Centenarians as a model for healthy aging

Abstract

For over 10 years we have studied centenarians as a model to address the biological basis of aging and longevity, with particular attention to immunology and genetics. The most important findings can be summarized as follows. (i) Human immunosenescence represents a complex remodelling, whereby clonotypical immunity deteriorates, while ancestral, innate immunity is largely preserved. (ii) Continuous exposure to antigens causes a lifelong, chronic antigenic stress, which is responsible, together with the involution of the thymus, for the accumulation of memory/effector T cells and the exhaustion of naïve T cells. (iii) Aging is characterized by a peculiar chronic inflammatory status that we propose to call 'inflammaging', which appears to be under genetic control, is detrimental for longevity and is more evident in men than in women. Inflammaging, i.e. the up-regulation of a variety of anti-stress responses at the cellular and molecular level, is the consequence of the ability of the body to adapt to and counteract the effects of a variety of stressors, which causes the accumulation of molecular and cellular scars. Inflammaging is considered the common and most important driving force of age-related pathologies, such as neurodegeneration, atherosclerosis, diabetes and sarcopenia, among others, all of which share an inflammatory pathogenesis. (iv) Possible strategies to counteract the major effects of immunosenescence and inflammaging, such as the systematic reduction of the lifelong antigenic load, the elimination of chronic infections, thymic rejuvenation and preventative treatment with anti-inflammatory drugs in people with a pro-inflammatory genotype, are envisaged.

Systematic expression profiling of innate immune genes defines a complex pattern of immunosenescence in peripheral and intestinal leukocytes

“…7,8 As both parameters represent critical cellular responses to TLR and NLR activation, we further assessed these signaling events in our samples. Indeed, we could confirm the results of the previous study in aged lymphocytes 37 and could extend this finding to the intestinal mucosa.…”

“…7 Proinflammatory cytokines (for example, interleukin (IL)-6 and IFN-g) appear to be involved in the development of most age-related conditions like type 2 diabetes, cardiovascular diseases or osteoporosis, while anti-inflammatory cytokines (for example, IL-10) have been shown to promote successful healthy aging. 8 These findings suggest a modulating role of the inflammatory state in the aging process and, ultimately, in life expectancy. 9 The aim of the present study was to characterize in detail at the transcriptome-level the age-related alterations of the innate immune gene repertoire in a large collection of tissue samples obtained from 153 individuals who span an extraordinarily broad age range from 16 to 99 years.…”

The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death

“…33 Namely, 28 healthy young people (aged 3073 years), 20 healthy aged people (aged 6971 years) selected from a group of actively exercising aged people, in a good physical performance status, 22 healthy centenarians, categorised 'A' for their healthy status, as previously described. 21,22 All the subjects were devoid of any clinical or biochemical abnormalities at the moment of blood collection or skin biopsy. As the p53 codon 72 proline/proline genotype is quite rare in the Italian population (about 8-10%), 33 and that the proline allele is likely to exert a dominant effect on the arginine one (Wu et al, 39 Biros et al 40 and preliminary data, data not shown), two groups of subjects were considered for this study: Pro þ (proline/proline and proline/arginine genotypes) and Arg þ (arginine/arginine genotype) subjects.…”

“…Consequently, data obtained from their cells offer the possibility to study the mechanisms of physiological (successful) in vivo ageing, disentangling these latter from those of age-related diseases. [21][22] 2-Deoxy-D-Ribose (dRib) was chosen as an oxidative stress-inducing agent. 23,24 This molecule belongs to a group of reducing sugars that trigger apoptosis, generating an increase in the levels of intracellular peroxide and carbonil radicals, as well as a decrease in intracellular GSH, all phenomena that can be abrogated by NAcetyl-Cysteine.…”

An immune origin of type 2 diabetes?

“…Cross-sectional and prospective studies in the general population, the elderly, and centenarians have shown that mildly elevated levels of CRP and proinflammatory cytokines are associated with, or predict, atherosclerosis, myocardial infarction, stroke, depression and Alzheimer's disease, and that longevity is associated with decreased systemic inflammation [105,[167][168][169][170][171]. Here, again, polymorphisms in immune genes modulate risk, implying a pathogenetic significance for immune gene products Table 4 Interventions that have an impact on the inflammatory state Inflammatory mediators whose concentrations are reduced by weight loss and/or physical exercise [190][191][192][193][194][195][196][197][198][199][200][201][202][203][204][205][206][207] CRP, TNF-α, soluble TNF-α receptor 2, IL-6, IL-18, MCP-1, PAI-1, t-PA, soluble ICAM-1, soluble VCAM-1, P-selectin Inflammatory mediators whose concentrations are reduced by glucose-lowering drugs [186,188,[208][209][210][211][212][213][214][215][216][217] Sulphonylurea: TNF-α Metformin: CRP Glitazones: CRP, SAA, TNF-α, soluble CD40 ligand, PAI-1 Insulin: CRP, IL-1, IL-6, TNF-α, soluble ICAM-1, MCP-1, PAI-1 SAA Serum amyloid A, t-PA tissue plasminogen activator, VCAM-1 vascular cell adhesion molecule-1 [171][172]…”