From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Abstract

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.

Figure 1

Pleiotropy of WRN action in DNA metabolism. WRN affects all key aspects of DNA metabolism (boxed), either directly through its helicase and exonuclease activities, or mediated through multiple protein-protein interactions (grey ovals — for clarity only a subset of known interacting proteins are shown) Inappropriate execution of these processes in the absence of WRN leads to the molecular outcomes shown below the arrows.

Figure 3

Drivers of senescence and therapeutic opportunities in WS and HGPs. Drivers, factors leading to the accumulation of DNA damage, are boxed at the top of the diagram, with causative factors shown in red. All result in DNA damage if unchecked; however, several therapeutic or modulatory options are now available. Blocking pre-lamin A farnesylation with farnesyl transferase inhibitors (FTIs), or depleting lamin A using either morpholinos or RNAi leads to a significant reduction in aberrant morphological changes of the nucleus usually associated with HGPS, and a reduction in resultant DNA damage. Mouse cells and mice models of HGPS treated with FTIs show significant improvement in proliferation, and the entrie organism shows better bone structure and increased longevity. FTIs are already licensed for treatment of malaria and various cancers. Statins also reduce farnesylation and may prove useful in HGPS. Telomere attrition leading to signalling into the DNA damage pathway can be overcome in cell cultures by ectopically supplying telomerase, whilst the problems with DNA replication and cell proliferation resulting from loss of WRN can be overcome using a Holliday junction resolving enzyme, resolvase. As far as Signal transduction is concerned, during adipose differentiation, SRBEP1 binds and stimulates the PPARγ transcription factor; SREBP1 sequestration by progerin may prevent this in HGPS. Use of the PPARγ agonist pioglitazone has proven valuable in diminishing several aspects of lipodystrophy and metabolic syndrome in WS patients and may play an equally important role in the treatment of HGPS. Once DNA damage has occurred, through whatever route, there is still scope to modulate the response of the cell by inhibiting the stress signal transducing kinase p38 with the inhibitor SB203580, a drug already licensed for use in diabetes. Moving on to effectors; inhibition of the tumour suppressor p53 may not be ideal as it would be expected to lead to increase in cancer incidence; however, interfering with its downstream effector p21^CDKN1 appears to reduce excess cell cycle exit and senescence in mouse models, without increasing cancer incidence. Gene deletion in people is not yet a viable option as in experimental animals, but RNAi may prove useful in this context. The flip side of preventing senescence using drugs is the possibility of causing senescence by design, with major benefits in cancer therapy. In particular, hyperactivating the p21^CDKN1 pathway through small-molecule drugs (e.g. nucleoside analogue CYC102) may prove a fruitful therapeutic route.

Figure 2

LaminA-processing pathway. Pre-laminA mRNA is encoded by the lamin A/C gene (lamin C is a shorter splice variant lacking the CAAX motif) It is translated by cytosolic ribosomes and then becomes farnesylated by the action of farnesyl transferase, providing it with a hydrophobic anchor by which it associates with the cytosolic side of the rough endoplasmic reticulum membrane. Proteolytic cleavage of the two aliphatic and adjacent residue of the CAAX motif leaves pre-lamin A with a farnesylated cysteine residue. Further cleavage by the Zmpste24 protease releases mature lamin A protein into the cytosol, from where it is transported into the nucleus. Once inside the nucleus, lamin A can associate with membrane-bound lamin B to form the nuclear lamina, or it can remain soluble in the nucleoplasm. Experimental or therapeutic interventions to relieve accumulation of pre-lamin A are shown in green, whilst deleterious impacts on the pathways (naturally occurring or experimentally induced mutations) are shown in red.