UVA Health researchers, led by Bimal N. Desai, found that mitochondria in immune cells lose their ability to take up and use calcium, leading to chronic inflammation responsible for many of the age-related ailments.

Contributed photo. Desai said the discovery provides potential treatment strategies to head off inflammatory cascades that lie at the heart of many cardiometabolic and neurodegenerative diseases. Macrophages are white blood cells that play critical roles in the immune system and good health.

They swallow up dead or dying cells, allowing the removal of cellular debris, and they patrol for pathogens and other foreign invaders. In this latter role, they act as important sentries for the immune system, calling for help from other immune cells as needed.

Scientists have known that macrophages become less effective with age, but it has been unclear why. These changes, the scientists believe, make the macrophages prone to chronic, low-grade inflammation at the best of times.

And when the immune cells are confronted by an invader or tissue damage, they can become hyperactive. Further, the UVA Health scientists suspect that the mechanism they have discovered will hold true not just for macrophages, but for many other related immune cells generated in the bone marrow.

That means we may be able to stimulate the proper functioning of those cells as well, potentially giving our immune systems a big boost in old age, when we become more susceptible to disease. The researchers have published their findings in the scientific journal Nature Aging.

The article is open-access, meaning it is free to read. In most cases, data have accrued from cross-sectional rather than longitudinal studies, but here we will follow the majority of reports and refer to changes rather than differences, although it mostly remains an assumption that the differences measured do indeed represent changes with age, at least most of the time.

Changes in the adaptive branch of the immune system occurring with age have been the most intensively studied, and then mostly in mice and humans. Here, we focus on the latter. The most frequently described phenotypic differences between elderly and young individuals are: i the decrease in the naïve T cell populations, ii the increase in memory subpopulations principally in potentially terminally-differentiated T cells [ 2 ] which downregulate membrane expression of the CD28 receptor [ 12 ], likewise those which re-express the CD45RA marker [ 13 ].

These are mostly adaptive changes rather than necessarily maladaptive, even the decrease of naïve T cells with age, which is mostly a consequence of developmentally pre-programmed thymic involution and its direct impact on thymic function reduction [ 14 ].

The maintenance of a highly diverse and functional naïve T cell pool depends on the continuous replacement of peripheral naïve T cells. This may result in a decreased capability to combat new pathogens as well as a decreased ability to mount vigorous recall responses for previously encountered pathogens, although robust data in support of this contention are limited in humans.

Additionally, the complex changes in acquired immunity are probably the result of epigenetic and metabolic modifications affecting immune cells.

In younger people, the hematopoietic stem cells HSCs provide a balanced output of myeloid and lymphoid progenitor cells.

An age-related shift from lymphoid to myeloid progenitors has been reported, suggesting the preferential differentiation of aged HSCs into common myeloid progenitor cells with the concomitant reduction in common lymphoid progenitor cell frequencies.

This is followed by a reduction in T and B cell production with aging [ 16 ]. However, the reasons for this skewing of immune cell output from the bone marrow remain unclear. There is much evidence indicating that chronic antigenic stimulation induced by the presence of persistent infections or by altered tissues and molecules, plays a major role in driving the peripheral T cell compartment into a state that is different in older individuals, possibly at least partially representing a state of exhaustion.

As occurs with other herpesviruses, CMV establishes latency in the host and reactivates periodically especially under immunosuppressive conditions such as stress. There has been a dearth of studies on populations other than those of the industrialized West, but comparative studies of other populations are beginning to emerge now, for example of Chinese [ 19 ] and Pakistanis [ 20 ].

Meanwhile, the naïve T cell compartment decreases Saavedra D et al. The Cuban population could be a particularly interesting cohort to study relationships between immunosenescence, inflammaging and chronic age-related diseases, due to the high antigenic load typical of a developing country in the tropical belt but coincident with low infant mortality, high life expectancy and an aged demographic pyramid, as a consequence of social interventions [ 22 ].

Although most of the literature on immunosenescence has focused on T cell changes, the B cell compartment is also different in older adults [ 23 ]. It is now clear that changes in B cells occur and have a significant impact on antibody production. The number of circulating B cells is reduced in the aged.

Advanced age is also accompanied by specificity repertoire changes, modified peripheral B cell dynamics, and weakened humoral responses [ 24 ]. Notably, the human obese adipose tissue AT , which increases in size with aging, contributes to systemic and B cell intrinsic inflammation reduced protective and increased pathogenic B cell responses leading to increased secretion of autoantibodies [ 25 ].

Two relevant issues in the current debate around the reinterpretation of immunosenescence are findings that the healthy elderly are able to sustain an adequate vaccine response compared with young subjects, and the increasing number of centenarians and semi-supercentenarians worldwide, mainly in the so-called blue zones [ 10 ].

As alluded to above, the most often cited vaccine failure in older adults is seasonal influenza, but while it is usually the case that the efficiency of this vaccine is lower in older than younger adults, this is not always true.

The reasons for the differential responses are manifold. Frailty limits the ability of standard inactivated influenza vaccines to prevent hospitalization [ 26 ] and this is possibly due to a decline in T-cell responses, because antibody responses are relatively unaffected.

In fact, surviving a prior influenza infection can restore influenza-specific T-cell responses on subsequent challenge by influenza vaccination. This suggests that poor immune stimulation reflects a limitation of current influenza vaccines rather than a limitation of the aging immune system [ 27 ].

Therefore, we need better vaccines, and there are many possibilities being investigated currently. A very recent vaccination success story is the unexpected efficacy of the COVID vaccine in older adults [ 28 ]. Future vaccines should include changes in composition, adding of adjuvants, changes in doses, more mechanistic interventions such as the use of IL-7, among others.

The challenge remains to identify the extrinsic vaccine type and intrinsic frailty factors predicting poor responsiveness at the individual level, in order to offer personalized protection not only against infectious disease but also possibly against cancer [ 29 ].

Centenarians are considered a model of successful aging because they succeed in preventing or delaying the onset of age-related diseases way beyond the average life expectancy.

Centenarians may not actually avoid diseases but they are better able to resist their deleterious effects. The immune response of centenarians maintains an adequate functionality; it seems that they are able to control inflammaging [ 10 ]. A study in Cuban centenarians found that they had a good health status and were mainly only moderately dependent on others for their activities of daily living.

This is a prime example of resistance to biological indicators that are detrimental to most of the population that does not reach such an advanced age. Data on Sicilian semi-super- and super-centenarians that show a slowdown in naïve T decline suggest that their maintenance of relatively healthy aging is linked to this slowdown, reinforcing the idea of the key role of this decline in the immunosenescence process [ 32 ].

Aging is by definition the single most important risk factor for all major age-related diseases and geriatric syndromes.

However, the aging process is very different for each individual, which means that aging is far from uniform in every human being. As noted above, the term inflammaging indicates the low-grade chronic inflammatory status characteristic of the older individual.

It was described for the first time as an explanation for the global reduction in efficient responses to new, as well as previously encountered antigens, concomitant with progressive increase in proinflammatory markers commonly seen in older individuals [ 33 ]. During the past decade, enough evidence has been collected indicating that different age-related diseases, such as atherosclerosis, cardiovascular diseases, type 2 diabetes, metabolic syndrome, osteoporosis, cognitive decline, neurodegenerative diseases and frailty have at least partially a common inflammatory pathogenesis [ 34 , 35 ].

It has been stated that inflammaging and immunosenescence are two sides of the same coin. This means that there is a mutual interaction between the inflammaging-producing factors inducing immunosenescence and the immunosenescence-producing factors which contribute to the maintenance of the inflammaging [ 5 ].

The low-grade chronic inflammatory process described in older adults is characterized by increases in the levels of pro-inflammatory cytokines, such as IL This pleiotropic cytokine has been associated with atherosclerosis, osteoporosis and sarcopenia, leading to functional decline, the development of disabilities and all-cause mortality [ 17 ].

Not only cytokines but also acute phase proteins, such as CRP and mannose-binding lectin, are markers of inflammaging [ 24 ]. Twenty years have now passed since the original introduction of the concept of inflammaging by Claudio Franceschi. During these years, it has been hypothesized that the inflammaging process is not developing exclusively from the cells of the innate or adaptive immune system.

Inflammaging is also driven by i cell senescence SASP ; ii the imbalance of microbiome composition, in various parts of the organism, especially in the gut; iii the innate immune memory of trained innate immunity; and iv metabolic epigenetic changes induced by the mitochondria [ 3 , 6 , 36 ].

An imbalance between commensal microbes and invasive microbes may occur at advanced age. Such invasive microbes may induce the production of proinflammatory mediators and enhance inflammation [ 6 , 37 ]. The trained innate immunity concept proposes that because of epigenetic and metabolic changes, the innate immune system is in a state of chronic activation.

This might be beneficial for the next response, that could be more efficient than the previous one. However, trained immunity could also be counterproductive and result in a paralyzed state, when crossing a threshold of no-return [ 6 , 38 ].

The metabolic changes manifested by the mitochondria during aging may also contribute to inflammaging. Mitochondria may increase the production of free radicals and the release of damage components into the cytosol that could be detected by the pattern recognition receptors, leading to innate inflammatory response [ 6 , 39 , 40 ].

Moreover, an important contribution to inflammaging may also derive from senescent cells [ 6 , 34 ]. Cellular senescence is a cell fate characterized by irreversible cell-cycle arrest with secretory features, macromolecular damage, and altered metabolism. It is implicated in various physiological processes in addition to aging, and is associated with a wide spectrum of age-related diseases.

Despite the name, therefore, cellular senescence is not a synonym for aging and is not exclusive to advanced age or pathologic processes. A cell can initiate the senescence program regardless of organismal age. It is present from the moment of embryogenesis, contributing to tissue development, and later on, in adulthood, plays a role in tissue repair and tumor suppression [ 41 , 42 ].

Based on this duality of beneficial and detrimental effects, cellular senescence has been proposed to be an example of evolutionary antagonistic pleiotropy [ 43 ]. Senescence primarily associated with detrimental effects can be triggered by a number of stress signals to the cell, including DNA damage, telomere shortening or dysfunction, oncogene activation or loss of tumor suppressor functions, mitochondrial dysfunction, nutrient deprivation, hypoxia and epigenetic changes [ 44 ].

The main cause of senescent stress is DNA damage, which activates the DNA damage response DDR and the canonical p53—p21 pathway, and in consequence leads to cell-cycle arrest [ 42 , 45 ]. The overexpression of p21 Cip1 and p16 INK4A is characteristic of senescent cells but not exclusively of senescent cells , and is widely recognized nowadays as a cellular senescence marker, especially together with telomere dysfunction.

However, a single marker cannot be used to asses senescence. Instead, a comprehensive multi-marker approach including evaluation of other cellular senescence hallmarks is needed [ 41 ].

Other characteristic traits of senescent cells include increased SA-ßgal activity, larger morphology, altered nuclear structure, changes in heterochromatin and the high production of reactive oxygen species ROS due to impaired mitochondrial function, termed senescence-associated mitochondrial dysfunction SAMD [ 46 ].

SAMD is able to drive NF-kB activation in cell senescence, which induces the SASP. The SASP constitutes a hallmark of senescence and mediates many of its patho-physiological effects. Senescent cells secrete bioactive molecules, especially pro-inflammatory cytokines and chemokines contributing to systemic sterile chronic inflammation associated with age-related diseases, frailty and mortality in the elderly.

However, the SASP includes more than pro-inflammatory factors, since ROS, growth factors, matrix-remodelling factors, non-coding RNAs as well as other peptides and proteins can be part of the phenotype. Moreover, SASP composition and intensity varies depending on the pro-senescence stimulus, the duration of senescence, and cell type and microenvironment.

So, the senescent secretome is different under different biological conditions [ 41 ]. As emphasized in the meeting, there is a close association between chronic inflammation and cell senescence.

The SASP reinforces and spreads senescence in an autocrine and a paracrine manner [ 47 , 48 , 49 ]. This ability of senescent cells to induce a senescent phenotype in surrounding cells through the SASP has been termed bystander senescence.

Thus, a positive feedback loop is established, in which senescence causes chronic inflammation and inflammation causes senescence [ 49 ].

Senescent cells accumulate with age in multiple tissues and may cause functional decline. In the immune system, senescence affects both innate and adaptive immunity, in particular follicular helper T cell and natural killer cell function. In order to define the contribution of immune system aging to organism aging a mouse model with a selective deletion of a DNA damage repair protein in hematopoietic cells was generated to induce senescence in the immune system only.

Remarkably, non-lymphoid organs from these mice also exhibited increases in senescence markers, which suggests that a senescent immune system has a causal role in driving systemic aging [ 9 ].

Because aging is the most significant risk factor for many diseases and conditions, targeting the aging process itself could have a large impact on human health. However, an increased understanding of aging phenomena and mechanisms must be followed by interventions aiming to improve human health.

Different ways and means are being explored to improve immune function in older adults. These strategies include low-tech approaches such as programs of physical exercise and healthy nutrition. Many signs of immunosenescence could be exacerbated by decreased physical activity often seen in older adults.

Consistent with this, the age-associated decrease of naïve T cells could be partially prevented in older adults who maintained high levels of physical activity throughout adult life [ 50 ]. In this context, at BIOHABANA , several proposals were discussed, which could be considered as of two types: non-pharmacological and pharmacological.

Within the non-pharmacological interventions, several studies were presented showing the effects of consumption of polyphenols contained in cocoa and those related to dietary restriction without malnutrition. There are several lines of evidence about how the consumption of certain flavonoids in fruit, vegetables and cocoa can modulate important networks of genes in blood cells involved in functional processes and interactions with the vascular endothelium, such as response to oxidative stress, cell-cell adhesion, apoptotic and senescence processes, or cellular transport.

Here, also the gut microbiota is sure to play an important role too [ 55 , 56 , 57 , 58 , 59 ]. Dietary restriction without malnutrition is the gold standard for delaying aging and extending life and health in various species. A thought-provoking analysis of the effects of dietary restriction, intermittent fasting and exercise on the production of physiological, metabolic, and molecular changes shows that those factors are responsible for the prevention of multiple diseases associated with aging in humans.

In particular, moderate dietary restriction in humans ameliorates multiple metabolic and hormonal factors that are implicated in the pathogenesis of type 2 diabetes, cardiovascular diseases, and cancer, the leading causes of morbidity, disability and mortality [ 60 ].

A crucial point to consider is that experiments have demonstrated that genetic and epigenetic background determines the response to dietary interventions, including dietary restriction in mice.

It is therefore very important that these findings will be clinically translated using a personalized food-as-medicine approach to identify how each person can improve his or her health and lifespan. This implies the need to educate the population on the benefits of a healthy diet and the limitations of the scientific consensus [ 61 , 62 , 63 ].

From the discussion in the sections above, it is clear that immune function is impaired with aging, leading to more severe infections and increased mortality.

Several recent studies demonstrated that reducing the senescent cell burden and the inflammatory SASP by treatment with senolytic and senomorphic compounds improves the immune response and reduces mortality [ 64 , 65 , 66 , 67 ].

These observations have led to several clinical trials to test the effect of senolytics and senomorphics [ 68 ]. Interestingly, exposure to pathogens can increase the extent of senescence through both direct and indirect mechanisms, especially in older adults, driving further immune dysfunction, senescence and non-specific inflammation.

This increase in inflammation driven by the SASP then contributes to increased mortality and morbidity [ 69 , 70 ].

Importantly, these observations suggest that developing approaches to limit senescence in the adaptive and innate immune cells would not only improve the immune response, but might also slow aging [ 71 ].

Other drugs, such as metformin, may also modulate the hallmarks of aging by enhancing nutrient sensing, autophagy, intercellular communication and mitochondrial function, protecting against macromolecular damage, delaying stem cell aging and regulating transcription [ 72 , 73 ].

These characteristics make metformin an attractive senomorphic and gerotherapeutic for anti-aging clinical trials, such as the TAME Targeting Aging by MEtformin clinical trial [ 74 ].

Two natural products from Cuba were presented at the workshop. Policosanol exerts its action through the improvement of the anti-inflammatory effect on high-density lipoproteins. It is a mixture of eight aliphatic primary alcohols purified from sugar cane wax Saccharum officinarum L.

These primary alcohols range from 24 to 34 carbon atoms, with octacosanol, triacontanol, dotriacontanol, hexacosanol and tetratriacotanol as the main constituents.

Policosanol improves the beneficial functions of HDL to maximize its antioxidant, antiglycation, and antiatherosclerotic activities, as well as cholesterol ester transfer protein inhibition. These improvements in HDL functionality could exert anti-aging and rejuvenating activity [ 75 , 76 ]. The other agent, Biomodulina T BT is a polypeptide fraction obtained from the bovine thymus.

Intervention with BT contributes to restoration of the normal thymic environment by slowing the reduction of the number of naïve T cells that occurs naturally during the aging process and may improve the efficacy of immunotherapy in older adults susceptible to recurrent infections and cancer [ 79 ].

Healthy human lifespan has been rapidly extended during the XIX and XX centuries, historically to a large extent by decreasing early mortality. Any further expansion must occur in the post-reproductive life, where natural selection of adaptive genetic traits does not occur anymore, no biological mechanism can be expected to drive the process.

Success will come from interventions into human aging, both social and biological, that address primarily healthspan, not only lifespan. Progress towards interventions in human aging will be a complex task. Aging is multifactorial and therefore no single molecular measurement can be efficient to stratify the human population or to monitor the impact of interventions.

We will need multivariate analysis of data, multicomponent indexes, and cluster identification, in order to move beyond chronological age measurement and to build a useful biological clock for human life. In a recent breakthrough, biomarkers of ageing based on DNA methylation data have enabled accurate age estimates for any tissue across the entire life course.

Although it is already known for years that cumulative epigenetic changes occur upon aging, DNA methylation patterns were only recently used to construct an epigenetic clock predictor for biological age, which is a measure of how well your body functions compared to your chronological age. Today, this epigenetic DNA methylation clock signature is increasingly applied as a biomarker to estimate aging disease susceptibility and mortality risk.

Moreover, the epigenetic clock signature could be used as a lifestyle management tool to monitor healthy aging, to evaluate preventive interventions against chronic aging disorders and to extend healthy lifespan [ 62 ]. Dissecting the mechanism of the epigenetic aging clock will yield valuable insights into the aging process and how it can be manipulated to improve health span [ 82 , 83 ].

Clinical trial designs will be challenging as aging is not a disease, and several age-associated changes reflect successful adaptation and not malfunction, as illustrated by data in centenarians. This double stratification could help to tailor intervention strategies according to both biological and chronological age simultaneously.

Young people without inflammatory markers would not require specific interventions beyond general health counseling. Old people but without inflammatory markers deserve further observation and longitudinal follow up.

Persons that are young but express markers of inflammaging or immunosenescence could be the subjects for trials of non-pharmacological interventions nutrition, exercise, and life style , whereas old people showing markers of inflammaging or immunosenescence could be the eligible population for clinical trials of drugs.

To build and to validate a multivariate index, including measurements able to provide non-redundant predictive power for meaningful clinical events, to stratify the human population according to these clusters, to develop new products targeting not only specific molecular markers for specific age-related disease but also the underlying senescence processes, are the challenges to face before the next Workshop.

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell ; — Caruso C, Ligotti ME, Accardi G, Aiello A, Candore G.

Expert Rev Clin Immunol. Franceschi C, Salvioli S, Garagnani P, de Eguileor M, Monti D, Capri M. Immunobiography and the heterogeneity of Immune responses in the Elderly: a focus on inflammaging and trained immunity.

Front Immunol. Pawelec G, Bronikowski A, Cunnane SC, Ferrucci L, Franceschi C, Fulop T, Gaudreau P, Gladyshev VN, Gonos ES, Gorbunova V, Kennedy BK, Larbi A, Lemaitre JF, Liu GH, Maier AB, Morais JA, Nobrega OT, Moskalev A, Rikkert MO, Seluanov A, Senior AM, Ukraintseva S, Vanhaelen Q, Witkowski J, Cohen AA.

Mech Ageing Dev. Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C. Immunosenescence and Inflamm-Aging as two sides of the same Coin: friends or foes?

Frontiers in immunology. Sex, gender and immunosenescence: a key to understand the different lifespan between men and women? Immun Ageing.

Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. Article PubMed Google Scholar. Cellular senescence: when bad things happen to good cells.

Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging.

Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J, Persistent DNA. Damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. Kuilman T, Peeper DS.

Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer. Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M, Burstain I, Morgenstern Y, Brachya G, Billauer H, Biton S, Snir-Alkalay I, Vucic D, Schlereth K, Mernberger M, Stiewe T, Oren M, Alitalo K, Pikarsky E, Ben-Neriah YA.

Senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell. A DNA damage checkpoint response in telomere-initiated senescence.

Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy J. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21 CIP1 , but not p16 INK4a. Mol Cell. DiLeonardo A, Linke SP, Clarkin K, Wahl GMDNA. Damage triggers a prolonged pdependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts.

Genes Dev. Article CAS Google Scholar. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ. Peeper DS. BRAFEassociated senescence- like cell cycle arrest of human nevi.

Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Jacobs JJ, de Lange T. Significant role for p16 INK4a in pindependent telomere-directed senescence.

Curr Biol. Rodier F, Muñoz DP, Teachenor R, Chu V, Le O, Bhaumik D, Coppé JP, Campeau E, Beauséjour CM, Kim SH, Davalos AR, Campisi J. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion.

J Cell Sci. Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut P, Luo W, Chicas A, Lee CS, Kogan SC, Lowe SW. Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Salminen A, Kauppinen A, Kaarniranta K.

Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype SASP. Cell Signal.

Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. Chemokine signaling via the CXCR2 receptor reinforces senescence.

Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil JA.

Complex secretory program orchestrated by the inflammasome controls paracrine senescence. Campisi J. Senescent cells, tumor suppression and organismal aging: good citizens, bad neighbors.

Hubackova S, Krejcikova K, Bartek J, Hodny Z. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

Bavik C, Coleman I, Dean JP, Knudsen B, Plymate S, Nelson PS. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res. Coppe JP, Kauser K, Campisi J, Beausejour CM. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence.

J Biol Chem. Glycomic biomarkers of biological aging and longevity: a link with in ammaging. Feldman N, Rotter-Maskowitz A, Okun EDAMP. As mediators of sterile inflammation in aging- related pathologies.

Franceschi C, Campisi J. Chronic inflammation inflammaging and its potential contribution to age-associated diseases.

J Gerontol A Biol Sci Med Sci. O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. Sekirov I, Russell SL, Antunes LCM, Finlay BB.

Gut microbiota in health and disease. Physiol Rev. Noverr MC, Huffnagle GB. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. Gut microbiota and aging. Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O'Sullivan O, Fitzgerald GF, Deane J, O'Connor M, Harnedy N, O'Connor K, O'Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O'Toole PW.

Gut microbiota composition correlates with diet and health in the elderly. Ticinesi A, Milani C, Lauretani F, Nouvenne A, Mancabelli L, Lugli GA, Turroni F, Duranti S, Mangifesta M, Viappiani A, Ferrario C, Maggio M, Ventura M, Meschi T.

Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients. Sci Rep. Lovat LB. Age related changes in gut physiology and nutritional status. Li Y, Kundu P, Seow SW, de Matos CT, Aronsson L, Chin KC, Karre K, Pettersson S, Greicius G.

Banna GL, Torino F, Marletta F, Santagati M, Salemi R, Cannarozzo E, Falzone L, Ferraù F, Libra M. Lactobacillus rhamnosus GG: an overview to explore the rationale of its use in cancer.

Front Pharmacol. Przemska-Kosicka A, Childs CE, Enani S, Maidens C, Dong H, Dayel IB, Tuohy K, Todd S, Gosney MA, Yaqoob P. Effect of a synbiotic on the response to seasonal influenza vaccination is strongly influenced by degree of immunosenescence. Ahima RS. Connecting obesity, aging and diabetes.

Nat Med. Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Hotamisligil GS.

Inflammation and metabolic disorders. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity.

Annu Rev Immunol. Shivappa N, Steck SE, Hurley TG, Hussey JR, Hébert JR. Designing and developing a literature-derived, population-based dietary inflammatory index.

Public Health Nutr. Zitvogel L, Pietrocola F, Kroemer G. Nutrition, inflammation and cancer. Nat Immunol. Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C.

Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: the ATTICA study. J Am Coll Cardiol. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial.

Esmaillzadeh A, Kimiagar M, Mehrabi Y, Azadbakht L, FB H, Willett WC. Fruit and vegetable intakes, C-reactive protein, and the metabolic syndrome. Am J Clin Nutr. CAS PubMed Google Scholar. Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, Martin A, Andres-Lacueva C, Senin U, Guralnik JM.

Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab. Carruba G, Cocciadiferro L, Di Cristina A, Granata OM, Dolcemascolo C, Campisi I, Zarcone M, Cinquegrani M, Traina A. Nutrition, aging and cancer: lessons from dietary intervention studies.

Shivappa N, Hébert JR, Taborelli M, Montella M, Libra M, Zucchetto A, Crispo A, Grimaldi M, La Vecchia C, Serraino D, Polesel J. Dietary inflammatory index and non-Hodgkin lymphoma risk in an Italian case-control study. Cancer Causes Control. Shivappa N, Hébert JR, Rosato V, Rossi M, Libra M, Montella M, Serraino D, La Vecchia C.

Dietary inflammatory index and risk of bladder cancer in a large Italian case-control study. Shivappa N, Hébert JR, Zucchetto A, Montella M, Libra M, Garavello W, Rossi M, La Vecchia C, Serraino D. Increased risk of nasopharyngeal carcinoma with increasing levels of diet-associated inflammation in an Italian case-control study.

Nutr Cancer. Harmon BE, Wirth MD, Boushey CJ, Wilkens LR, Draluck E, Shivappa N, Steck SE, Hofseth L, Haiman CA, Le Marchand L, Hébert JR. The dietary inflammatory index is associated with colorectal cancer risk in the multiethnic cohort. J Nutr. Hodge AM, Bassett JK, Shivappa N, Hébert JR, English DR, Giles GG, Severi G.

Dietary in ammatory index, Mediterranean diet score, and lung cancer: a prospective study. Shivappa N, Blair CK, Prizment AE, Jacobs DR, Hebert JR. Prospective study of the dietary in ammatory index and risk of breast cancer in postmenopausal women.

Mol Nutr Food Res. Sjöström L, Gummesson A, Sjöström CD, Narbro K, Peltonen M, Wedel H, Bengtsson C, Bouchard C, Carlsson B, Dahlgren S, Jacobson P, Karason K, Karlsson J, Larsson B, Lindroos AK, Lönroth H, Näslund I, Olbers T, Stenlöf K, Torgerson J, Carlsson LM.

Swedish obese subjects study. Effects of bariatric surgery on cancer incidence in obese patients in Sweden Swedish obese subjects study : a prospective, controlled intervention trial. Lancet Oncol.

Aiello A, Accardi G, Candore G, Gambino CM, Mirisola M, Taormina G, Virruso C, Caruso C. Nutrient sensing pathways as therapeutic targets for healthy ageing.

Expert Opin Ther Targets. Davinelli S, Willcox DC, Scapagnini G. Extending healthy ageing: nutrient sensitive pathway and centenarian population.

Scapagnini G, Davinelli S, Kaneko T, Koverech G, Koverech A, Calabrese EJ, Calabrese V. Dose response biology of resveratrol in obesity.

J Cell Commun Signal. Davinelli S, Maes M, Corbi G, Zarrelli A, Willcox DC, Scapagnini G. Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges.

Pandima DK, Rajavel T, Daglia M, Nabavi SF, Bishayee A, Nabavi SM. Targeting miRNAs by polyphenols: novel therapeutic strategy for cancer. Semin Cancer Biol. Low glycemic index diet, exercise and vitamin D to reduce breast cancer recurrence DEDiCa : design of a clinical trial.

BMC Cancer. Park K, Kim KB. miRTar hunter: a prediction system for identifying human microRNA target sites. Molecules and Cells.