Biogerontology

A Biojector device fitted with a CO2 cartridge was used to prepare single cellsuspensions from kidneys of 12-month-(middle-aged) and 24-month-old (old) C57Bl/6mice. Microgel electrophoresis of DNA fromthese cells revealed a modest but significant7.3% increase (P = 0.04) in DNA double-strand breaks in old mice. This increase is equivalent to the DNA damage induced by 0.1 Gray of X-rays (5 double-strand breaks) in kidney cells of 10-month-old mice, as determined by a standard calibration curve. Greater DNA damage with aging was also positively correlated with higher levels of pathology in the kidneys.

Thrombotic risk increases in elderly, therefore, the understanding of the genetic predisposition of hypercoagulability could make the difference in the prevention of venous and/or arterial thrombotic events. Laboratory evaluation of hyperfibrinogenemia, increased Factor VII levels, antiphospholipid antibodies presence and hyperhomocysteinemia are considered to have a consistent high predictivity for arterial thrombophilic diseases. Anyway, a large debate exists on the validity of testing Leiden Factor V (FV) G1691A and/or prothrombin (FII) G20210A polymorphisms in patients affected by arterial thrombotic diseases, despite of the several observations described. Here we report data strongly suggesting that at least the FII G20210A polymorphism might be considered an important risk factor for acute myocardial infarction in aged patients (55–80 years old). On the other hand, in spite of a not different genotypic and allelic distribution for the Leiden FV G1691A mutation, the presence of one or both the two polymorphisms is significantly higher among cases than in controls. In conclusion, our data suggest that FII G20210A and/or Leiden FV might be involved as risk factor for arterial disorders in about 5% of old subjects, justifying the opportunity of a genetic screening and an eventual preventive treatment, in particular in old subjects in which other and major risk factors, as hypertension and atherosclerosis, are detected.

Extended longevity mutants are extremelyuseful to understand the molecular mechanism oflongevity determination. Here we reportidentification and characterization of the Drosophila Plenty of SH3s (DPOSH) gene,a candidate that might be associated with theextended longevity phenotype. DPOSHencodes a protein containing a RING fingerdomain and four SH3 domains. We showed thatneural-specific overexpression of DPOSHcould extend the mean longevity of adult fliesby 14% at 25 °C without affectingviability or morphology. In contrast, forcedexpression of DPOSH in developingimaginal discs produced various phenotypesincluding lethality and morphological defectssuch as loss of crossvein, notched wing, anddisordered hair polarity. Puckered, atarget gene of JNK/SAPK pathway, was activatedby overexpression of DPOSH and the forcedexpression phenotypes were suppressed byintroducing a mutation of Drosophila JNK(bsk) or JNKK (hep),suggesting that the JNK/SAPK signaling pathwayis one of the critical elements in thedetermination of longevity.

Process point of view (POV) models of mortality, such as the Strehler–Mildvan and stochastic vitality models, represent death in terms of the loss of survival capacity through challenges and dissipation. Drawing on hallmarks of aging, we link these concepts to candidate biological mechanisms through a framework that defines death as challenges to vitality where distal factors defined the age-evolution of vitality and proximal factors define the probability distribution of challenges. To illustrate the process POV, we hypothesize that the immune system is a mortality nexus, characterized by two vitality streams: increasing vitality representing immune system development and immunosenescence representing vitality dissipation. Proximal challenges define three mortality partitions: juvenile and adult extrinsic mortalities and intrinsic adult mortality. Model parameters, generated from Swedish mortality data (1751–2010), exhibit biologically meaningful correspondences to economic, health and cause-of-death patterns. The model characterizes the twentieth century epidemiological transition mainly as a reduction in extrinsic mortality resulting from a shift from high magnitude disease challenges on individuals at all vitality levels to low magnitude stress challenges on low vitality individuals. Of secondary importance, intrinsic mortality was described by a gradual reduction in the rate of loss of vitality presumably resulting from reduction in the rate of immunosenescence. Extensions and limitations of a distal/proximal framework for characterizing more explicit causes of death, e.g. the young adult mortality hump or cancer in old age are discussed.

Senescence can impair the therapeutic potential of stem cells. In this study, senescence-associated morphofunctional changes in periosteum-derived progenitor cells (PDPCs) from old and young individuals were investigated by combining cytofluorimetry, immunohistochemistry, and transmission electron microscopy. Cell cycle analysis demonstrated a large number of G0/G1 phase cells in PDPCs from old subjects and a progressive accumulation of G0/G1 cells during passaging in cultures from young subjects. Cytofluorimetry documented significant changes in light scattering parameters and closely correlated with the ultrastructural features, especially changes in mitochondrial shape and autophagy, which are consistent with the mitochondrial-lysosomal axis theory of ageing. The combined morphological, biofunctional, and ultrastructural approach enhanced the flow cytometric study of PDPC ageing. We speculate that impaired autophagy, documented in replicative senescent and old PDPCs, reflect a switch from quiescence to senescence. Its demonstration in a tissue with limited turnover—like the cambium layer of the periosteum, where reversible quiescence is the normal stem cell state throughout life—adds a new piece to the regenerative medicine jigsaw in an ageing society.

Ageing, a complex process that results in progressive decline in intrinsic physiological function leading to an increase in mortality rate, has been shown to be affected by early life nutrition. Accumulating data from animal and epidemiological studies indicate that exposure to a suboptimal nutritional environment during fetal life can have long-term effects on adult health. In this paper, we discuss the impact of early life nutrition on the development of age-associated diseases and life span. Special emphasis is given to studies that have investigated the molecular mechanisms underlying these effects. These include permanent structural and cellular changes including epigenetics modifications, oxidative stress, DNA damage and telomere shortening. Potential strategies targeting these mechanisms, in order to prevent or alleviate the detrimental effects of suboptimal early nutrition on lifespan and age-related diseases, are also discussed. Although recent reports have already identified effective therapeutic interventions, such as antioxidant supplementation, further understanding of the extent and nature of how early nutrition influences the ageing process will enable the development of novel and more effective approaches to improve health and extend human lifespan in the future.