Mechanisms of exceptional longevity in the world's longest-lived animal

The project will investigate the mechanisms behind the exceptional longevity displayed in the bivalve mollusc, the ocean quahog, which is the world's longest-lived animal. This will be achieved by evaluating three plausible mechanisms of aging which have been suggested to determine life span during investigations of the traditional shorter-lived species e.g. nematodes, fruit flies and rodents. These mechanisms will be investigated in the ocean quahog and 6 other shorter-lived bivalve species. These species span a range of longevities, from less than one year in one species to greater than 400 years in the ocean quahog. Our overall hypothesis is that one or more of the mechanisms of aging suggested will explain the enormous range of longevities observed in bivalves. The aging of human populations makes research into potential therapies to enhance a healthy life span particularly timely with dramatic social and economic significance. Significant advances in our understanding of the aging processes have been made using the classical model organisms (e.g. fruit flies and rodents). Despite the advantages of these organisms they have been primarily chosen for convenience, rather than for specific features pertinent to human aging. An alternative approach, taking advantage of the astounding diversity of aging rates prevalent in nature, is a comparative investigation of short-lived, poorly aging species with other long-lived species i.e. those that age slowly. These latter are demonstrably successful at resisting aging processes and might yield novel insights into mechanisms responsible for the achievement of a long life span. Bivalve molluscs (e.g. clams, scallops and oysters) have been virtually ignored by aging researchers despite their obvious advantages for investigating aging. Specifically, in most bivalves the precise age of an individual can usually be ascertained using growth structures on or within the shell. As a consequence of this feature, we now understand that there is an enormous range of longevities amongst bivalves (from <1 to >400 years), unheard of in any other animal group. Large numbers of individuals can be obtained from natural populations in many locations and because of their commercial importance many bivalve species as food sources, techniques for their culture are well-developed. Thus bivalves have the potential to become valuable informative investigative tools to reveal how nature has dramatically modified life- and health span. The proposed project involves a unique collaboration between marine biologists in the UK (who are experts in the biology, maintenance and age-determination of bivalves) and aging researchers in the USA (who are experts in molecular and biochemical aspects of aging research). The project design involves seven carefully selected bivalve species, spanning a range of maximum lifespans, and critically evaluating three plausible hypotheses about mechanisms which potentially determine the life span of a species. In the proposed research we will evaluate: 1) whether the efficiency of the mitochondria (the cellular power plants) at producing ATP (chemical energy) while minimizing the production of harmful reactive oxygen species is a critical determinant of longevity; 2) whether proteome stability, the ability of proteins to resist damage and 'unfolding', is a critical determinant of longevity and 3) whether the ability to resist stress is a critical determinant of longevity. This work will not only underpin future research into aging in long-lived bivalves but also have generic relevance for other animals, including people. Although molluscs appear anatomically different to humans, the symptoms of aging are similar across the animal groups (e.g. sarcopenia/muscle loss with age in worms and people); therefore insights provided by research into aging in bivalves will be of relevance to the whole biogerontology community and assist in directing future aging research.

The project investigates the mechanisms behind the exceptional longevity observed in bivalve molluscs, including the ocean quahog the world's longest-lived animal. This will be achieved by evaluating three plausible mechanisms of aging, previously suggested to determine longevity, in the ocean quahog and 6 other related species spanning a range of longevities (from <1 to >400 years) and our overall hypothesis is that one or more of the mechanisms suggested will explain the range in natural longevities. In the service of this hypothesis, we have three objectives. Objective 1 will evaluate the hypothesis that mitochondrial efficiency at producing ATP while minimizing the reactive oxygen species production is a critical determinant of longevity. We will assess mitochondrial oxygen consumption, ATP production, inner membrane potential, and total ROS production as well as that associated with each mitochondrial electron transport chain complex. Objective 2 will evaluate the hypothesis that proteome stability is a critical determinant of longevity by assessing the level of protein carbonyls in both the soluble and insoluble cellular fractions of multiple tissues as well as evaluating the steady-state fraction of ubiquitinated proteins and the rate of protein degradation via the proteosome. We will employ a new novel assay to quantify cellular capacity to resist protein misfolding and the aggregation of misfolded proteins. Thus we will comprehensively evaluate the proteostasis capacity of the cells in each species. Objective 3 will evaluate the hypothesis that cellular ability to resist stress is a critical determinant of longevity by exposing each species to an oxidative stressor (gamma-irradiation) and assessing both the damage done by the stressor and the rate of repair/recovery (specifically measuring oxidative damage to proteins, lipids, and DNA and also resultant global protein misfolding with a newly developed assay and single- and double DNA strand breaks).

The aging of human populations makes research into potential therapies to enhance healthy life span particularly timely with dramatic social and economic significance. The investigation of long-lived species which are demonstrably successful at resisting aging processes might yield novel insights into mechanisms responsible for the achievement of a long life span. Although molluscs are anatomically different to humans the symptoms of aging are similar across the taxonomic groups (e.g. sarcopenia (muscle loss with age) observed in worms and people), therefore insights provided by research into ageing in bivalves will have wider biogerontological interest. The ultimate beneficiaries of this research are the elderly. The paradigm of an aging society may be a cause for celebration, but the transition brings enormous challenges. In Britain, the morbidity and disability in later years may be increasing with the result that the healthy life span is falling behind life span itself. The economic gains from enhancing a healthy life span would not just benefit individuals it would also benefit society in general and the government. If UK life expectancy were to increase by 5 years it is estimated that the UK GDP would increase by up to £5 billion/year. Some economists consider the financial benefits of extending life span far higher than the associated elevated pension costs [1]. Aging research is important to society. It leads to considerable benefits for people and to those organisations which provide services to the elderly. The elderly and a range of organisations now recognise the value of aging research clearly focused on meeting their needs, even where, as in the case of the proposed research, there may not be an immediate obvious application. Realistically the timescales for observing the benefits to the elderly are long term. We propose to investigate the basic mechanisms of aging and it takes time for this to translate into technological or pharmaceutical advancements. Further our understanding of the mechanisms of aging enables pharmaceutical interventions to be better targeted. The immediate users to benefit from the proposed research will be the scientific community. Through the investigation of aging in the traditional model species a number of potential mechanisms of aging have been suggested, investigating these enables future research to be better targeted which facilitates the work of the research funding bodies. The work will also underpin future research on this taxonomic group, if the exceptional longevity can be attributed to a particular aging mechanism then future research on long-lived bivalves can be concentrated on that mechanism. To ensure beneficiaries benefit from this research the results and their interpretation will be published in high quality peer-reviewed journals, disseminated at national and international conferences and articles written for the general press and we will also continue to utilise rapid publication mechanisms provided by the newsletters of scientific societies and funding bodies. Based on our previous experience in dealing with the broadcast and written media we propose to build on this initial interest by engaging with the media to develop a deeper understanding of the scientific motivation for investigating such long-lived animals [2]. As part of the project the proposed PDRA at Bangor will undergo further career development; although already working on a Research into Aging funded project, further training in molecular and cellular techniques at the Barshop Institute, Texas, will equip him with additional adaptable and transferable skills that will be readily employed in future research opportunities. REFERENCES 1. Murphy, K.M. & Topel, R.H. 2003. Diminishing Returns?: The Costs and Benefits of Improving Health. Perspectives in Biology and Medicine 46, (3) S108-S128 2. Farrar, S., Ming the mollusc holds secret to long life. The Sunday Times. October 28, 2007.