Valter D. Longo's research while affiliated with Università degli Studi di Palermo and other places

Publications (254)

Chapter
The last decades have seen the identification of a number of drugs targeting oncogene pathways, therefore contributing to moving the cancer therapy field toward precision medicine. However, existing and acquired resistance to targeted therapies represent major obstacles against their long-term effectiveness. In fact, the initial efficacy of targete...
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The restriction of proteins, amino acids or sugars can have profound effects on the levels of hormones and factors including growth hormone, IGF-1 and insulin. In turn, these can regulate intracellular signaling pathways as well as cellular damage and aging, but also multisystem regeneration. Both intermittent (IF) and periodic fasting (PF) have be...
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In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients’ nutritional status. We assessed the feasibility and safety of a 5-day “Fasting-...
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Purpose of review: This article reviews the current literature on dietary interventions, including time-restricted eating (TRE), intermittent fasting (IF), and fasting-mimicking diets (FMD) and their effects on weight loss. Recent findings: Dietary interventions, primarily known for their potential health benefits, are attracting considerable in...
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Purpose In the phase II DIRECT study a fasting mimicking diet (FMD) improved the clinical response to neoadjuvant chemotherapy as compared to a regular diet. Quality of Life (QoL) and illness perceptions regarding the possible side effects of chemotherapy and the FMD were secondary outcomes of the trial. Methods 131 patients with HER2-negative sta...
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Intermittent and periodic fasting (IF and PF, respectively) are emerging as safe strategies to affect longevity and healthspan by acting on cellular aging and disease risk factors, while causing no or minor side effects. IF lasting from 12 to 48 hours and repeated every 1 to 7 days and PF lasting 2 to 7 days and repeated once per month or less have...
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Purpose of Review Cardiovascular disease (CVD) is one of the leading causes of death globally. Nutrition plays a central role in CVD risk by affecting aging, adiposity, glycemia, blood pressure, cholesterol, inflammation, and other risk factors and can affect CVD risk not only based on calorie intake and dietary composition but also the timing and...
Conference Paper
Breast cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, a...
Conference Paper
Breast cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, a...
Article
Background Alterations in brain‐gut‐microbiome interactions have been implicated as an important factor in obesity. This study aimed to explore the relationship between food addiction (FA) and the brain‐gut‐microbiome axis, using a multi‐omics approach involving microbiome data, metabolomics, and brain imaging. Methods Brain magnetic resonance ima...
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In search of anti-aging interventions with differential effects on normal and cancer cells, we show that cycles of a fasting-mimicking diet plus pharmacological doses of vitamin C can be effective in targeting KRAS-mutant cancers. This approach represents a promising strategy able to protect the organism while killing cancer cells.
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Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasti...
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Background: Caloric restriction is an effective way to treat Type 2 diabetes (T2D). However, chronic and severe restriction of food intake is difficult to sustain and is known to promote slower metabolism. Intermittent and frequent fasting can exert similar metabolic effects, but may be even more challenging for most patients. A fasting-mimicking...
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Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mic...
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Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m−2, to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoa...
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Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimickin...
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Background: We have shown that subjects with Laron syndrome (LS) due to growth hormone receptor deficiency (GHRD) and their relatives have comparable brain structure and function; moreover, the brain of individuals affected with GHRD appears like those of younger people. While the functionally absent growth hormone receptor and the diminished conc...
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Dietary modifications, including caloric restriction, dietary restriction, various intervals of fasting, and even limiting the time when food is consumed can have a pronounced impact on longevity. In addition, dietary modifications are powerful interventions to delay, prevent, or treat many aging-related diseases such as cancer and diabetes. Restri...
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Cycles of fasting reduce autoimmunity and activate lymphocyte-dependent killing of cancer cells, but the mechanisms remain poorly understood. Three studies in this issue of Cell begin to reveal the drastic and complex effects of fasting and severe calorie restriction on the levels and localization of different immune cells and the mechanisms respon...
Article
Cardiovascular disease (CVD) is the leading cause of death in many developed countries and remains one of the major diseases strongly affected by the diet. Nutrition can affect CVD directly by contributing to the accumulation of vascular plaques and also indirectly by regulating the rate of aging. This review summarizes research on nutrition and CV...
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Dietary interventions are potentially effective therapies for inflammatory bowel diseases (IBDs). We tested the effect of 4-day fasting-mimicking diet (FMD) cycles on a chronic dextran sodium sulfate (DSS)-induced murine model resulting in symptoms and pathology associated with IBD. These FMD cycles reduced intestinal inflammation, increased stem c...
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Background: Short term fasting (STF) protects from toxicity, while enhancing the efficacy of chemotherapy in cancer bearing mice and is a promising strategy to enhance the efficacy and tolerability of chemotherapy in humans. A specifically designed low calorie, low amino acid substitution diet (“Fasting Mimicking Diet”, FMD) has similar effects in...
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The identification of conserved genes and pathways that regulate lifespan but also healthspan has resulted in an improved understanding of the link between nutrients, signal transduction proteins, and aging but has also provided evidence for the existence of multiple “longevity programs,” which are selected based on the availability of nutrients. P...
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The vulnerability of cancer cells to nutrient deprivation and their dependency on specific metabolites are emerging hallmarks of cancer. Fasting or fasting-mimicking diets (FMDs) lead to wide alterations in growth factors and in metabolite levels, generating environments that can reduce the capability of cancer cells to adapt and survive and thus i...
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Abstract Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices. Mounting evidence suggests that humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease....
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Cancer cells are characterized by dysregulation in signal transduction and metabolic pathways leading to increased glucose uptake, altered mitochondrial function, and the evasion of antigrowth signals. Fasting and fasting-mimicking diets (FMDs) provide a particularly promising intervention to promote differential effects in normal and malignant cel...
Conference Paper
Background: The fasting mimicking diet (FMD), a plant-based, low-calorie, low-protein, low-carbohydrate diet, modulates systemic metabolism and anticancer immunity, and displays anticancer activity in many preclinical tumor models. However, safety, metabolic, and activity data in the clinical setting are lacking. Methods: At Fondazione IRCCS Istitu...
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Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and play...
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Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such tox...
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Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexametha-sone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such to...
Data
Experimental schematic representation for the induction of heart damage in vivo and for STS, dexamethasone/rapamycin treatments with doxorubicin. (A) C57BL/6 mice were divided into 4 groups and underwent ad libitum feeding (ad lib), STS (48 h fasting) and/or doxorubicin treatment (DXR, 8 mg/kg). DXR was administrated at the end of each STS cycle. (...
Data
AMPK activation by GR, metformin, and its analog phenformin induce the expression of Egr1, MnSOD, and FoxO downstream genes. (A, B) H9c2 cardiomyocytes transfected with Egr1-promoter luciferase were treated with GR or metformin (20 mM). Luciferase activity was carried out 6 h post-treatment. (C) Body weight of mice undergoing control and metformin...
Data
Cellular respiration, MnSOD, and FOXO responsive genes are regulated in a PKA/EGR1-dependent manner. (A-C). Egr1+/+ and Egr1-/- MEFs were transfected with (A) FHRE-luc, (B) MnSOD-mt-luc, or (C) MnSOD-luc, and treated with H89. Luciferase activity was assessed 18 h after treatment. (D-F) The regulation of MnSOD and FOXO responsive genes in Egr1-depe...
Data
FMD induces the expression of Egr1 and antioxidant genes. (A-G) Heart tissues from ad lib (AL) and FMD-treated mice were collected and protein and mRNA levels for the indicated genes were assessed by (A) Western blotting and (B-G) qRT-PCR, respectively. P-value <0.05 were considered significant (p-value<0.05, 0.01 and 0.001 are indicated as *, *, a...
Data
siRNA-mediated knock-down of (A) EGR1 and (B) AMPKα2 and AMPKα1/2 in H9c2 cells following glucose restriction. (TIF)
Data
Underlying data and method of statistical analysis. (XLSX)
Chapter
Aging represents the major risk factor for cancer. Cancer and aging are characterized by a similar dysregulated metabolism consisting in upregulation of glycolysis and downmodulation of oxidative phosphorylation. In this respect, metabolic interventions can be viewed as promising strategies to promote longevity and to prevent or delay age-related d...
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Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application. We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-...
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Reduced caloric intake including fasting, as well as the dietary composition or the timing of food intake impact longevity, likely through a modification in the onset or the severity of chronic aging-related diseases such as cancer. As with pre- and post-operative dietary recommendations, evidence-based nutritional advice from healthcare profession...
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Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing...
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GRP78, a multifunctional protein with potent cytoprotective properties, is an emerging therapeutic target to combat cancer development, progression and drug resistance. The biological consequences of prolonged reduction in expression of this essential chaperone which so far has been studied primarily in young mice, was investigated in older mice, a...
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Complex and coordinated signals are necessary to initiate and sustain the activation, proliferation, and differentiation of lymphocytes. These signals, which are known to determine T-cell fate and function, also depend on the metabolic state of the organism. Recent studies indicate that both the type and levels of nutrients can influence the genera...
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Significance statement: People and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans it is unknown whether cognitive function and brain structure are affected by GHRD. Using magnetic resonance imaging, we examined cognition in an Ecuado...
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It is necessary to employ myeloablative irradiation or chemotherapy to deplete the HSC niche to optimize hematopoietic stem cell transplantation. In a recent issue of Science , Taya and colleagues provide evidence for an alternative to the toxic chemoirradiative procedure by showing that a valine-restricted diet is sufficient to empty the bone marr...
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Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacologic approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutri...
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Humans in modern societies typically consume food at least three times daily, while laboratory animals are fed ad libitum. Overconsumption of food with such eating patterns often leads to metabolic morbidities (insulin resistance, excessive accumulation of visceral fat, etc.), particularly when associated with a sedentary lifestyle. Because animals...
Chapter
Cancer is the second leading cause of death in the USA and among the leading major diseases in the world. It is anticipated to continue to increase because of the growth of the aging population and prevalence of risk factors such as obesity, smoking, and/or poor dietary habits. Cancer treatment has remained relatively similar during the past 30 yea...
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Importance: Defining what represents a macronutritionally balanced diet remains an open question and a high priority in nutrition research. Although the amount of protein may have specific effects, from a broader dietary perspective, the choice of protein sources will inevitably influence other components of diet and may be a critical determinant...
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Dietary intake and composition can have profound effects on aging and age-related pathologies including cancer. As such, studies of fasting (the complete withdrawal of food) and dietary restriction (DR, generally described as a 20- 40% reduction in calories) have contributed to the understanding of the relationship between nutrients, cellular aging...
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Cancer immunotherapy is a promising intervention for the targeted killing of tumor cells. However, tumor-localized immunosuppression induced by cancer cells (immunoresistance) often leads to limited T cell-mediated cytotoxicity. Moreover, chemotherapy- and radiotherapy-induced immunosuppression can further reduce the efficacy of immune-based treatm...
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Background Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients. Methods3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and rec...
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Most animals alternate periods of feeding with periods of fasting often coinciding with sleep. Upon >24 hr of fasting, humans, rodents, and other mammals enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources. Both intermittent and periodic fasting result in benefits ranging from the prevention to...
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Recent studies indicate that dietary interventions have the potential to prevent and even treat cardiovascular disease, which is the leading cause of death. Many of these studies have focused on various animal models that are able to recreate one or more conditions or elevate risk factors that characterize the disease. Here, we highlight macronutri...
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Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely...
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Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates. However, caloric restriction, which in most cases entails a 20-40% reduction of food consumption relative to...