Publications by authors named "Ardijana Novaj"

3 Publications

  • Page 1 of 1

Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice.

Geroscience 2019 04 10;41(2):185-208. Epub 2019 May 10.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer Bldg, Rm 236, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.

Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.
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http://dx.doi.org/10.1007/s11357-019-00065-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544744PMC
April 2019

Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice.

Nat Commun 2018 06 19;9(1):2394. Epub 2018 Jun 19.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.

Diminished growth factor signaling improves longevity in laboratory models, while a reduction in the somatotropic axis is favorably linked to human aging and longevity. Given the conserved role of this pathway on lifespan, therapeutic strategies, such as insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibodies (mAb), represent a promising translational tool to target human aging. To this end, we performed a preclinical study in 18-mo-old male and female mice treated with vehicle or an IGF-1R mAb (L2-Cmu, Amgen Inc), and determined effects on aging outcomes. Here we show that L2-Cmu preferentially improves female healthspan and increases median lifespan by 9% (P = 0.03) in females, along with a reduction in neoplasms and inflammation (P ≤ 0.05). Thus, consistent with other models, targeting IGF-1R signaling appears to be most beneficial to females. Importantly, these effects could be achieved at advanced ages, suggesting that IGF-1R mAbs could represent a promising therapeutic candidate to delay aging.
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http://dx.doi.org/10.1038/s41467-018-04805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008442PMC
June 2018

Dietary Walnuts Protect Against Obesity-Driven Intestinal Stem Cell Decline and Tumorigenesis.

Front Nutr 2018 31;5:37. Epub 2018 May 31.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.

Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and related mortality. Thus, given the alarmingly high rates of obesity in the US and globally, it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts have been increasingly recognized to mitigate cancer risk, and contain many bioactive constituents with antioxidant and anti-inflammatory properties that could potentially counteract pathways thought to be initiators of obesity-related cancer. Therefore, the purpose of this study was to determine if walnuts could preserve intestinal homeostasis, and attenuate tumorigenesis and growth in the context of obesity and a high calorie diet. To this end, we studied effects of walnuts on these parameters under different dietary conditions in wildtype mice, two independent models ( and ), and in MC38 colon cancer cells , respectively. Walnuts did not alter the metabolic phenotype or intestinal morphology in normal mice fed either a low-fat diet (LFD), LFD with 6% walnuts (LFD+W), high-fat diet (HFD), or HFD with 7.6% walnuts (HFD+W). However, walnuts did lead to a significant reduction in circulating CCL5 and preserved intestinal stem cell (ISC) function under HFD-fed conditions. Furthermore, walnuts reduced tumor multiplicity in male HFD+W animals, as compared to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; = 0.015), tended to reduce the number of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; = 0.07), and preferentially limited tumor growth in male mice ( = 0.019) fed a high-calorie western-style diet. In summary, these data demonstrate that walnuts confer significant protection against intestinal tumorigenesis and growth and preserve ISC function in the context of a high-calorie diet and obesity. Thus, these data add to the accumulating evidence connecting walnuts as a potentially effective dietary strategy to break the obesity-colon cancer link.
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http://dx.doi.org/10.3389/fnut.2018.00037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990619PMC
May 2018