Risk Of Age-associated Diseases Research Articles

Biomarkers of aging in frailty and age-associated disorders: state of the art and future perspective.

According to the Geroscience concept that organismal aging and age-associated diseases share the same basic molecular mechanisms, the identification of biomarkers of age that can efficiently classify people as biologically older (or younger) than their chronological (i.e. calendar) age is becoming of paramount importance. These people will be in fact at higher (or lower) risk for many different age-associated diseases, including cardiovascular diseases, neurodegeneration, cancer, etc. In turn, patients suffering from these diseases are biologically older than healthy age-matched individuals. Many biomarkers that correlate with age have been described so far. The aim of the present review is to discuss the usefulness of some of these biomarkers (especially soluble, circulating ones) in order to identify frail patients, possibly before the appearance of clinical symptoms, as well as patients at risk for age-associated diseases. An overview of selected biomarkers will be discussed in this regard, in particular we will focus on biomarkers related to metabolic stress response, inflammation, and cell death (in particular in neurodegeneration), all phenomena connected to inflammaging (chronic, low-grade, age-associated inflammation). In the second part of the review, next-generation markers such as extracellular vesicles and their cargos, epigenetic markers and gut microbiota composition, will be discussed. Since recent progresses in omics techniques have allowed an exponential increase in the production of laboratory data also in the field of biomarkers of age, making it difficult to extract biological meaning from the huge mass of available data, Artificial Intelligence (AI) approaches will be discussed as an increasingly important strategy for extracting knowledge from raw data and providing practitioners with actionable information to treat patients.

Abstract LB-066: Proteomic-based senescent biomarker identification and characterization in non-small cell lung cancer

Abstract There is widespread interest in the relationship between aging and cancer, and the involvement of senescence in both processes. The accumulation of senescent cells imparts elevated risk of age-associated disease, including cancer; however, a continuing challenge in the field is the lack of senescence-specific biomarkers. Chemotherapy and radiotherapy are potent inducers of senescence, and the pro-inflammatory secretion of persistent senescent cells has been shown to propel tumor evolution and metastatic dissemination. Thus, there is a need to define how much senescence can be tolerated in tissue prior to physiologic dysfunction; however defining senescence ‘burden’ in aged tissue or cancer cannot be accurately determined with existing markers due to their redundancy. To address this shortcoming, we undertook a proteomic-based analysis to identify novel senescent biomarkers in K-Ras mutant non-small cell lung cancer (NSCLC). Importantly, quiescent cells were also included in the experimental design to enable the identification of proteins associated with general dormancy and not specific to senescence. Cell surface proteins from senescent, quiescent and asynchronous cancer cells were labeled with biotin, enriched and analyzed using tandem mass spectrometry. An average of 850 proteins were detected in each replicate, and 287 were unique to senescence. Gene ontology analysis of proteins detected in senescence indicated functions enriched for metabolism, DNA damage checkpoint integrity, membrane organization, wound healing and cytoskeletal remodeling; all consistent with a senescent phenotype. Data were filtered by strict criteria to derive a final list of 31 proteins unique to senescence. Initial validation of a subset of these for which specific commercial antibodies were available, was done by immunoblotting whole cell lysates and plasma membrane-enriched fractions. Some candidates had enriched expression in senescence; while others were increased in both senescence and quiescence and thus are more useful as dormancy markers. Additional validation by immunofluorescence was performed to deduce expression and localization of four senescent candidates. Novel patterns of localization were found whereby some candidates showed enrichment in structures resembling large vesicles and invadopodia-like extensions that connected with neighboring senescent cells. Lastly, immunohistochemical (IHC) analyses of formalin-fixed tissue obtained from chemotherapy-treated NSCLC patients revealed intense staining in enlarged cells with polymorphic nuclei, a characteristic of senescent cells. Thus, we have identified a unique cohort of senescence-specific biomarkers, some of which are amenable to IHC analyses. Ongoing studies will determine their utility as prognostic and predictive biomarkers of senescence tumor burden in NSCLC, with potential extrapolation to other malignancies and pathologies. Citation Format: Meagan Vogt, Chia-Ping H. Yang, Edward Nieves, Kenny Ye, Perry Cohen, Steven Keller, Hayley M. McDaid. Proteomic-based senescent biomarker identification and characterization in non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-066.

Abstract 14881: Shortened Telomere Length is Associated with Paroxysmal but Not Persistent/Permanent Atrial Fibrillation in Cardiovascular Patients Referred for Angiography

BACKGROUND: Telomeres are hexanucleotide repeats at chromosome ends that prevent chromosome degradation. Short telomere length (TL) correlates with biological ageing and is associated with risk for age-associated diseases. Atrial fibrillation (AF) can occur as paroxysmal (Px), persistent (Ps) or permanent (Pm). Progression from Px to Ps/Pm AF is accompanied by increased risk for AF-associated adverse events. We t found that short TL is associated with a history of AF; for the present study we examined TL in relationship to the types of AF. METHODS: Peripheral blood DNA was obtained from sequential consenting patients (pts) (n=3576) at angiography. TL was measured in triplicate by monochrome (SYBR Green I) multiplex quantitative PCR (Bio-Rad CFX384 Detection System) and normalized to a quantitatively-measured, single-copy gene (albumin). AF history was extracted from Intermountain Healthcare’s electronic records and AF type determined by chart review for 246 of 325 (75.7%) AF patients. Non-parametric tests were used. RESULTS: For the 246 subtyped AF pts, 66.3% were male, 94.3% Caucasian, mean age was 70 yrs. The leading AF type was Px (43.5%), followed by Pm (32.9%), and Ps (23.6%). Mean TL for non-AF pts was 0.954 ±0.325 and the mean TL for AF pts was 0.912±0.30. The mean Px TL (Table) was significantly shorter than for Ps or Pm AF. Ps and Pm TL did not differ. Adjusting for age, gender, prior CVA, PCI, statin use, disease severity; TL (per unit of decrease) was associated with Px AF compared to Ps/Pm AF (OR=6.64; CI 2.17, 20.32; p=0.0009). CONCLUSIONS: The association of shorter TL with Px AF but not Ps/Pm AF suggests that decreased TLs is associated with an etiologic AF subtype. No association between shortened TL and Ps/Pm AF may further suggest that TL measurement for pts with Px AF may have prognostic utility with respect to AF progression. Further study into the physiological basis of these observations is warranted.

Incident hypertension in older women and men with or at risk for HIV infection

Antiretroviral (ARV) therapy has prolonged the life expectancy of HIV-infected persons, increasing their risk of age-associated diseases, including atherosclerosis (AS). Decreased risk of AS has been associated with the prevention and control of hypertension (HTN). We conducted a cohort study of perimenopausal women and older men with or at risk of HIV infection to identify risk factors for incident HTN. Standardized interviews, physical examinations, and laboratory examinations were scheduled at 6-month intervals. Interview data included demographics, medical, family, sexual behaviour and drug use histories, and physical activity. There were 330 women and 329 men eligible for inclusion in the study; 27% and 35% of participants developed HTN during a median follow-up period of 1080 and 1071 days, respectively. In gender-stratified analysis, adjusting for traditional HTN risk factors (age, race, body mass index, smoking, diabetes, family history of HTN, alcohol dependence, physical activity and high cholesterol), HIV infection was not associated with incident HTN in women [hazard ratio (HR) 1.31; 95% confidence interval (CI) 0.56, 3.06] or men (HR 1.67; 95% CI 0.75, 3.74). Among HIV-infected women, although exposure to ARVs was not significantly associated with incident HTN (HR 0.72; 95% CI 0.26, 1.99), CD4 T-cell count was positively associated with incident HTN (HR 1.15 per 100 cells/μL; 95% CI 1.03, 1.28). Among physically active HIV-infected men, exposure to ARVs was negatively associated with incident HTN (HR 0.15; 95% CI 0.03, 0.78). HIV infection was not associated with incident HTN in older men or women. This study provides additional evidence supporting a causal relationship between immune function and incident HTN, which warrants further study.

Complex roles of Sirtuin 1 in cancer and aging

Aging is a process associated with structural and functional decline across diverse multiple organ systems, which leads to an increase in the risk of age-associated diseases and mortality rate over time. Aging is an increasing global issue because the world population is rapidly aging. It is estimated that the number of people aged 60 and older will double from 650 million (11% global population) to 2 billion people (22% global population) between 2006 and 2050.1 At the middle of the 21st century, the people older than 80 years will be much greater than children younger than 14 years.

Human chronotypes in the North

Long-term exposure to the climatic and social factors of the North cause desynchronization of the human circadian system, which can lead to an increase in the risk of age-associated diseases. Earlier, on a small sample, I showed that the higher the latitude at which a person resides in the North, the higher the frequency of the late chronotype. In addition, the parameters of diurnal rhythm in a late-chronotype subject are less expressed than in an early-chronotype one. The purpose of this study was to estimate the frequency distribution of various chronotypes depending on the latitude at which a person resides. Chronotypes were assessed by the Munich Chronotype Questionnaire (MCTQ). My study included 772 inhabitants of the Republic of Komi. It was shown that there was a significant northward trend towards a higher prevalence of the late chronotype. Thus, an increase in the frequency of the late chronotype, whose circadian rhythm is most sensitive to the negative action of climatic and social factors of the North, may be one of the causes of its desynchronization and an increase in the risk of age-associated diseases in northerners.

Monkeys' Life Span Extended by Caloric Restriction

Caloric restriction of about 30% daily extends the life span of many simple animals and many mammals, and also lowers risk for age-associated diseases