Network strategies to understand the aging process and help age-related drug design

Recent studies have demonstrated that network approaches are highly appropriate tools for understanding the extreme complexity of the aging process. Moreover, the generality of the network concept helps to define and study the aging of technological and social networks and ecosystems, which may generate novel concepts for curing age-related diseases. The current review focuses on the role of protein-protein interaction networks (inter-actomes) in aging. Hubs and inter-modular elements of both interactomes and signaling networks are key regulators of the aging process. Aging induces an increase in the permeability of several cellular compartments, such as the cell nucleus, introducing gross changes in the representation of network structures. The large overlap between aging genes and genes of age-related major diseases makes drugs that aid healthy aging promising candidates for the prevention and treatment of age-related diseases, such as cancer, atherosclerosis, diabetes and neurodegenerative disorders. We also discuss a number of possible research options to further explore the potential of the network concept in this important field, and show that multi-target drugs (representing 'magic-buckshots' instead of the traditional 'magic bullets') may become an especially useful class of age-related drugs in the future.

[1]  K. Bergmann,et al.  Handbook of the biology of aging , 1979 .

[2]  P. M. Allen,et al.  Evolution: Why the Whole is Greater Than the Sum of the Parts , 1988 .

[3]  T. Kirkwood,et al.  A network theory of ageing: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the ageing process. , 1996, Mutation research.

[4]  T. Oki,et al.  Design of Total Runoff Integrating Pathways (TRIP)—A Global River Channel Network , 1998 .

[5]  A. Yashin,et al.  The network and the remodeling theories of aging: historical background and new perspectives , 2000, Experimental Gerontology.

[6]  Steven N. Austad,et al.  Why do we age? , 2000, Nature.

[7]  K. Davies,et al.  Mitochondrial free radical generation, oxidative stress, and aging. , 2000, Free radical biology & medicine.

[8]  M. Mather,et al.  Aging Enhances the Activation of the Permeability Transition Pore in Mitochondria , 2000, Biochemical and biophysical research communications.

[9]  Aging effects in the quantum dynamics of a dissipative free particle: non-Ohmic case. , 2001, Physical review. E, Statistical, nonlinear, and soft matter physics.

[10]  B. Bond,et al.  Aging in Pacific Northwest forests: a selection of recent research. , 2002, Tree physiology.

[11]  S. Rattan.  N6-Furfuryladenine (Kinetin) as a Potential Anti-Aging Molecule , 2002 .

[12]  D. Promislow.  Protein networks, pleiotropy and the evolution of senescence , 2004, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[13]  George W Rebok,et al.  Social network characteristics and cognition in middle-aged and older adults. , 2004, The journals of gerontology. Series B, Psychological sciences and social sciences.

[14]  Luca Ferrarini,et al.  A more efficient search strategy for aging genes based on connectivity , 2005, Bioinform..

[15]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[16]  Aging, memory and rejuvenation: some lessons from simple models , 2005, cond-mat/0512309.

[17]  B. Friguet,et al.  Algae extract-mediated stimulation and protection of proteasome activity within human keratinocytes exposed to UVA and UVB irradiation. , 2006, Antioxidants & redox signaling.

[18]  H. Takeshima,et al.  Muscle aging is associated with compromised Ca2+ spark signaling and segregated intracellular Ca2+ release , 2006, The Journal of cell biology.

[19]  A. Budovsky,et al.  Longevity network: Construction and implications , 2007, Mechanisms of Ageing and Development.

[20]  Mate S. Szalay,et al.  How to design multi-target drugs , 2007, Expert opinion on drug discovery.

[21]  P. Csermely,et al.  Aging cellular networks: Chaperones as major participants , 2006, Experimental Gerontology.

[22]  István A. Kovács,et al.  How to design multi-target drugs , 2007, Expert opinion on drug discovery.

[23]  C. Caruso,et al.  Inflammatory networks in ageing, age-related diseases and longevity , 2007, Mechanisms of Ageing and Development.

[24]  J. Rich,et al.  Malignant glioma drug discovery – targeting protein kinases , 2007, Expert opinion on drug discovery.

[25]  J. Han,et al.  A modular network model of aging , 2007, Molecular systems biology.

[26]  J. Lehár,et al.  Multi-target therapeutics: when the whole is greater than the sum of the parts. , 2007, Drug discovery today.

[27]  M. Newman,et al.  Hierarchical structure and the prediction of missing links in networks , 2008, Nature.

[28]  D. Terrian,et al.  Senescence-associated exosome release from human prostate cancer cells. , 2008, Cancer research.

[29]  Brian Uzzi,et al.  Asymmetric disassembly and robustness in declining networks , 2008, Proceedings of the National Academy of Sciences.

[30]  Daniel L. Rubin,et al.  Network Analysis of Intrinsic Functional Brain Connectivity in Alzheimer's Disease , 2008, PLoS Comput. Biol..

[31]  Robin Palotai,et al.  Critical Review Chaperones as Integrators of Cellular Networks: Changes of Cellular Integrity in Stress and Diseases Structural Properties of Cellular Networks , 2007 .

[32]  Sasha F. Levy,et al.  Network Hubs Buffer Environmental Variation in Saccharomyces cerevisiae , 2008, PLoS biology.

[33]  M. Serrano,et al.  The Arf / p 53 Pathway in Cancer and Aging , 2008 .

[34]  P. Csermely.  Creative elements: network-based predictions of active centres in proteins and cellular and social networks. , 2008, Trends in biochemical sciences.

[35]  Manuel Serrano,et al.  The Arf/p53 pathway in cancer and aging. , 2008, Cancer research.

[36]  E. Greer,et al.  Signaling networks in aging , 2008, Journal of Cell Science.

[37]  Huba J. M. Kiss,et al.  Ageing as a price of cooperation and complexity Self-organization of complex systems causes the ageing of constituent networks , 2008 .

[38]  Arie Budovsky,et al.  The Human Ageing Genomic Resources: online databases and tools for biogerontologists , 2009, Aging cell.

[39]  M. Tso,et al.  Autophagy and Exosomes in the Aged Retinal Pigment Epithelium: Possible Relevance to Drusen Formation and Age-Related Macular Degeneration , 2009, PloS one.

[40]  Old Nuclei Spring New Leaks , 2009, Cell.

[41]  Marco Pahor,et al.  Rapamycin fed late in life extends lifespan in genetically heterogeneous mice , 2009, Nature.

[42]  R. Chettier,et al.  A Human Protein Interaction Network Shows Conservation of Aging Processes between Human and Invertebrate Species , 2009, PLoS genetics.

[43]  M. D'Angelo,et al.  Age-Dependent Deterioration of Nuclear Pore Complexes Causes a Loss of Nuclear Integrity in Postmitotic Cells , 2009, Cell.

[44]  Csaba Böde,et al.  Perturbation waves in proteins and protein networks: applications of percolation and game theories in signaling and drug design. , 2008, Current protein & peptide science.

[45]  John Boyle,et al.  Cytoscape: a community-based framework for network modeling. , 2009, Methods in molecular biology.

[46]  Christian von Mering,et al.  STRING 8—a global view on proteins and their functional interactions in 630 organisms , 2008, Nucleic Acids Res..

[47]  T. Hofer,et al.  Bioenergetics and permeability transition pore opening in heart subsarcolemmal and interfibrillar mitochondria: Effects of aging and lifelong calorie restriction , 2009, Mechanisms of Ageing and Development.

[48]  Huba J. M. Kiss,et al.  Ageing as a price of cooperation and complexity , 2008, BioEssays : news and reviews in molecular, cellular and developmental biology.

[49]  M. Wolfson,et al.  The signaling hubs at the crossroad of longevity and age-related disease networks. , 2009, The international journal of biochemistry & cell biology.