Peripheral blood lymphocyte subsets of two groups of patients affected by Down's syndrome (DS), i... more Peripheral blood lymphocyte subsets of two groups of patients affected by Down's syndrome (DS), ie, 28 children and nine adults of relatively advanced age (>34 years), were investigated and compared with those of age-and sexmatched healthy controls (13 children and 20 adults). Particular attention was devoted to cells with markers of natural killer (NK) activity. Double-and triple-color cytofluorimetric analysis was used to better characterize the phenotypic features of the different subsets. Apart from a reduced number of T lymphocytes (CD3+) in DS children and of B lymphocytes (CD19+) in both DS groups, the major alteration we found was a marked age-related increase of the OWN'S SYNDROME (DS) is the most frequent Phenotype Analysis and Flow Cytometry Cells labeled with monoclonal antibodies (MoAbs) for cytofluorimetric analysis were prepared from whole blood following standard methods."
We previously reported that exposure of human mitogen-stimulated peripheral blood lymphocytes (PB... more We previously reported that exposure of human mitogen-stimulated peripheral blood lymphocytes (PBl) to extremely low frequency pulsed electromagnetic fields (PEMFs) could restore the defective proliferative capability of PBl from aged subjects. The effects of exposure to PEMFs were studied in PBl from 25 patients with Down's syndrome (OS), a syndrome of premature aging characterized by precocious immune system derangement, including age-related defective PBl proliferative capability. PBl were stimulated with different doses of phytohemagglutinin, and cell proliferation was assessed by measuring the incorporation of tritiated thymidine. After PEMF-exposure, a significant increase in cell proliferation was observed in cells from OS children and young adults, but it was much more evident in PBl from relatively aged OS patients. The age-related effect of PEMFs on OS lymphocytes demonstrates that age must be considered a major variable when studies on OS are performed, and confirms that OS must be regarded as a syndrome of accelerated aging.
Annals of the New York Academy of Sciences, Nov 1, 1992
Mammalian aging is associated with a complex derangement of the immune system. In particular, an ... more Mammalian aging is associated with a complex derangement of the immune system. In particular, an impaired capability of T lymphocytes to proliferate when stimulated with a variety of mitogens has been reported. This defect was ascribed to a defective production and utilization of a lymphokirie that is crucial for T-cell proliferation, that is, interleukin-2 (IL-2). I
Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) a... more Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer's disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian' offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.
The expression of CD45RA and CD45R0 isoforms of the leukocyte common antigen - characteristic of ... more The expression of CD45RA and CD45R0 isoforms of the leukocyte common antigen - characteristic of virgin and memory T cells, respectively - has been studied by three colour cytofluorimetric analysis on CD4+ or CD8+ peripheral blood CD3+ cells from 131 healthy donors 0-106 years old. As expected, at birth 95-99% of the CD3+ lymphocytes expressed CD45RA isoform. A rapid increase of CD45R0+ cells was observed in the first 2-3 decades of life, this phenomenon being much more pronounced on CD4+ cells. Subsequently, the increase of the memory compartment was much less rapid. After the tenth decade of life a consistent reservoire of CD45RA+ among CD4+ cells was still present (about 20%). At this advanced age the percentage of virgin cells among CD8+ T lymphocytes was even higher (about 50%), and only slightly lower than that of young donors (about 55-60%). The significance of the age-related unbalance in the proportion of virgin and memory cells between CD4+ and CD8+ T lymphocytes is unknown. The presence of a great number of virgin T lymphocytes within the CD4+ and the CD8+ T cell subsets even in the peripheral blood of centenarians poses the problem of their origin (thymus? extrathymic sites?) and their functional role
Aging is a complex process which is accompanied with the decline and the reshaping of different f... more Aging is a complex process which is accompanied with the decline and the reshaping of different functions of the body. In particular the immune system is characterized, during ageing (immunosenescence) by a remodeling of innate immunity (well preserved, up-regulated) and clonotypical immunity (severely altered) and by the occurrence of a chronic inflammatory process (inflammaging) which are, at least in part, genetically controlled. In this scenario, it can be anticipated that a crucial role is played by age-related structural and functional alterations and modifications of proteasomes and immunoproteasomes, the last being a key component of antigen processing and MHC class I antigen presentation. A variety of experimental data are available, suggesting that proteasomes are affected by age, and that in centenarians they are relatively preserved. On the contrary, few data are available on immunoproteasomes, likely as a consequence of the poverty of suitable cellular models. Lymphoblastoid cell lines from EBV immortalized B cells from old donors is envisaged as a possible model for the study of immunoproteasomes in humans and their changes with age. Thus, basic questions such as those related to possible consequences, for immune responses in infectious diseases and cancer, of age-related alterations of antigen processing and presenting, change with age of self-antigen repertoire, and the genetic basis of immunoprotesome activity and its change with age, remain largely unanswered.
Centenarians are people who escaped from major common diseases, including cancer, and reached the... more Centenarians are people who escaped from major common diseases, including cancer, and reached the extreme limits of human lifespan. The analysis of demographic data indicates that cancer incidence and mortality show a levelling off around the age of 85-90 years, and suggests that oldest old people and centenarians are protected from cancer onset and progression. In this paper, we review data of recent literature on the distribution in centenarians of germ-line polymorphisms, which are supposed to affect the individual susceptibility to cancer (p53, HRAS1, BRCA1, glutathione transferases, cytochrome oxidases, steroid-5 alpha-reductase enzyme type II). Moreover, we add new data on two p53 polymorphisms in a total of 1086 people of different age, including 307 centenarians. In addition, we put forth the hypothesis that the remodelling of the immune system occurring with age is capable of creating a hostile environment for the growth of cancer cells in these exceptional individuals. We conclude that future studies on centenarians regarding the germ-line variability of genes involved in the control of the immune response, including apoptosis (ApoJ), are likely to be of fundamental importance in understanding the basic mechanisms for cancer, aging and their complex relationship.
The effects of the exposure of mitogen-stimulated human lymphocytes from aged subjects to low-fre... more The effects of the exposure of mitogen-stimulated human lymphocytes from aged subjects to low-frequency pulsed electromagnetic fields (PEMFs) were studied by measuring the production of interleukin-2 (IL-2) and the expression of IL-2 receptor. PEMF-exposed cultures that presented increased PH]thymidine incorporation showed lower amounts of IL-2 in their supernatants, but higher percentages of IL-2 receptor-positive cells and of T-activated lymphocytes. Taken together, these data suggest that PEMFs were able to modulate mitogen-induced lymphocyte proliferation by provoking an increase in utilization of IL-2, most likely acting on the expression of its receptor on the plasma membrane.
Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible... more Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated (r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be ...
Epigenetic clocks were initially developed to track chronological age, but accumulating evidence ... more Epigenetic clocks were initially developed to track chronological age, but accumulating evidence indicates that they can also predict biological age. They are usually based on the analysis of DNA methylation by genome-wide methods, but targeted approaches, based on the assessment of a small number of CpG sites, are advisable in several settings. In this study, we developed a targeted epigenetic clock purposely optimized for the measurement of biological age. The clock includes six genomic regions mapping in ELOVL2, NHLRC1, AIM2, EDARADD, SIRT7 and TFAP2E genes, selected from a re-analysis of existing microarray data, whose DNA methylation is measured by EpiTYPER assay. In healthy subjects (n = 278), epigenetic age calculated using the targeted clock was highly correlated with chronological age (Spearman correlation = 0.89). Most importantly, and in agreement with previous results from genome-wide clocks, epigenetic age was significantly higher and lower than expected in models of in...
Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the c... more Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-t...
Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribo... more Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribosomal genes (rDNA) are organized in repeated clusters on chromosomes 13, 14, 15, 21, and 22, trisomy of chromosome 21 confers an excess of rDNA copies to persons with Down syndrome (DS). Previous studies showed an alteration of ribosome biogenesis in children with DS, but the epigenetic regulation of rDNA genes has not been investigated in adults with DS so far. In this study, we used a targeted deep-sequencing approach to measure DNA methylation (DNAm) of rDNA units in whole blood from 69 adults with DS and 95 euploid controls. We further evaluated the expression of the precursor of ribosomal RNAs (RNA45S) in peripheral blood mononuclear cells (PBMCs) from the same subjects. We found that the rDNA promoter tends to be hypermethylated in DS concerning the control group. The analysis of epihaplotypes (the combination of methylated and unmethylated CpG sites along the same DNA molecule) sh...
Summary. At present, women show a higher life expectancy than men and this gender diff erence is ... more Summary. At present, women show a higher life expectancy than men and this gender diff erence is becoming a world-wide phenomenon indicating the central demographic role of gender in ageing and longevity. A combination of genetic, environmental, historical, anthropological, socio-economic and cultural aspects as well as the geographical origin is at the basis of the longer survival of women. Maternal transmission is determining in all the three pillars of human genetics of ageing and longevity (nuclear genetics, mitochondria genetics, and microbiome genetics). Moreover, mothers and grandmothers play a key role in the off spring and grandchildren care/survival by contributing to their wellbeing and transmitting traditional and hygienic habits able to modulate life-long health status and lifespan. Finally, women live longer than men but they show a worse quality of life in advanced age indicating that gender is probably the most signifi cant variable for the lifelong health status.
The study of longevity may help us understand how human beings can delay or survive the most freq... more The study of longevity may help us understand how human beings can delay or survive the most frequent age-related diseases and morbidities. In this scenario, the gut microbiome has been proposed as one of the variables to monitor and possibly support healthy aging. Indeed, the disruption of host-gut microbiome homeostasis has been associated with inflammation and intestinal permeability as well as a general decline in bone and cognitive health. Here, we performed a metagenomic assessment of fecal samples from semisupercentenarians, i.e., 105 to 109 years old, in comparison to young adults, the elderly, and centenarians, shedding light on the longest compositional and functional trajectory of the human gut microbiome with aging. In addition to providing a fine taxonomic resolution down to the species level, our study emphasizes the progressive age-related increase in degradation pathways of pervasive xenobiotics in Western societies, possibly as a result of a supportive process withi...
While many diseases of aging have been linked to the immunological system, immune metrics capable... more While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.
Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades... more Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular...
Background and Aim: A state of chronic, subclinical inflammation known as inflammaging is present... more Background and Aim: A state of chronic, subclinical inflammation known as inflammaging is present in elderly people and represents a risk factor for all age-related diseases. Dietary supplementation with ad hoc fortified foods seems an appealing strategy to counteract inflammaging. The purpose of this study was to test the efficacy of elderly-tailored fortified milk on inflammaging and different health parameters. Methods: A double-blind randomized cross-over study was performed on forty-eight volunteers aged 63–80 years. The fortified milk was enriched with ω-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA), vitamins (25-hydroxyvitamin D, E, C, B6, B9, B12), and trace elements (zinc, selenium). The two intervention periods lasted for 12 weeks, with a 16-week washout intermission. Results: Compared to placebo, the consumption of fortified milk increased the circulating levels of different micronutrients, including vitamins and the ω-3 index of er...
Peripheral blood lymphocyte subsets of two groups of patients affected by Down's syndrome (DS), i... more Peripheral blood lymphocyte subsets of two groups of patients affected by Down's syndrome (DS), ie, 28 children and nine adults of relatively advanced age (>34 years), were investigated and compared with those of age-and sexmatched healthy controls (13 children and 20 adults). Particular attention was devoted to cells with markers of natural killer (NK) activity. Double-and triple-color cytofluorimetric analysis was used to better characterize the phenotypic features of the different subsets. Apart from a reduced number of T lymphocytes (CD3+) in DS children and of B lymphocytes (CD19+) in both DS groups, the major alteration we found was a marked age-related increase of the OWN'S SYNDROME (DS) is the most frequent Phenotype Analysis and Flow Cytometry Cells labeled with monoclonal antibodies (MoAbs) for cytofluorimetric analysis were prepared from whole blood following standard methods."
We previously reported that exposure of human mitogen-stimulated peripheral blood lymphocytes (PB... more We previously reported that exposure of human mitogen-stimulated peripheral blood lymphocytes (PBl) to extremely low frequency pulsed electromagnetic fields (PEMFs) could restore the defective proliferative capability of PBl from aged subjects. The effects of exposure to PEMFs were studied in PBl from 25 patients with Down's syndrome (OS), a syndrome of premature aging characterized by precocious immune system derangement, including age-related defective PBl proliferative capability. PBl were stimulated with different doses of phytohemagglutinin, and cell proliferation was assessed by measuring the incorporation of tritiated thymidine. After PEMF-exposure, a significant increase in cell proliferation was observed in cells from OS children and young adults, but it was much more evident in PBl from relatively aged OS patients. The age-related effect of PEMFs on OS lymphocytes demonstrates that age must be considered a major variable when studies on OS are performed, and confirms that OS must be regarded as a syndrome of accelerated aging.
Annals of the New York Academy of Sciences, Nov 1, 1992
Mammalian aging is associated with a complex derangement of the immune system. In particular, an ... more Mammalian aging is associated with a complex derangement of the immune system. In particular, an impaired capability of T lymphocytes to proliferate when stimulated with a variety of mitogens has been reported. This defect was ascribed to a defective production and utilization of a lymphokirie that is crucial for T-cell proliferation, that is, interleukin-2 (IL-2). I
Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) a... more Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer's disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian' offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.
The expression of CD45RA and CD45R0 isoforms of the leukocyte common antigen - characteristic of ... more The expression of CD45RA and CD45R0 isoforms of the leukocyte common antigen - characteristic of virgin and memory T cells, respectively - has been studied by three colour cytofluorimetric analysis on CD4+ or CD8+ peripheral blood CD3+ cells from 131 healthy donors 0-106 years old. As expected, at birth 95-99% of the CD3+ lymphocytes expressed CD45RA isoform. A rapid increase of CD45R0+ cells was observed in the first 2-3 decades of life, this phenomenon being much more pronounced on CD4+ cells. Subsequently, the increase of the memory compartment was much less rapid. After the tenth decade of life a consistent reservoire of CD45RA+ among CD4+ cells was still present (about 20%). At this advanced age the percentage of virgin cells among CD8+ T lymphocytes was even higher (about 50%), and only slightly lower than that of young donors (about 55-60%). The significance of the age-related unbalance in the proportion of virgin and memory cells between CD4+ and CD8+ T lymphocytes is unknown. The presence of a great number of virgin T lymphocytes within the CD4+ and the CD8+ T cell subsets even in the peripheral blood of centenarians poses the problem of their origin (thymus? extrathymic sites?) and their functional role
Aging is a complex process which is accompanied with the decline and the reshaping of different f... more Aging is a complex process which is accompanied with the decline and the reshaping of different functions of the body. In particular the immune system is characterized, during ageing (immunosenescence) by a remodeling of innate immunity (well preserved, up-regulated) and clonotypical immunity (severely altered) and by the occurrence of a chronic inflammatory process (inflammaging) which are, at least in part, genetically controlled. In this scenario, it can be anticipated that a crucial role is played by age-related structural and functional alterations and modifications of proteasomes and immunoproteasomes, the last being a key component of antigen processing and MHC class I antigen presentation. A variety of experimental data are available, suggesting that proteasomes are affected by age, and that in centenarians they are relatively preserved. On the contrary, few data are available on immunoproteasomes, likely as a consequence of the poverty of suitable cellular models. Lymphoblastoid cell lines from EBV immortalized B cells from old donors is envisaged as a possible model for the study of immunoproteasomes in humans and their changes with age. Thus, basic questions such as those related to possible consequences, for immune responses in infectious diseases and cancer, of age-related alterations of antigen processing and presenting, change with age of self-antigen repertoire, and the genetic basis of immunoprotesome activity and its change with age, remain largely unanswered.
Centenarians are people who escaped from major common diseases, including cancer, and reached the... more Centenarians are people who escaped from major common diseases, including cancer, and reached the extreme limits of human lifespan. The analysis of demographic data indicates that cancer incidence and mortality show a levelling off around the age of 85-90 years, and suggests that oldest old people and centenarians are protected from cancer onset and progression. In this paper, we review data of recent literature on the distribution in centenarians of germ-line polymorphisms, which are supposed to affect the individual susceptibility to cancer (p53, HRAS1, BRCA1, glutathione transferases, cytochrome oxidases, steroid-5 alpha-reductase enzyme type II). Moreover, we add new data on two p53 polymorphisms in a total of 1086 people of different age, including 307 centenarians. In addition, we put forth the hypothesis that the remodelling of the immune system occurring with age is capable of creating a hostile environment for the growth of cancer cells in these exceptional individuals. We conclude that future studies on centenarians regarding the germ-line variability of genes involved in the control of the immune response, including apoptosis (ApoJ), are likely to be of fundamental importance in understanding the basic mechanisms for cancer, aging and their complex relationship.
The effects of the exposure of mitogen-stimulated human lymphocytes from aged subjects to low-fre... more The effects of the exposure of mitogen-stimulated human lymphocytes from aged subjects to low-frequency pulsed electromagnetic fields (PEMFs) were studied by measuring the production of interleukin-2 (IL-2) and the expression of IL-2 receptor. PEMF-exposed cultures that presented increased PH]thymidine incorporation showed lower amounts of IL-2 in their supernatants, but higher percentages of IL-2 receptor-positive cells and of T-activated lymphocytes. Taken together, these data suggest that PEMFs were able to modulate mitogen-induced lymphocyte proliferation by provoking an increase in utilization of IL-2, most likely acting on the expression of its receptor on the plasma membrane.
Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible... more Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated (r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be ...
Epigenetic clocks were initially developed to track chronological age, but accumulating evidence ... more Epigenetic clocks were initially developed to track chronological age, but accumulating evidence indicates that they can also predict biological age. They are usually based on the analysis of DNA methylation by genome-wide methods, but targeted approaches, based on the assessment of a small number of CpG sites, are advisable in several settings. In this study, we developed a targeted epigenetic clock purposely optimized for the measurement of biological age. The clock includes six genomic regions mapping in ELOVL2, NHLRC1, AIM2, EDARADD, SIRT7 and TFAP2E genes, selected from a re-analysis of existing microarray data, whose DNA methylation is measured by EpiTYPER assay. In healthy subjects (n = 278), epigenetic age calculated using the targeted clock was highly correlated with chronological age (Spearman correlation = 0.89). Most importantly, and in agreement with previous results from genome-wide clocks, epigenetic age was significantly higher and lower than expected in models of in...
Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the c... more Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-t...
Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribo... more Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribosomal genes (rDNA) are organized in repeated clusters on chromosomes 13, 14, 15, 21, and 22, trisomy of chromosome 21 confers an excess of rDNA copies to persons with Down syndrome (DS). Previous studies showed an alteration of ribosome biogenesis in children with DS, but the epigenetic regulation of rDNA genes has not been investigated in adults with DS so far. In this study, we used a targeted deep-sequencing approach to measure DNA methylation (DNAm) of rDNA units in whole blood from 69 adults with DS and 95 euploid controls. We further evaluated the expression of the precursor of ribosomal RNAs (RNA45S) in peripheral blood mononuclear cells (PBMCs) from the same subjects. We found that the rDNA promoter tends to be hypermethylated in DS concerning the control group. The analysis of epihaplotypes (the combination of methylated and unmethylated CpG sites along the same DNA molecule) sh...
Summary. At present, women show a higher life expectancy than men and this gender diff erence is ... more Summary. At present, women show a higher life expectancy than men and this gender diff erence is becoming a world-wide phenomenon indicating the central demographic role of gender in ageing and longevity. A combination of genetic, environmental, historical, anthropological, socio-economic and cultural aspects as well as the geographical origin is at the basis of the longer survival of women. Maternal transmission is determining in all the three pillars of human genetics of ageing and longevity (nuclear genetics, mitochondria genetics, and microbiome genetics). Moreover, mothers and grandmothers play a key role in the off spring and grandchildren care/survival by contributing to their wellbeing and transmitting traditional and hygienic habits able to modulate life-long health status and lifespan. Finally, women live longer than men but they show a worse quality of life in advanced age indicating that gender is probably the most signifi cant variable for the lifelong health status.
The study of longevity may help us understand how human beings can delay or survive the most freq... more The study of longevity may help us understand how human beings can delay or survive the most frequent age-related diseases and morbidities. In this scenario, the gut microbiome has been proposed as one of the variables to monitor and possibly support healthy aging. Indeed, the disruption of host-gut microbiome homeostasis has been associated with inflammation and intestinal permeability as well as a general decline in bone and cognitive health. Here, we performed a metagenomic assessment of fecal samples from semisupercentenarians, i.e., 105 to 109 years old, in comparison to young adults, the elderly, and centenarians, shedding light on the longest compositional and functional trajectory of the human gut microbiome with aging. In addition to providing a fine taxonomic resolution down to the species level, our study emphasizes the progressive age-related increase in degradation pathways of pervasive xenobiotics in Western societies, possibly as a result of a supportive process withi...
While many diseases of aging have been linked to the immunological system, immune metrics capable... more While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.
Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades... more Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular...
Background and Aim: A state of chronic, subclinical inflammation known as inflammaging is present... more Background and Aim: A state of chronic, subclinical inflammation known as inflammaging is present in elderly people and represents a risk factor for all age-related diseases. Dietary supplementation with ad hoc fortified foods seems an appealing strategy to counteract inflammaging. The purpose of this study was to test the efficacy of elderly-tailored fortified milk on inflammaging and different health parameters. Methods: A double-blind randomized cross-over study was performed on forty-eight volunteers aged 63–80 years. The fortified milk was enriched with ω-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA), vitamins (25-hydroxyvitamin D, E, C, B6, B9, B12), and trace elements (zinc, selenium). The two intervention periods lasted for 12 weeks, with a 16-week washout intermission. Results: Compared to placebo, the consumption of fortified milk increased the circulating levels of different micronutrients, including vitamins and the ω-3 index of er...
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Papers by Daniela Monti