuntary weight loss. Does a negative baseline evaluation provide adequate reassurance?. Thanks for visiting. Don't miss your FREE gift. The Best Diets for Cognitive Fitness , is yours absolutely FREE when you sign up to receive Health Alerts from Harvard Medical School. Sign up to get tips for living a healthy lifestyle, with ways to fight inflammation and improve cognitive health , plus the latest advances in preventative medicine, diet and exercise , pain relief, blood pressure and cholesterol management, and more.

Get helpful tips and guidance for everything from fighting inflammation to finding the best diets for weight loss from exercises to build a stronger core to advice on treating cataracts.

PLUS, the latest news on medical advances and breakthroughs from Harvard Medical School experts. Sign up now and get a FREE copy of the Best Diets for Cognitive Fitness. Stay on top of latest health news from Harvard Medical School. Recent Blog Articles. Flowers, chocolates, organ donation — are you in?

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