Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2–10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18–95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases. Aptamer-based proteomic analysis of plasma from healthy individuals aged 18–95 years reveals wave-like patterns of protein expression that are associated with age-related diseases and phenotypic traits.

Undulating changes in human plasma proteome profiles across the lifespan

Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD+ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.

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The quest to slow ageing through drug discovery

Molecular mechanisms of renal aging.

This paper studies how to efficiently apply device-to-device (D2D) communications underlaying a cellular system to support vehicle-to-vehicle (V2V) connection (termed D2D-V). By considering the geographic features of the D2D-V system, we propose a D2D-V grouping, reuse channel selection (RS), and power control (PC) framework to achieve the optimal performance of the D2D-V system, in terms of either maximized sum rate or maximized minimally achievable rate. First, in a full channel state information (CSI) scenario, we apply difference of two convex functions (D.C.) programming to obtain the optimal PC. However, because the CSI between some terminals is hard to obtain and some interference can be appropriately inhibited by taking advantage of the vehicles' geographic features, we make a series of simplifications to the PC problem to reduce the requirement of full CSI, the dependence of centralized control, and the computational complexity. The suitable conditions of each simplification are elaborated. Each step of our simplifications are shown as a certain tradeoff between performance and complexity. Furthermore, we provide an investigation into the service quality that one vehicle can achieve when it passes through the covered segment of the highway and propose the location–service curve to portray this. We use numerical simulations to verify the accuracy and feasibility of each step of our suboptimal PC and specific features embedded in the location–service curve.

Power Control in D2D-Based Vehicular Communication Networks

Complex networks have been studied intensively for a decade, but research still focuses on the limited case of a single, non-interacting network. Modern systems are coupled together and therefore should be modelled as interdependent networks. A fundamental property of interdependent networks is that failure of nodes in one network may lead to failure of dependent nodes in other networks. This may happen recursively and can lead to a cascade of failures. In fact, a failure of a very small fraction of nodes in one network may lead to the complete fragmentation of a system of several interdependent networks. A dramatic real-world example of a cascade of failures (‘concurrent malfunction’) is the electrical blackout that affected much of Italy on 28 September 2003: the shutdown of power stations directly led to the failure of nodes in the Internet communication network, which in turn caused further breakdown of power stations. Here we develop a framework for understanding the robustness of interacting networks subject to such cascading failures. We present exact analytical solutions for the critical fraction of nodes that, on removal, will lead to a failure cascade and to a complete fragmentation of two interdependent networks. Surprisingly, a broader degree distribution increases the vulnerability of interdependent networks to random failure, which is opposite to how a single network behaves. Our findings highlight the need to consider interdependent network properties in designing robust networks.

http://absimage.aps.org/image/MAR10/MWS_MAR10-2009-001087.pdf

Catastrophic cascade of failures in interdependent networks

The GDF11 expression pattern and its effect on organ regeneration after acute injury in the elderly population are highly controversial topics. In our study, GDF11/8 expression increased after kidney ischemia–reperfusion injury (IRI), and the relatively lower level of GDF11/8 in the kidneys of aged mice was associated with a loss of proliferative capacity and a decline in renal repair, compared to young mice. In vivo, GDF11 supplementation in aged mice increased vimentin and Pax2 expression in the kidneys as well as the percentage of 5-ethynyl-2′-deoxyuridine (EdU)-positive proximal tubular epithelial cells. GDF11 improved the renal repair, recovery of renal function, and survival of elderly mice at 72 h after IRI. Moreover, the addition of recombinant GDF11 to primary renal epithelial cells increased proliferation, migration, and dedifferentiation by upregulating the ERK1/2 pathway in vitro. Our study indicates that GDF11/8 in the kidney decreases with age and that GDF11 can increase tubular cell dedifferentiation and proliferation as well as improve tubular regeneration after acute kidney injury (AKI) in old mice.

GDF11 improves tubular regeneration after acute kidney injury in elderly mice.

Whether changes in internal body environment affect kidney aging remains unclear. Specifically, it is unknown whether transplanted kidneys from older donors recover from tissue damage after placement in younger recipients. In this study, a parabiosis animal model was established to investigate the effects of a young internal body environment on aged kidneys. The animals were divided into six groups: young (Ycon) and old control (Ocon) groups, isochronic youth-youth group (Y-IP), elderly-elderly group (O-IP), and heterochronic youth (Y-HP) and elderly (O-HP) groups. After parabiosis, tubule and interstitial tissue scores in the O-HP group were significantly lower than in the Ocon and O-IP groups. The expression of aging-related protein p16 and SA-β-gal in the O-HP group was significantly reduced compared with the Ocon and O-IP groups. Autophagy factors Atg5 and LC3BII were significantly upregulated, whereas the expression of the autophagic degradation marker (P62) was significantly downregulated in the O-HP group compared with the Ocon and O-IP groups. With the same comparison, the positive cells of TUNEL staining and the expression of IL-6 and IL-1β were significantly reduced, whereas the total/cleaved caspase-3 and total/pNF-κB were significantly increased in the O-HP group. The results demonstrated that a young blood environment significantly reduces kidney aging. These findings provide new evidence supporting an increase in the upper age limit for human kidney transplantation donors.

A Young Blood Environment Decreases Aging of Senile Mice Kidneys

Youthful systemic milieu alleviates renal ischemia-reperfusion injury in elderly mice

This paper applies device-to-device technique to vehicular-to-vehicular communications (D2D-V) in an underlay fashion. Different from conventional D2D systems focusing on smart phones, whose positions are usually assumed to be statical, the D2D-V system suffers more mobility and uncertainties. These dynamic features indeed complicate the design of D2D-V system, but also, give more potential to accomplish some geographic based algorithms. Armed with the geographic knowledge of highway and the dynamic GPS information in each vehicle, we propose a geographic based reuse cellular user selection scheme and two different distributed power control schemes to serve various applications in vehicular networks. We model the problem firstly, then formulate two metrics: the sum rate and the minimum-achievable rate to evaluate the performance of the proposed schemes. Simulations are proposed to validate our schemes and analysis. Influences of different system settings are also discussed here.

Applying LTE-D2D to Support V2V Communication Using Local Geographic Knowledge

Discontinuous reception (DRX) techniques have successfully been proposed for energy savings in 4G radio access systems, which are deployed on legacy 2GHz spectrum bands with signal features of omni ...

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Dong Liu

Papers

GDF11 improves tubular regeneration after acute kidney injury in elderly mice.

A Young Blood Environment Decreases Aging of Senile Mice Kidneys

Youthful systemic milieu alleviates renal ischemia-reperfusion injury in elderly mice

Applying LTE-D2D to Support V2V Communication Using Local Geographic Knowledge

Discontinuous Reception for Multiple-Beam Communication