Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as ...a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with ...anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys.
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•Resveratrol elicits transcriptional changes in visceral and subcutaneous WAT•Resveratrol exerts anti-inflammatory effects in visceral WAT of HFS-fed monkeys•Resveratrol’s anti-inflammatory effect coincides with improved insulin sensitivity•Adipocytes play a key role in the adaptations evoked by resveratrol
Closing the Gap in Cancer Genomic Testing Schilsky, Richard L.; Longo, Dan L.
The New England journal of medicine,
12/2022, Letnik:
387, Številka:
23
Journal Article
Recenzirano
Genomic analysis of tumor tissue and circulating tumor DNA is an increasingly important component of cancer care. But evidence indicates underutilization of tumor genomic testing.
It has been reported that Mitofusin2 (Mfn2) inhibits cell proliferation when overexpressed. We wanted to study the role of endogenous Mfn2 in cell proliferation, along with the structural features of ...Mfn2 that influence its mitochondrial localization and control of cell proliferation. Mfn2‐knockdown clones of a B‐cell lymphoma cell line BJAB exhibited an increased rate of cell proliferation. A 2‐fold increase in cell proliferation was also observed in Mfn2‐knockout mouse embryonic fibroblast (MEF) cells as compared with the control wild‐type cells, and the proliferative advantage of the knockout MEF cells was blocked on reintroduction of the Mfn2 gene. Mfn2 exerts its antiproliferative effect by acting as an effector molecule of Ras, resulting in the inhibition of the Ras‐Raf‐ERK signaling pathway. Furthermore, both the N‐terminal (aa 1–264) and the C‐terminal (aa 265–757) fragments of Mfn2 blocked cell proliferation through distinct mechanisms: the N‐terminal‐mediated inhibition was due to its interaction with Raf‐1, whereas the C‐terminal fragment of Mfn2 inhibited cell proliferation by interacting with Ras. The inhibition of proliferation by the N‐terminal fragment was independent of its mitochondrial localization. Collectively, our data provide new insights regarding the role of Mfn2 in controlling cellular proliferation.—Chen, K.‐H., Dasgupta, A., Ding, J., Indig, F. E., Ghosh, P., Longo, D. L. Role of Mitofusin 2 (Mfn2) in controlling cellular proliferation. FASEB J. 28, 382–394 (2014). www.fasebj.org
In many countries, the availability of vaccines has marked a turning point in the Covid-19 pandemic. Although the vaccines are imperfect, breakthrough infections in fully vaccinated people remain ...quite rare, even with recently emerging variants. Countries with high vaccination rates have largely been able to reopen, and rates of severe illness and death have dropped dramatically. But this has not been a smooth process. Different vaccines have become available at different times, and access to them has varied markedly from country to country. Thus, the choice of which vaccine to use has been driven in great part by availability rather . . .
CAR T Cells for Neuroblastoma Yeku, Oladapo O.; Longo, Dan L.
The New England journal of medicine,
04/2023, Letnik:
388, Številka:
14
Journal Article
Recenzirano
This editorial explains the science behind a study of chimeric antigen receptor–expressing T cells to treat a series of 27 patients with neuroblastoma.
This editorial describes the science behind a clinical trial performed by Prager and colleagues: a test of trifluridine–tipiracil and bevacizumab to treat patients with refractory metastatic ...colorectal cancer.
A Milestone for CAR T Cells Tran, Eric; Longo, Dan L; Urba, Walter J
The New England journal of medicine,
12/2017, Letnik:
377, Številka:
26
Journal Article
Recenzirano
More than 7 years have passed since the regression of advanced lymphoma was first reported in a patient who had undergone the infusion of T cells engineered to express a chimeric antigen receptor ...(CAR) targeting the CD19 antigen expressed on the surface of both normal and malignant B cells.
1
Subsequent trials of CD19-targeted CAR T-cell therapy showed a complete response in some patients with relapsed or chemotherapy-refractory hematologic cancers for which there were no effective therapies.
2-5
This personalized therapeutic approach entails the removal of peripheral-blood T cells from a patient, followed by in vitro activation, genetic modification, and expansion of . . .
Aging is characterized by an increasing morbidity and functional decline that eventually results in the death of an organism. Aging is the largest risk factor for numerous human diseases, and ...understanding the aging process may thereby facilitate the development of new treatments for age-associated diseases. The use of humans in aging research is complicated by many factors, including ethical issues; environmental and social factors; and perhaps most importantly, their long natural life span. Although cellular models of human disease provide valuable mechanistic information, they are limited in that they may not replicate the in vivo biology. Almost all organisms age, and thus animal models can be useful for studying aging. Herein, we review some of the major models currently used in aging research and discuss their benefits and pitfalls, including interventions known to extend life span and health span. Finally, we conclude by discussing the future of animal models in aging research.
The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors ...impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.
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