Elisa Fabbri

Aging and Multimorbidity: New Tasks, Priorities, and Frontiers for Integrated Gerontological and Clinical Research

Aging is characterized by rising susceptibility to development of multiple chronic diseases and, therefore, represents the major risk factor for multimorbidity. From a gerontological perspective, the progressive accumulation of multiple diseases, which significantly accelerates at older ages, is a milestone for progressive loss of resilience and age-related multisystem homeostatic dysregulation. Because it is most likely that the same mechanisms that drive aging also drive multiple age-related chronic diseases, addressing those mechanisms may reduce the development of multimorbidity. According to this vision, studying multimorbidity may help to understand the biology of aging and, at the same time, understanding the underpinnings of aging may help to develop strategies to prevent or delay the burden of multimorbidity. As a consequence, we believe that it is time to build connections and dialogue between the clinical experience of general practitioners and geriatricians and the scientists who study aging, so as to stimulate innovative research projects to improve the management and the treatment of older patients with multiple morbidities.

Aging and the Burden of Multimorbidity: Associations With Inflammatory and Anabolic Hormonal Biomarkers

BACKGROUND Multimorbidity increases with aging, but risk factors beyond age are unknown. OBJECTIVE To investigate the association of inflammatory and anabolic hormonal biomarkers with presence and prospective development of multimorbidity. METHODS Nine-year longitudinal study of 1018 participants aged 60 years or older (InCHIANTI Study). Multimorbidity was evaluated at baseline and follow-up visits as number of diagnosed diseases from a predefined list of 15 candidate chronic conditions, defined according to standard clinical criteria. Linear mixed models were used to test cross-sectional and longitudinal associations between candidate biomarkers and multimorbidity. RESULTS At baseline, multimorbidity was significantly higher in older participants (p < .001) and higher IL-6, IL-1ra, TNF-α receptor II (TNFAR2), and lower dehydroepiandrosterone sulfate were associated with higher number of diseases, independent of age, sex, body mass index, and education. The rate of longitudinal increase in number of chronic diseases was significantly steeper in participants who were older at baseline (p < .001). In addition, higher baseline IL-6 and steeper increase of IL-6 levels were significantly and independently associated with a steeper increase in multimorbidity over time (p < .001 and p = .003, respectively). Sensitivity analyses, performed using 15 different models obtained by removing each of 15 conditions included in the original list of candidate diseases, confirmed that results were not driven by any specific condition. CONCLUSIONS Accumulation of chronic diseases accelerates at older ages and in persons with higher baseline levels and steeper increase over time of IL-6. High IL-6 and increase in IL-6 may serve as early warning sign to better target interventions aimed at reducing the burden of multimorbidity.

Energy Metabolism and the Burden of Multimorbidity in Older Adults: Results From the Baltimore Longitudinal Study of Aging

Excessively elevated resting metabolic rate (RMR) for persons of a certain age, sex, and body composition is a mortality risk factor. Whether elevated RMR constitutes an early marker of health deterioration in older adult has not been fully investigated. Using data from the Baltimore Longitudinal Study of Aging, we hypothesized that higher RMR (i) was cross-sectionally associated with higher multimorbidity and (ii) predicted higher multimorbidity in subsequent follow-ups. The analysis included 695 Baltimore Longitudinal Study of Aging participants, aged 60 or older at baseline, of whom 248 had follow-up data available 2 years later and 109 four years later. Multimorbidity was assessed as number of chronic diseases. RMR was measured by indirect calorimetry and was tested in regression analyses adjusted for covariates age, sex, and dual-energy x-ray absorptiometry-measured total body fat mass and lean mass. Baseline RMR and multimorbidity were positively associated, independent of covariates (p = .002). Moreover, in a three-wave bivariate autoregressive cross-lagged model adjusted for covariates, higher prior RMR predicted greater future multimorbidity above and beyond the cross-sectional and autoregressive associations (p = .034). RMR higher than expected, given age, sex, and body composition, predicts future higher multimorbidity in older adults and may be used as early biomarker of impending health deterioration. Replication and the development of normative data are required for clinical translation.

Association Between Accelerated Multimorbidity and Age-Related Cognitive Decline in Older Baltimore Longitudinal Study of Aging Participants without Dementia

To explore the association between rate of physical health deterioration, operationalized as rising multimorbidity overtime, and longitudinal decline in cognitive function in older adults without dementia.

Changes of liver enzymes and bilirubin during ischemic stroke: mechanisms and possible significance

BackgroundSmall changes of bilirubin and liver enzymes are often detected during the acute phase of stroke, but their origin and significance are still poorly understood.MethodsOn days 0, 3, 7, and 14 after admission, 180 patients with ischemic stroke underwent serial determinations of bilirubin, GOT, GPT, γGT, alkaline phosphatase, C-reactive protein (CRP) and complete blood count. On days 0 and 7 common bile duct diameter was measured by ultrasound, and on day 3 cerebral infarct volume (IV) was calculated from CT scan slices.ResultsDuring the first week GOT, GPT, γGT (P < 0.001) and CRP (P = 0.03) increased with subsequent plateau, while significant decrements (P < 0.001) concerned unconjugated bilirubin, erythrocytes and haemoglobin. Alkaline phosphatase, direct bilirubin and common bile duct diameter remained stable. IV correlated with CRP, leukocytes, GOT, γGT (r > 0.3, P < 0.001 for all) and direct bilirubin (r = 0.23, P = 0.008). In multivariate analysis only CRP and GOT remained independently associated with IV (P < =0.001). The correlation of IV with GOT increased progressively from admission to day 14. GOT independently correlated with GPT which, in turn, correlated with γGT. γGT was also highly correlated with leukocytes. Unconjugated bilirubin correlated with haemoglobin, which was inversely correlated with CRP.ConclusionsThe changes of bilirubin and liver enzymes during ischemic stroke reflect two phenomena, which are both related to IV: 1) inflammation, with consequent increment of CRP, leukocytes and γGT, and decrease of haemoglobin and unconjugated bilirubin and 2) an unknown signal, independent from inflammation, leading to increasing GOT and GPT levels.

Plasma Biomarkers of Poor Muscle Quality in Older Men and Women from the Baltimore Longitudinal Study of Aging

Aging is characterized by progressive decline in muscle mass, strength, and quality all of which contribute to functional impairment, falls, mobility disability, and frailty. Circulating factors may provide clues on the mechanisms for decline in muscle quality with aging. Characterizing the metabolic profile associated with reduced muscle quality in older persons could have important translational implications for the early identification of subjects at high risk of developing sarcopenia and the identification of targets for new preventive strategies and treatments. In a pilot cross-sectional, case-control study nested in the Baltimore Longitudinal Study on Aging, we compared circulating metabolites between 79 participants with low muscle quality ratio and 79 controls with high muscle quality, matched by age, sex, and height. The concentrations of 180 metabolites were determined by LC MS/MS, using the Biocrates p180 system, a targeted metabolomics approach. Participants with low muscle quality had significantly higher levels of leucine, isoleucine, tryptophan, serotonin, and methionine, while those with high muscle quality had significantly lower levels of putrescine and the selected phophatidylcholine (PCs) and lysoPCs. The results of this study open a new road for future investigations aimed at identifying new metabolic pathways involved in the decline of muscle quality with aging.

The Human Skeletal Muscle Proteome Project: a reappraisal of the current literature

Skeletal muscle is a large organ that accounts for up to half the total mass of the human body. A progressive decline in muscle mass and strength occurs with ageing and in some individuals configures the syndrome of ‘sarcopenia’, a condition that impairs mobility, challenges autonomy, and is a risk factor for mortality. The mechanisms leading to sarcopenia as well as myopathies are still little understood. The Human Skeletal Muscle Proteome Project was initiated with the aim to characterize muscle proteins and how they change with ageing and disease. We conducted an extensive review of the literature and analysed publically available protein databases. A systematic search of peer‐reviewed studies was performed using PubMed. Search terms included ‘human’, ‘skeletal muscle’, ‘proteome’, ‘proteomic(s)’, and ‘mass spectrometry’, ‘liquid chromatography‐mass spectrometry (LC‐MS/MS)’. A catalogue of 5431 non‐redundant muscle proteins identified by mass spectrometry‐based proteomics from 38 peer‐reviewed scientific publications from 2002 to November 2015 was created. We also developed a nosology system for the classification of muscle proteins based on localization and function. Such inventory of proteins should serve as a useful background reference for future research on changes in muscle proteome assessed by quantitative mass spectrometry‐based proteomic approaches that occur with ageing and diseases. This classification and compilation of the human skeletal muscle proteome can be used for the identification and quantification of proteins in skeletal muscle to discover new mechanisms for sarcopenia and specific muscle diseases that can be targeted for the prevention and treatment.

Insulin Resistance Is Associated With Reduced Mitochondrial Oxidative Capacity Measured by 31P-Magnetic Resonance Spectroscopy in Participants Without Diabetes From the Baltimore Longitudinal Study of Aging

Whether individuals with insulin resistance (IR) but without criteria for diabetes exhibit reduced mitochondrial oxidative capacity is unclear; addressing this question could guide research for new therapeutics. We investigated 248 participants without diabetes from the Baltimore Longitudinal Study of Aging (BLSA) to determine whether impaired mitochondrial capacity is associated with prediabetes, IR, and duration and severity of hyperglycemia exposure. Mitochondrial capacity was assessed as the postexercise phosphocreatine recovery time constant (τPCr) by 31P-magnetic resonance spectroscopy, with higher τPCr values reflecting reduced capacity. Prediabetes was defined using the American Diabetes Association criteria from fasting and 2-h glucose measurements. IR and sensitivity were calculated using HOMA-IR and Matsuda indices. The duration and severity of hyperglycemia exposure were estimated as the number of years from prediabetes onset and the average oral glucose tolerance test (OGTT) 2-h glucose measurement over previous BLSA visits. Covariates included age, sex, body composition, physical activity, and other confounders. Higher likelihood of prediabetes, higher HOMA-IR, and lower Matsuda index were associated with longer τPCr. Among 205 participants with previous OGTT data, greater severity and longer duration of hyperglycemia were independently associated with longer τPC. In conclusion, in individuals without diabetes a more impaired mitochondrial capacity is associated with greater IR and a higher likelihood of prediabetes.

The Human Skeletal Muscle Proteome Project: A reappraisal of the current literature

Skeletal muscle is a large organ that accounts for up to half the total mass of the human body. A progressive decline in muscle mass and strength occurs with ageing and in some individuals configures the syndrome of ‘sarcopenia’, a condition that impairs mobility, challenges autonomy, and is a risk factor for mortality. The mechanisms leading to sarcopenia as well as myopathies are still little understood. The Human Skeletal Muscle Proteome Project was initiated with the aim to characterize muscle proteins and how they change with ageing and disease. We conducted an extensive review of the literature and analysed publically available protein databases. A systematic search of peer‐reviewed studies was performed using PubMed. Search terms included ‘human’, ‘skeletal muscle’, ‘proteome’, ‘proteomic(s)’, and ‘mass spectrometry’, ‘liquid chromatography‐mass spectrometry (LC‐MS/MS)’. A catalogue of 5431 non‐redundant muscle proteins identified by mass spectrometry‐based proteomics from 38 peer‐reviewed scientific publications from 2002 to November 2015 was created. We also developed a nosology system for the classification of muscle proteins based on localization and function. Such inventory of proteins should serve as a useful background reference for future research on changes in muscle proteome assessed by quantitative mass spectrometry‐based proteomic approaches that occur with ageing and diseases. This classification and compilation of the human skeletal muscle proteome can be used for the identification and quantification of proteins in skeletal muscle to discover new mechanisms for sarcopenia and specific muscle diseases that can be targeted for the prevention and treatment.

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54-96 years from the Baltimore Longitudinal Study of Aging.

Cardiorespiratory fitness (VO2 peak) declines with age and is an independent risk factor for morbidity and mortality in older adults. Identifying biomarkers of low fitness may provide insight for why some individuals experience an accelerated decline of aerobic capacity and may serve as clinically valuable prognostic indicators of cardiovascular health. We investigated the relationship between circulating ceramides and VO2 peak in 443 men and women (mean age of 69) enrolled in the Baltimore Longitudinal Study of Aging (BLSA). Individual species of ceramide were quantified by HPLC–tandem mass spectrometry. VO2 peak was measured by a graded treadmill test. We applied multiple regression models to test the associations between ceramide species and VO2 peak, while adjusting for age, sex, blood pressure, serum LDL, HDL, triglycerides, and other covariates. We found that higher levels of circulating C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramides were strongly associated with lower aerobic capacity (P < 0.001, P < 0.001, P = 0.018, and P < 0.001, respectively). The associations held true for both sexes (with men having a stronger association than women, P value for sex interaction <0.05) and were unchanged after adjusting for confounders and multiple comparison correction. Interestingly, no significant association was found for C16:0, C22:0, C24:0, C26:0, and C22:1 ceramide species, C24:0 dihydroceramide, or total ceramides. Our analysis reveals that specific long‐chain ceramides strongly associate with low cardiovascular fitness in older adults and may be implicated in the pathogenesis of low fitness with aging. Longitudinal studies are needed to further validate these associations and investigate the relationship between ceramides and health outcomes.