Select Committee on Science and Technology Written Evidence


Memorandum by Dr Jane Preston, Dr Alan Hipkiss and Professor Robert Weale

CONTROLLING THE ONSET OF AGE-RELATED DYSFUNCTION AND CONSEQUENT PATHOLOGIES

  1.  It is a truism to say that in order to suppress deleterious age-related change we should remain young. This aphorism is applicable to studies at both cellular and molecular levels and we are beginning to understand quite clearly the biological reasons for the existence of ageing (Holliday 2004) and the underlying cellular and molecular processes. What is far less clear is how this understanding can be harnessed to improve human health and longevity. The merit in this approach is that by understanding the basic tenets of cell and molecular ageing, we have the potential to understand multiple age related diseases (Hayflick 2000), an approach that complements the more traditional disease focussed research process. This paper summarises promising areas of cellular and molecular research, and gaps in current knowledge of how to translate the in vitro studies into health benefits in later life.

CELLULAR AND MOLECULAR APPROACHES

  2.   Oxidative stress. The involvement of free radicals and reactive oxygen species in ageing and disease has been a popular avenue for research since the 1950s. Oxygen species are produced as a by-product of normal cell metabolism and also have specific functions as intracellular signals, but in excess produce oxidative stress, damaging all intracellular components, eventually leading to cell death. High free radical plasma load is correlated with poor cognitive function and reduced physical activity in men and women in their 80s (Maugeri et al 2004) and oxidative stress is implicated in a wide variety of health problems including neurodegeneration (Emerit et al 2004), vascular disease, muscle weakness and cancer. Interestingly, production of some reactive oxygen species is lower in women compared to men, which may help explain some of the differential in longevity. Thus, this avenue of research has enormous potential in the treatment of long-term illnesses.

  3.  Although it seems logical to expect that antioxidants (which reduce oxidative stress in experimental cell and molecular models) can prevent such oxidative damage, use of antioxidant vitamin supplements in a variety of combinations has been very disappointing in clinical trial (Tran 2001), with little or no positive outcome on disease progression. An explanation of the poor effect in human trials has been put forward by Lane (2003) and is based on the cell's need for a nominal level of oxidative stress to trigger gene responses to infection for example. Since intracellular detection of oxidative stress is essential, mechanisms have evolved to buffer exogenous antioxidants so that they do not dampen the desired response to infection. In the young this is a positive adaptation, but persists in old cells, even though by that time it would be desirable to reduce the, now damaging, oxidative load. He further suggests that excess antioxidants may be harmful since they would delay the resolution of infections and physiological stress. While there is no doubt that oxidative stress maintains a central place in understanding ageing, much more information is needed about the genetic and physiological regulation of endogenous intracellular antioxidants.

  4.   Calorie restriction. The only experimental approach consistently shown to improve health and longevity in animal models is calorie restriction—a reduction of up to 50 per cent of the calorie intake, while maintaining all other nutritional components. It is effective in delaying the onset of diabetes, CVD, muscle weakness, neuropathy in rats (Merry 2004) even in mild restriction studies (80 per cent of normal calories, Usuki et al 2004).

  5.  There is increasing evidence that the positive effects are a result of reduced oxidative stress due to slow production of free radicals by the mitochondria sub-cellular organelles (Lambert and Merry 2004). These positive effects are reversed by insulin (Lambert and Merry 2004) which increases production of reactive oxygen species by the mitochondria (Mahadev et al 2001). Insulin resistance and high blood insulin levels are common in older people, and characteristic of age-related Type 2 (non-insulin dependent) diabetes. Diabetes itself is a risk factor for Alzheimer's disease and CVD/stroke, so potential translation therapies from calorie restriction studies linking cellular oxidative stress and deleterious effects of insulin are great. This should include the effects of early life nutrition, from conception onward, since poor early nutrition and small weight at birth are major risk factors for diabetes, cardiovascular disease and stroke in later life (Barker 2003).

  6.   Altered Proteins. Ageing in humans, human cells in culture and in animal models is accompanied by intracellular accumulations of altered or aberrant protein forms. Age-related conditions such cataracts in the eye lens, amyloid plaque and tangles in Alzheimer's disease, Lewy bodies in Parkinson's disease and inclusion bodies in Huntingdons's disease and motor neurone disease (amyotrophic lateral sclerosis) provide exaggerated pathological examples of the same phenomenon (Bossy-Wetzel et al 2004, Ross and Poirier 2004).

  7.  Altered proteins of almost any origin, including those damaged by oxygen free-radicals, are normally selectively destroyed intracellularly by proteasomes, multicatalytic proteases which beak down proteins to their constituent parts (Grune et al 2004). It is important that the cell maintains sufficient proteasome activity to remove rapidly any altered proteins that are formed before they interact deleteriously with other cellular components (Luxford et al 2002, Morgan et al 2002). Compromised proteasome activity can also affect mitochondrial metabolism causing accumulation of dysfunctional mitochondria (Bota and Davies 2001), an increase in oxygen free-radical generation and formation of more altered proteins (Terman and Brunk 2004).

  8.  There is now convincing evidence to show that ageing generally is accompanied by a decline in proteasome activity (Caballero et al 2004), and that in many age-related pathologies this function is severely compromised in the relevant tissues (Keller et al 2004). Consequently, it is crucially important to study how the high proteasome activity of young cells is maintained, and determine the underlying causes of the age-related fall in this function. Caloric restriction in animals attenuates the decline in proteasome activity (Selsby et al 2004), which suggests that the system can be manipulated physiologically. It may, therefore, be possible to develop agents that mimic caloric restriction (CR mimetics) which help maintain proteasome activity at levels characteristic of the juvenile state. CR mimetics that maintain juvenile proteasome activity could therefore delay onset of those age-related pathologies where aberrant proteins accumulate.

  9.   Replicative senescence. As a concept, the idea that dividing cells have an inherent limit to their ability to replicate (Hayflick 1965) is a very attractive explanation of cellular ageing. There has been some criticism of the cell culture methods used to investigate and interpret this phenomenon (Rubin 2004) in particular that erosion of end regions of DNA, the telomeres, with each cell division function as a counting mechanism or "clock". Another interpretation is that telomere erosion is due to oxidative stress and replicative senescence is a stress response (von Zglinicki 2003). If we consider ageing to be a "function of rising intracellular oxidative stress rather than chronological time" (Lane 2003) the two interpretations become complementary and help explain the large variability in telomere loss within a cohort of the same age group.

  10.  Replicative senescence and the accompanying phenotypic changes to the cell, have been implicated in vascular disease, reduced skin healing and arthritis. A great strength of this line of research has been in understanding dysfunction of the immune system in later life. Correct function of the immune system is reliant on extremely rapid cell division to expand the population of T cells in response to infection. In later life, new naïve T cells produced by the thymus gland are reduced (Aspinall et al 2004), and as many as 50 per cent of the CD8 T cell pool (involved in response to viral infections) have shorter telomeres, reduced replicative potential (Effros 2004), and therefore reduced ability to respond to infection. Identification of these T cells may be a useful biomarker for ageing, since they correlate with osteoporosis and early mortality (Posnett et al 1999, Wikby et al 2002, Effros 2004). Recent research on the use of Interleukin-7 to stimulate the thymus gland in mice has shown increased T cell responsiveness (Aspinall et al 2004) and is a promising novel therapy.

BIOMARKERS AND LIFE EXPECTANCY

  11.  It is clear from the accumulated knowledge in biogerontology that ageing is not entirely chronologically determined; a rat is old at three years of age, while a three year old human is barely starting life. Although it is true that the risk of ill health increases with time, biogerontology would point to this being due to accumulation of cell and molecular damage. Research into valid and reliable biomarkers of senescence and longevity would help "unmask" the biological heterogeneity of the older population and identify areas for fruitful gerontological research. Discussing indices of a patient's state of health, Borkan and Norris (1980) reported that, from a statistical point of view, a general practitioner's subjective assessment was very reliable. However, there have been numerous attempts to base estimates of life expectancy on a more objective basis. Borkan & Norris' results have been found to be incompatible with the data based on the application of the Seineur Protocol, a rigorous immunological study which led to the conclusion that appearances can be deceptive (Steinmann 1984; Lightart and al 1990).

  12.  Earlier authors had examined numerous human biological attributes as a function of age, but their results did not lead to any definition of biological, as distinct from calendar age. In several cases the choice of function was misguided. For example, Alex Comfort (1969) suggested the visual threshold and pupil diameter as suitable (but see Weale 1970). More recently, there have been suggestions as to what collection of functions might be useful (Jackson, Weale and Weale 2003). The number should be minimal, involve as little of the professional's and patient's time as possible, and involve as few invasive tests as possible. Subjective tests should be avoided. The choice of functions should demonstrably lead to a prediction of health and life expectancy. That this may be possible has been elaborated in Jackson & al's study.

  13.  The Medical Research Council is currently engaged in a longitudinal study, partly devoted to some of the above objectives. Unfortunately the starting age selected is near "mid-life", whereas a great deal of evidence suggests that functional decrement starts much earlier, in the 20s, if not at, or even before, birth (Weale 2004).

  14.  It thus seems appropriate to suggest that the study of biomarkers should form part of public health policy, because its results would be of use in the National Health Service, in pension arrangements, in matters relating to insurance, and in those relating to employment.

  15.  That said, it needs to be added that such data would be of little once-and-for-all value. Demographic and other population changes, skeletal growth, dietary influences, etc may influence the situation at any one time. Arrangements should be made for the creation of a monitoring agency, perhaps in analogy with the Health and Safety Executive, which would collect data at intervals of not more than every 10 years.

ARE THERE GAPS IN RESEARCH?

IS THERE SUFFICIENT RESEARCH CAPABILITY IN UK?

  16.  Some areas highlighted in this paper indicate gaps in our current knowledge and current methodologies.

  17.   Longitudinal studies; there is a fundamental need for longitudinal studies to help control for the cohort effects and increasing variability with age that masks the effects of biological ageing. The approach of the MRC is very welcome, however, we would strongly suggest that such studies begin with very early life (ideally conception or birth) and extend across the life course. "Snap-shot" comparisons of younger and older adults ignores the fact that all the changes described are occurring from the moment life begins; the only way to understand how "young" cells are capable of maintaining themselves more effectively than "old" cells is to study every life stage.

  18.   Biomarkers of ageing; ageing is not simply chronologically determined but due to accumulation of cell and molecular damage. Research into valid and reliable biomarkers would help identify those areas for fruitful research by reducing confounding factors in a heterogeneous older population.

  19.   Cellular and molecular approaches; although oxidative stress is well represented in biogerontological research, some fundamental questions about the control of oxidative stress remain to be answered before this can be translated in real health benefits, including the role of nutrition in early and adult life.

  20.  The study of proteasome function in removing aberrant proteins has potential for relatively rapid production of viable therapies for neurodegenerative diseases and is an area poorly represented in the UK.

  21.  In contrast, research on replicative senescence is well represented in the UK and is much further advanced in making the links between biogerontology and health benefits.

IS RESEARCH BEING USED TO INFORM POLICY?

  22.  There is a recognised tendency, both in the UK and internationally, for clinical and basic biomedical research to be compartmentalized into disease models or discipline specific approaches. Although this is being addressed by the BBSRC (for example the recent strategic area on nutrition and vascular disease throughout the life course), there is still considerable scope for greater collaboration between MRC and BBSRC; for example to fund basic exploratory biological research. In terms of health promotion policy, it is clear that nutritional and epidemiological evidence is being used currently to raise awareness of disease risk factors. It is less clear that biogerontological evidence is, or indeed can currently be, used to inform health promotion policy.

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October 2004




 
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