Dietary Walnuts Preserve Aspects of Health Span and Alter the Hippocampal Lipidome in Aged High-Fat Diet-Fed Mice.

Evidence continues to accrue that aging and its diseases can be delayed by pharmacologic and dietary strategies that target the underlying hallmarks of the aging process. However, identifying simple, safe, and effective dietary strategies involving the incorporation of whole foods that may confer some protection against the aging process is also needed. Recent observational studies have suggested that nut consumption can reduce mortality risk in humans. Among these, walnuts are particularly intriguing, given their high content of n-3 fatty acids, fiber, and antioxidant and anti-inflammatory compounds. To this end, 12-month-old male CB6F1 mice were provided either a defined control low-fat diet (LFD), a control high-fat diet (HFD), or an isocaloric HFD containing 7.67% walnuts by weight (HFD + W), and measures of healthspan and related biochemical markers (n = 10-19 per group) as well as survival (n = 20 per group) were monitored. Mice provided the HFD or HFD + W demonstrated marked weight gain, but walnuts lowered baseline glucose (p < 0.05) and tended to temper the effects of HFD on liver weight gain (p < 0.05) and insulin tolerance (p = 0.1). Additional assays suggested a beneficial effect on some indicators of health with walnut supplementation, including preservation of exercise capacity and improved short-term working memory, as determined by Y maze (p = 0.02). However, no effect was observed via any diet on inflammatory markers, antioxidant capacity, or survival (p = 0.2). Ingenuity Pathway Analysis of the hippocampal transcriptome identified two processes predicted to be affected by walnuts and potentially linked to cognitive function, including estrogen signaling and lipid metabolism, with changes in the latter confirmed by lipidomic analysis. In summary, while walnuts did not significantly improve survival on a HFD, they tended to preserve features of healthspan in the context of a metabolic stressor with aging.

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

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.

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

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 Apc models (Apc1638N/+ and ApcΔ14), and in MC38 colon cancer cells in vivo, 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 Apc1638N/+ male HFD+W animals, as compared to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; P = 0.015), tended to reduce the number of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; P = 0.07), and preferentially limited tumor growth in ApcΔ14 male mice (P = 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.

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

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.