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1.
Sarcopenia: no consensus, no diagnostic criteria, and no approved indication-How did we get here?
Evans, WJ, Guralnik, J, Cawthon, P, Appleby, J, Landi, F, Clarke, L, Vellas, B, Ferrucci, L, Roubenoff, R
GeroScience. 2024;(1):183-190
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Abstract
In addition to the role of skeletal muscle in movement and locomotion, muscle plays a critical role in a broad array of metabolic processes that can contribute to improved health or risk of disease. The age-associated loss of muscle has been termed sarcopenia. The muscle is the primary site of insulin-stimulated glucose disposal and the largest component of basal metabolic rate, directly and indirectly affects bone density, produces myokines with pleiotropic effect on muscle and other tissues including the brain, and stores essential amino acids essential for the maintenance of protein synthesis during periods of reduced food intake and stress. As such, not surprisingly deterioration of skeletal muscle health, typically operationalized as decline of muscle mass and muscle strength is both a powerful risk factor and main consequence of chronic diseases, disability, and loss of independence, and it is one of the strongest risk factors for mortality. However, skeletal muscle remains one of the most plastic of all tissues, with rapid changes in rates of protein synthesis and degradation in response to physical activity and inactivity, inflammation, and nutritional and hormonal status. This has made the development of pharmacological therapies to increase muscle mass (or prevent loss), an important goal for decades. However, while remarkable advances in the understanding of molecular and cellular regulation of muscle protein metabolism have occurred recently, there are no approved drugs for the treatment of sarcopenia, the loss of skeletal muscle affecting millions of older people. The goal of this paper is to describe the possible reasons for the lack of new and effective pharmacotherapies to treat one of the most important risk factors for age-associated disease and loss of independence.
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2.
Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts.
Ong, KL, Marklund, M, Huang, L, Rye, KA, Hui, N, Pan, XF, Rebholz, CM, Kim, H, Steffen, LM, van Westing, AC, et al
BMJ (Clinical research ed.). 2023;:e072909
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Abstract
OBJECTIVE To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN Pooled analysis. DATA SOURCES A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2 and <75% of baseline rate. RESULTS 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I2=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I2=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I2=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 v <60 years), estimated glomerular filtration rate (60-89 v ≥90 mL/min/1.73 m2), hypertension, diabetes, and coronary heart disease at baseline. CONCLUSIONS Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.
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Impact of Geroscience on Therapeutic Strategies for Older Adults With Cardiovascular Disease: JACC Scientific Statement.
Forman, DE, Kuchel, GA, Newman, JC, Kirkland, JL, Volpi, E, Taffet, GE, Barzilai, N, Pandey, A, Kitzman, DW, Libby, P, et al
Journal of the American College of Cardiology. 2023;(7):631-647
Abstract
Geroscience posits that cardiovascular disease (CVD) and other chronic diseases result from progressive erosion of the effectiveness of homeostatic mechanisms that oppose age-related accumulation of molecular damage. This hypothetical common root to chronic diseases explains why patients with CVD are often affected by multimorbidity and frailty and why older age negatively affects CVD prognosis and treatment response. Gerotherapeutics enhance resilience mechanisms that counter age-related molecular damage to prevent chronic diseases, frailty, and disability, thereby extending healthspan. Here, we describe the main resilience mechanisms of mammalian aging, with a focus on how they can affect CVD pathophysiology. We next present novel gerotherapeutic approaches, some of which are already used in management of CVD, and explore their potential to transform care and management of CVD. The geroscience paradigm is gaining traction broadly in medical specialties, with potential to mitigate premature aging, reduce health care disparities, and improve population healthspan.
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Mitophagy in human health, ageing and disease.
Picca, A, Faitg, J, Auwerx, J, Ferrucci, L, D'Amico, D
Nature metabolism. 2023;(12):2047-2061
Abstract
Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities. Preclinical and clinical studies have shown that impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. Strategies to boost mitophagy have been successfully tested in model organisms, and, recently, some have been translated into clinics. In this Review, we describe the basic mechanisms of mitophagy and how mitophagy can be assessed in human blood, the immune system and tissues, including muscle, brain and liver. We outline mitophagy's role in specific diseases and describe mitophagy-activating approaches successfully tested in humans, including exercise and nutritional and pharmacological interventions. We describe how mitophagy is connected to other features of ageing through general mechanisms such as inflammation and oxidative stress and forecast how strengthening research on mitophagy and mitophagy interventions may strongly support human health.
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Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study.
Das, JK, Banskota, N, Candia, J, Griswold, ME, Orenduff, M, de Cabo, R, Corcoran, DL, Das, SK, De, S, Huffman, KM, et al
Aging cell. 2023;22(12):e13963
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Plain language summary
Reducing calorie intake by 12% has been shown in one randomised control trial (RCT) called the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, to result in both fat and muscle loss but without any changes to muscle strength and function. The present study aimed to take 90 of the individuals from the original CALERIE study to understand the mechanisms behind this. The results showed that after 12 months individuals who were given a calorie reduced diet lost significant amounts of weight compared to control and this loss was maintained after 2 years. This included muscle loss, but despite this, there was no change in muscle strength of individuals on calorie reduced diet. Genetic analysis showed that genes are involved in muscle quality and anti-ageing. It was concluded that 2 years of calorie restriction resulted in both fat and muscle loss but did not compromise muscle function. The upregulation of genes involved in muscle quality and anti-ageing may be responsible for this.
Expert Review
Conflicts of interest:
None
Take Home Message:
- CR can aid weight loss and sustain losses long-term. Some lean muscle loss may also be seen, but this does not mean that muscle function has been compromised
- CR can trigger molecular and cellular mechanisms involved in skeletal muscle, sustaining functionality during a weight loss programme.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) randomised control trial (RCT) showed that 12% caloric restriction (CR) induced muscle loss, without compromising muscle strength. This analysis of 90 individuals from that study aimed to determine the mechanisms behind this.
Methods
- The CALERIE study was an RCT that assessed the effects of 25% CR over 2 years compared to an ad libitum control group
- This study ran alongside the CALERIE study and took skeletal muscle biopsies from a subset of 90 individuals at baseline, 12 months, and 24 months from the CR group and ad libitum control group
- This yielded 162 muscle biopsies over 2 years
- Skeletal muscle was taken from the vastus lateralis muscle and lean leg mass, and muscle strength were assessed
- In addition, RNA was extracted, and gene expression assessed.
Results
- Participants on CR lost significant amounts of weight (P=<0.001) at 12 months, with no further improvements at 2 years. Quantity or range of weight loss data was not provided
- Control participants maintained their weight over 2 years
- There were no changes in muscle strength in CR individuals despite a significant loss of muscle mass (no P value given)
- Although adjustments for change in lean leg mass resulted in less of a decline in the isokinetic muscle strength test compared to control (average power P=0.0058 and peak torque P=0.0144)
- RNA analysis showed 797 genes were overexpressed and 206 underexpressed in CR compared to control
- CR was associated with enhanced anti-ageing mechanisms with genes such as those involved in androgen receptor signalling, autophagy, circadian rhythms, DNA repair, FOXO mediated transcription, and mitochondrial biogenesis all upregulated and inflammatory genes downregulated
- These changes were responsible for the positive effect on muscle quality in individuals in the CR group.
Conclusion
- It was concluded that 2 years of CR preserved muscle function despite muscle mass loss, through upregulation of the genes involved in muscle quality and anti-ageing.
Clinical practice applications:
- Healthcare professionals may consider a 12% CR diet for individuals who would like to lose weight and maintain its loss long-term, without compromising muscle function
- Although lean muscle mass may be lost, muscle function should not be affected, but should be monitored to ensure functionality.
Considerations for future research:
- The possible effects of combining CR with muscle strength exercises should be considered for future research to determine if muscle mass loss is prevented and whether this impacts further fat loss.
Abstract
The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear. We performed high-depth RNA-Seq (387-618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12- and 24-month follow-up from the 90 CALERIE participants randomized to CR and "ad libitum" control. Using linear mixed effect model, we identified protein-coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation. Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans.
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Challenges in developing Geroscience trials.
Rolland, Y, Sierra, F, Ferrucci, L, Barzilai, N, De Cabo, R, Mannick, J, Oliva, A, Evans, W, Angioni, D, De Souto Barreto, P, et al
Nature communications. 2023;(1):5038
Abstract
Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This unprecedented paradigm shift requires optimizing the design of future clinical studies related to aging in humans. Researchers will face a number of challenges, including ideal populations to study, which lifestyle and Gerotherapeutic interventions to test initially, selecting key primary and secondary outcomes of such clinical trials, and which age-related biomarkers are most valuable for both selecting interventions and predicting or monitoring clinical responses ("Gerodiagnostics"). This article reports the main results of a Task Force of experts in Geroscience.
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Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.
Waziry, R, Ryan, CP, Corcoran, DL, Huffman, KM, Kobor, MS, Kothari, M, Graf, GH, Kraus, VB, Kraus, WE, Lin, DTS, et al
Nature aging. 2023;(3):248-257
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Abstract
The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.
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Blood Biomarkers for Healthy Aging.
Ubaida-Mohien, C, Tanaka, T, Tian, Q, Moore, Z, Moaddel, R, Basisty, N, Simonsick, EM, Ferrucci, L
Gerontology. 2023;(10):1167-1174
Abstract
Measuring the abundance of biological molecules and their chemical modifications in blood and tissues has been the cornerstone of research and medical diagnoses for decades. Although the number and variety of molecules that can be measured have expanded exponentially, the blood biomarkers routinely assessed in medical practice remain limited to a few dozen, which have not substantially changed over the last 30-40 years. The discovery of novel biomarkers would allow, for example, risk stratification or monitoring of disease progression or the effectiveness of treatments and interventions, improving clinical practice in myriad ways. In this review, we combine the biomarker discovery concept with geroscience. Geroscience bridges aging research and translation to clinical applications by combining the framework of medical gerontology with high-technology medical research. With the development of geroscience and the rise of blood biomarkers, there has been a paradigm shift from disease prevention and cure to promoting health and healthy aging. New -omic technologies have played a role in the development of blood biomarkers, including epigenetic, proteomic, metabolomic, and lipidomic markers, which have emerged as correlates or predictors of health status, from disease to exceptional health.
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The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.
Xu, Y, Derakhshan, A, Hysaj, O, Wildisen, L, Ittermann, T, Pingitore, A, Abolhassani, N, Medici, M, Kiemeney, LALM, Riksen, NP, et al
The lancet. Diabetes & endocrinology. 2023;(10):743-754
Abstract
BACKGROUND Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING None.
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A metabolomic signature of the APOE2 allele.
Sebastiani, P, Song, Z, Ellis, D, Tian, Q, Schwaiger-Haber, M, Stancliffe, E, Lustgarten, MS, Funk, CC, Baloni, P, Yao, CH, et al
GeroScience. 2023;(1):415-426
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Abstract
With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR < 10%. The group includes 10 glycerolipids and 4 glycerophospholipids that were all higher in E2 carriers compared to E3, with fold change ranging from 1.08 to 1.25. The organic acid 6-hydroxyindole sulfate, previously linked to changes in gut microbiome that were reflective of healthy aging and longevity, was also higher in E2 carriers compared to E3 carriers. Three sterol lipids and one sphingolipid species were significantly lower in carriers of the E2 genotype group. For some of these metabolites, the effect of the E2 genotype opposed the age effect. No metabolites reached a statistically significant association with the E4 group. This work confirms and expands previous results connecting the APOE gene to lipid regulation and suggests new links between the e2 allele, lipid metabolism, aging, and the gut-brain axis.