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Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

ABSTRACT: Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings allow for longer-term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.

SUBMITTER: Schwarz C

PROVIDER: S-EPMC5807086 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

Schwarz Claudia C Stekovic Slaven S Wirth Miranka M Benson Gloria G Royer Philipp P Sigrist Stephan J SJ Pieber Thomas T Dammbrueck Christopher C Magnes Christoph C Eisenberg Tobias T Pendl Tobias T Bohlken Jens J Köbe Theresa T Madeo Frank F Flöel Agnes A

Aging 20180101 1

Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance st ...[more]

PMID: 29315079

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Project description:BackgroundGiven the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer's disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters.MethodsThe SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12 months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18 months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention.DiscussionThe SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer's disease.Trial registrationClinicalTrials.gov, NCT03094546 . Registered 29 March 2017-retrospectively registered.Protocol versionBased on EA1/250/16 version 1.5.

Project description:Background and Objectives:Subjective cognitive decline (SCD), the self-reported experience of worsening or more frequent confusion or memory loss, may be associated with the development or worsening of chronic conditions or complicating their self-management. The objectives of this study were to (i) establish the prevalence of chronic conditions and multiple chronic conditions among adults with SCD, and (ii) compare the prevalence of chronic conditions among people with and without SCD and SCD-related functional limitations. Research Design and Methods:Data were analyzed from the Cognitive Decline module of the Behavioral Risk Factor Surveillance System administered in 49 states, DC, and Puerto Rico during 2015-2017. Analyses included 220,221 respondents aged 45 years or older who answered the SCD screening question and reported their chronic conditions. Weighted estimates were calculated and chi-square tests were used for comparisons. Results:Persons with a history of stroke, heart disease, and chronic obstructive pulmonary disorder had significantly higher prevalence of SCD compared to those without. The prevalence of having at least one chronic condition was higher among adults with SCD compared to adults without SCD in each age group (45-64 years: 77.4% vs 47.1%, p < .001; ?65 years: 86.3% vs 73.5%, p < .001). Among those with SCD, the prevalence of an SCD-related functional limitation was higher among those with at least one chronic condition compared to those with none (45-64 years: 63.3% vs 42.4%, p < .001; ?65 years: 40.0% vs 25.1%, p < .001). Only half of adults with SCD and a chronic condition had discussed their SCD with a health care professional. Discussion and Implications:SCD and chronic conditions commonly co-occur. Having a chronic condition was associated with greater SCD-related functional limitations. SCD might complicate the management of chronic conditions, and patients and providers should be aware of increased risk for cognitive decline in the presence of chronic diseases.

Project description:BackgroundOlder adults with mild cognitive impairment (MCI) have slower gait speed and poor gait performance under dual-task conditions. However, gait kinematic and kinetic characteristics in older adults with MCI or subjective cognitive decline (SCD) remain unknown. This study was designed to explore the difference in gait kinematics and kinetics during level walking among older people with MCI, SCD, and normal cognition (NC).MethodsThis cross-sectional study recruited 181 participants from July to December 2019; only 82 met the inclusion criteria and consented to participate and only 79 completed gait analysis. Kinematic and kinetic data were obtained using three-dimensional motion capture system during level walking, and joint movements of the lower limbs in the sagittal plane were analyzed by Visual 3D software. Differences in gait kinematics and kinetics among the groups were analyzed using multivariate analysis of covariance (MANCOVA) with Bonferroni post-hoc analysis. After adjusting for multiple comparisons, the significance level was p < 0.002 for MANCOVA and p < 0.0008 for post-hoc analysis.ResultsTwenty-two participants were MCI [mean ± standard deviation (SD) age, 71.23 ± 6.65 years], 33 were SCD (age, 72.73 ± 5.25 years), and 24 were NC (age, 71.96 ± 5.30 years). MANCOVA adjusted for age, gender, body mass index (BMI), gait speed, years of education, diabetes mellitus, and Geriatric Depression Scale (GDS) revealed a significant multivariate effect of group in knee peak extension angle (F = 8.77, p < 0.0001) and knee heel strike angle (F = 8.07, p = 0.001) on the right side. Post-hoc comparisons with Bonferroni correction showed a significant increase of 5.91° in knee peak extension angle (p < 0.0001) and a noticeable decrease of 6.21°in knee heel strike angle (p = 0.001) in MCI compared with NC on the right side. However, no significant intergroup difference was found in gait kinetics, including dorsiflexion, plantar flexion, knee flexion, knee extension, hip flexion, and hip extension(p > 0.002).ConclusionAn increase of right knee peak extension angle and a decrease of right knee heel strike angle during level walking were found among older adults with MCI compared to those with NC.

Project description:OBJECTIVES:Physical frailty (or loss of physiologic reserve) is associated with cognitive impairment and dementia. Subjective cognitive decline (SCD) may represent early pathologic changes of dementia. The association between these disease markers is unclear. DESIGN:Cross-sectional analysis. SETTING:Community-based participants from the Vanderbilt Memory & Aging Project. PARTICIPANTS:A total of 306 older adults with normal cognition (NC; n = 174) or mild cognitive impairment (MCI; n = 132). MEASUREMENTS:Frailty was measured using standard methods, and a composite frailty score was calculated. SCD was quantified using the Everyday Cognition Scale (ECog; total score and four domain scores). Objective cognition was assessed with the Montreal Cognitive Assessment (MoCA). Proportional odds models, stratified by sex, related the frailty composite to MoCA and total ECog score adjusting for age, education, body mass index, cognitive diagnosis, depressed mood, Framingham Stroke Risk Profile, apolipoprotein E (APOE ?4) carrier status, and height (for gait speed models). Secondary models related individual frailty components to SCD domains and explored associations in NC only. RESULTS:In women, frailty composite was related to MoCA (odds ratio [OR] = .56; P?=?.04), a finding attenuated in sensitivity analysis (OR?=?.59; P?=?.08). Frailty composite related to ECog total (OR = 2.27; P?=?.02), planning (OR = 2.63; P?=?.02), and organization scores (OR = 2.39; P?=?.03). Increasing gait speed related to lower ECog total (OR?=?.06; P?=?.003) and memory scores (OR?=?.03; P?<?.001). Grip strength related to lower ECog planning score (OR?=?.91; P?=?.04). In men, frailty was unrelated to objective and subjective cognition (P values >.07). Findings were consistent in the NC group. CONCLUSION:Frailty component and composite scores are related to SCD before the presence of overt dementia. Results suggest that this association is present before overt cognitive impairment. Results suggest a possible sex difference in the clinical manifestation of frailty, with primary associations noted in women. Further studies should investigate mechanisms linking early changes among frailty, SCD, and cognition. J Am Geriatr Soc, 1-9, 2019. J Am Geriatr Soc 67:1803-1811, 2019.

Dataset Information

Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

Publications

Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

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