Strategic outline of interventions targeting extracellular matrix for promoting healthy longevity.

The extracellular matrix (ECM), composed of interlinked proteins outside of cells, is an important component of the human body that helps maintain tissue architecture and cellular homeostasis. As people age, the ECM undergoes changes that can lead to age-related morbidity and mortality. Despite its importance, ECM aging remains understudied in the field of geroscience. In this review, we discuss the core concepts of ECM integrity, outline the age-related challenges and subsequent pathologies and diseases, summarize diagnostic methods detecting a faulty ECM, and provide strategies targeting ECM homeostasis. To conceptualize this, we built a technology research tree to hierarchically visualize possible research sequences for studying ECM aging. This strategic framework will hopefully facilitate the development of future research on interventions to restore ECM integrity, which could potentially lead to the development of new drugs or therapeutic interventions promoting health during aging.

The Resistance of Drosophila melanogaster to Oxidative, Genotoxic, Proteotoxic, Osmotic Stress, Infection, and Starvation Depends on Age According to the Stress Factor.

We studied how aging affects the ability of Drosophila melanogaster to tolerate various types of stress factors. Data were obtained on the resistance of D. melanogaster to oxidative and genotoxic (separately paraquat, Fe3+, Cu2+, and Zn2+ ions), proteotoxic (hyperthermia, Cd2+ ions), and osmotic (NaCl) stresses, starvation, and infection with the pathological Beauveria bassiana fungus at different ages. In all cases, we observed a strong negative correlation between age and stress tolerance. The largest change in the age-dependent decline in survival occurred under oxidative and osmotic stress. In most experiments, we observed that young Drosophila females have higher stress resistance than males. We checked whether it is possible to accurately assess the biological age of D. melanogaster based on an assessment of stress tolerance. We have proposed a new approach for assessing a biological age of D. melanogaster using a two-parameter survival curve model. For the model, we used an algorithm that evaluated the quality of age prediction for different age and gender groups. The best predictions were obtained for females who were exposed to CdCl2 and ZnCl2 with an average error of 0.32 days and 0.36 days, respectively. For males, the best results were observed for paraquat and NaCl with an average error of 0.61 and 0.68 days, respectively. The average accuracy for all stresses in our model was 1.73 days.

Stochastic non-enzymatic modification of long-lived macromolecules - A missing hallmark of aging.

Damage accumulation in long-living macromolecules (especially extracellular matrix (ECM) proteins, nuclear pore complex (NPC) proteins, and histones) is a missing hallmark of aging. Stochastic non-enzymatic modifications of ECM trigger cellular senescence as well as many other hallmarks of aging affect organ barriers integrity and drive tissue fibrosis. The importance of it for aging makes it a key target for interventions. The most promising of them can be AGE inhibitors (chelators, O-acetyl group or transglycating activity compounds, amadorins and amadoriases), glucosepane breakers, stimulators of elastogenesis, and RAGE antagonists.

Circadian clock genes' overexpression in Drosophila alters diet impact on lifespan.

Diet restriction is one of the most accurately confirmed interventions which extend lifespan. Genes coding circadian core clock elements are known to be the key controllers of cell metabolism especially in aging aspect. The molecular mechanisms standing behind the phenomenon of diet-restriction-mediated life extension are connected to circadian clock either. Here we investigate the effects of protein-rich and low-protein diets on lifespan observed in fruit flies overexpressing core clock genes (cry, per, Clk, cyc and tim). The majority of core clock genes being upregulated in peripheral tissues (muscles and fat body) on protein-rich diet significantly decrease the lifespan of male fruit flies from 5 to 61%. Nevertheless, positive increments of median lifespan were observed in both sexes, males overexpressing cry in fat body lived 20% longer on poor diet. Overexpression of per also on poor medium resulted in life extension in female fruit flies. Diet restriction reduces mortality caused by overexpression of core clock genes. Cox-regression model revealed that diet restriction seriously decreases mortality risks of flies which overexpress core clock genes. The hazard ratios are lower for flies overexpressing clock genes in fat body relatively to muscle-specific overexpression. The present work suggests a phenomenological view of how two peripheral circadian oscillators modify effects of rich and poor diets on lifespan and hazard ratios.

Markers of arterial health could serve as accurate non-invasive predictors of human biological and chronological age.

The decline in functional capacity is unavoidable consequence of the process of aging. While many anti-aging interventions have been proposed, clinical investigations into anti-aging medicine are limited by lack of reliable techniques for evaluating the rate of ageing. Here we present simple, accurate and cost-efficient techniques for estimation of human biological age, Male and Female Arterial Indices. We started with developing a model which accurately predicts chronological age. Using machine learning, we arrived on a set of four predictors, all of which reflect the functioning of the cardiovascular system. In Arterial Indices models, results of carotid artery duplex scan that show the thickness of the intima media complex and quantitatively describe the degree of stenosis are combined with pulse wave velocity and augmentation index measurements performed by applanation tonometry. In our cohort, the age of men was determined with MAE = 6.91 years (adjusted R-squared = 0.55), and the age of women with MAE = 5.87 years (adjusted R2 = 0.69). The Epsilon-accuracies of age-predicting models were at 86.5% and 80% for women and men, respectively. Substantially higher differences between the predicted age and the calendar age were noted for patients with Type 2 Diabetes Mellitus (T2D) as compared to non-T2D controls, indicating that the model could serve as a good approximation for an elusive biological age. Notably, in females with chronological and biological ages mismatching by 5 or more years, significant increases in in Framingham CVD scores and lower levels of IGF-1 were observed. Proposed Male and Female Arterial Indices derive biological age from the results of functional tests which do not require specialized laboratory equipment and, therefore, could be performed in hospitals and community health clinics.

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic.

In the coming decades, a massive shift in the aging segment of the population will have major social and economic consequences around the world. One way to offset this increase is to expedite the development of geroprotectors, substances that slow aging, repair age-associated damage and extend healthy lifespan, or healthspan. While over 200 geroprotectors are now reported in model organisms and some are in human use for specific disease indications, the path toward determining whether they affect aging in humans remains obscure. Translation to the clinic is hampered by multiple issues including absence of a common set of criteria to define, select, and classify these substances, given the complexity of the aging process and their enormous diversity in mechanism of action. Translational research efforts would benefit from the formation of a scientific consensus on the following: the definition of 'geroprotector', the selection criteria for geroprotectors, a comprehensive classification system, and an analytical model. Here, we review current approaches to selection and put forth our own suggested selection criteria. Standardizing selection of geroprotectors will streamline discovery and analysis of new candidates, saving time and cost involved in translation to clinic.

The influence of pro-longevity gene Gclc overexpression on the age-dependent changes in Drosophila transcriptome and biological functions.

BACKGROUND: Transcriptional changes that contribute to the organism's longevity and prevent the age-dependent decline of biological functions are not well understood. Here, we overexpressed pro-longevity gene encoding glutamate-cysteine ligase catalytic subunit (Gclc) and analyzed age-dependent changes in transcriptome that associated with the longevity, stress resistance, locomotor activity, circadian rhythmicity, and fertility. RESULTS: Here we reproduced the life extension effect of neuronal overexpression of the Gclc gene and investigated its influence on the age-depended dynamics of transcriptome and biological functions such as fecundity, spontaneous locomotor activity and circadian rhythmicity, as well as on the resistance to oxidative, proteotoxic and osmotic stresses. It was shown that Gclc overexpression reduces locomotor activity in the young and middle ages compared to control flies. Gclc overexpression slowed down the age-dependent decline of locomotor activity and circadian rhythmicity, and resistance to stress treatments. Gclc level demonstrated associations with the expression of genes involved in a variety of cellular processes including Jak-STAT, MAPK, FOXO, Notch, mTOR, TGF-beta signaling pathways, translation, protein processing in endoplasmic reticulum, proteasomal degradation, glycolysis, oxidative phosphorylation, apoptosis, regulation of circadian rhythms, differentiation of neurons, synaptic plasticity and transmission. CONCLUSIONS: Our study revealed that Gclc overexpression induces transcriptional changes associated with the lifespan extension and uncovered pathways that may be associated with the age-dependent decline of biological functions.