Abstract
Extending life expectancy and lifespan: How far can we go?
An October editorial in the highly cited journal Nature makes a plea for science to respect ‘the limits to human lifespan’. The plea follows a study in the journal using demographic data to model a lifespan beyond which human beings simply cannot go – just because they’re human. 1 Thus, according to the study, maximum lifespan is, in contrast to life expectancy, generally assumed to be a stable characteristic of the species.
This principle, say the authors, depends on the distinction between ‘lifespan’ and ‘life expectancy’; it is the former which seems finite and the latter subject to inexorable (but ever diminishing) increments, notably among women. Indeed, life expectancy at birth has increased in most countries over the past century, not because people have longer lifespans, but mainly because infectious disease does not kill as many infants as it once did. Factors such as poverty and warfare have conspired to decrease life expectancy, but our better public health, nutrition and lifestyle have all contributed to its gradual extension.
Lifespan, unlike life expectancy, is dependent on a multiplicity of genetic, developmental and metabolic factors, which probably means, say the study authors, that very few humans will ever make it past their 120th birthday. Indeed, Nature reports that the oldest recorded age at death (122) was in the 1990s, and that the greatest improvement in lifespan survival appeared to plateau around 1980, further suggesting that human lifespan may have a natural limit. Thus, in this study model, age at death in four countries (France, Japan, UK and USA) did not increase significantly after 1995 – and in fact decreased slightly by 0.28 years per year, with no further increases observed thereafter.
With further calculation, the authors report that the probability of a maximum reported age at death exceeding 125 in any given year is less than 1 in 10,000. Thus, while there is no scientific reason why efforts to extend lifespan could not be successful, ‘the possibility is essentially constrained by the myriad of genetic variants that collectively determine species-specific lifespan’.
Yet the quest for the elixir of life seems to fascinate science and the public alike. Within the past few months two reports, both originating as abstracts at the Annual Meeting of ESHRE, have each suggested that the menopause may be ‘reversed’. First, Evelyn Telfer and colleagues from the University of Edinburgh reported in a prize-winning presentation that the ABVD combination of cancer drugs used in treating Hodgkin lymphoma does not (as do most chemotherapies) reduce the number and development of ovarian follicles. 2 Indeed, her analysis of ovarian biopsies collected from a small group of young patients showed an increase in the number of non-growing follicles in the ovarian cortex of those treated with ABVD for lymphoma. The implication of the study – as suggested in one or two subsequent press reports – was that the ABVD drugs may have the potential to replenish the ovary with newly developed follicles.
This was the same biological timebomb which Jonathan Tilly exploded more than a decade ago when his group proposed the existence of female germline stem cells in the mammalian ovary which appeared able to support new oocyte production during adulthood. Thus, in this one report, Tilly overturned an essential biological doctrine that the number of follicles in the ovary is finite and degenerates until depletion and the menopause. Just two years ago, he described the isolation of these elusive stem cells from human ovaries and their manipulation into bona fide oocytes. These same ‘egg precursor cells’ are now the basis of a controversial adjunctive IVF treatment which seeks to energise oocytes from the mitochondria of these same egg precursor cells.
Another study – of just eight subjects – also presented during ESHRE’s Annual Meeting this year – investigated ‘ovarian rejuvenation and folliculogenesis reactivation’ in perimenopausal women after autologous platelet-rich plasma treatment. 3 The latter, the investigators explained, is a concentrated source of growth factors and cytokines, which in numerous studies have demonstrated beneficial effects on tissue and angiogenesis regeneration. In this study, the plasma preparation was infused into the ovaries of eight perimenopausal women who had been without menstrual cycles for around five years. Successful ovarian rejuvenation was confirmed by menstrual cycle restoration around three months after treatment. Oocyte retrieval was later successful in all cases. The study was taken up by the magazine New Scientist, whose report sparked widespread interest. 4 The results, said investigator Konstantinos Sfakianoudis, offer ‘a window of hope that menopausal women will be able to get pregnant using their own genetic material’; he added that the platelet-rich plasma had been given to around 30 women all aged between 46 and 49.
So far, science seems to find the reproductive lifespan more amenable to extension than the absolute lifespan – as reflected in its simplest form in the many cases of successful egg donation and IVF in postmenopausal women. Yet, if the revised biology of Tilly and colleagues does prove as valid as he himself proposes, there may be in the stem cell-driven regenerated physiology of a new reproductive lifespan the model for a lifespan which the human species has not yet revealed. However, as Nature suggested, elite athletes might shave a few milliseconds off the world record for the 100 m, but they’ll never run it in, say, 5 seconds, or 2. ‘Human beings are simply not made that way’, said Nature.
Meanwhile, the latest life expectancy report from the WHO shows that life expectancy has increased by about 5 years in the last 15 years, the fastest rise seen since the 1960s. The biggest gains were seen in Africa. According to the report, average life expectancy for a baby born in 2015 was 71 years for women and 69 for men, with women in Japan and men in Switzerland typically living the longest.
References
Hormone therapy and the timing hypothesis
It is now 14 years and 5 months since the first Women’s Health Initiative (WHI) study appeared in the Journal of the American Medical Association, yet time has done little to heal the upsets it caused. Has ever a large-scale randomised trial been so discredited for so long? For there now seems widespread agreement that the progestogen in the combined therapy (medroxypropgesterone acetate) was inappropriate for the study population, the route of delivery less than optimum in a trial designed to test cardiovascular risk, and the age range ill-suited to a study of postmenopausal hormone therapy.
Speaking on the last subject at this year’s IMS World Congress on Menopause in September, WHI investigator Robert Langer, a principal at one of the trial’s 40 clinical centres, said it was wrong to generalise results from this older patient group (aged up to 79 and on average 12 years beyond the menopause) to all postmenopausal women, especially those whose only indication for treatment was the relief of symptoms.
‘Let’s get past the misinformation and hysteria of the WHI and stop denying the benefits of hormone therapy,’ said Langer. ‘There’s good evidence from 50 years of observational studies and clinical trials that the benefits outweigh the risks when started early.’
This whole question of timing and age beyond menopause – which now seems the biggest bone of contention in the WHI’s results – was prompted by the WHI itself in a U-turn of epic proportions. Thus, in 2007, the WHI investigators themselves following a ‘secondary’ analysis of all the cardiovascular data formally acknowledged that ‘women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause’. 1 As a disingenuous counterpoint to any accusation that this might constitute a U-turn, the US National Institutes of Health press release at the time said that the effect may vary by age and that these findings ‘are consistent with the primary publications from the WHI trials’. It was out of this re-analysis that arose the ‘timing hypothesis’ for postmenopausal hormone therapy.
Since then, other studies – randomised trials included – have supported the timing hypothesis and the contention that the WHI’s extrapolation of its results to the whole range of postmenopausal age groups had done a disservice to many younger women who would otherwise have benefitted both from its cardiovascular effects as well its relief of symptoms. A statement from the International Menopause Society, published in 2011 and cited by Langer himself in an introduction to Climacteric’s 10-year review of the WHI, said: The excessive conservatism engendered by the presentation to the media of the first results of the WHI in 2002 has disadvantaged nearly a decade of women who may have unnecessarily suffered severe menopausal symptoms and who may have missed the potential therapeutic window to reduce their future cardiovascular, fracture and dementia risk.2,3
Thus, earlier this year a RCT from Howard Hodis and colleagues reported in the New England Journal of Medicine found that oral estradiol was associated with less progression of subclinical atherosclerosis (measured as carotid artery wall thickness) than was placebo when therapy was initiated within six years after menopause, but not when started 10 or more years after. 4 The same group has recently found some support for the timing hypothesis in cognitive effects, finding that estradiol initiated within six years of menopause has no adverse effect on cognition at 2.5 years (in contrast to findings from the Women’s Health Initiative Memory Study). 5
But perhaps the biggest recent shock to the WHI’s initial all-embracing age inclusion (that is, ‘most women with an intact uterus in the decades following menopause’, according to the 2002 paper) came a year ago when researchers from Finland in a registry study of more than 300,000 women taking hormones between 1992 and 2009 found that in the first year after discontinuation of therapy a woman’s risk for cardiovascular mortality is significantly higher than if she’d continued the therapy. 6 The results were first presented at last year’s meeting of the North American Menopause Society, where investigator Tomi Mikkola said that in women aged 50–60 ‘we clearly see’ that discontinuation ‘is doing more harm than benefit’. ‘If women are otherwise healthy, they could continue hormone therapy as long as they wish’. The same group in a similar registry study (almost 500,000 subjects) recently found a reduced risk of breast cancer in women with a history of hormone use, with a significantly larger risk reduction in the 50–59 years age group compared with 60–69 s or 70–79 s. 7
There was a suggestion in Langer’s presentation to the World Congress on Menopause that the WHI did have results calibrated according to age stratification in its initial findings, but the writing group went ahead with publication with only the assertion that the results applied to all.
References
Still no reliable test to predict age at menopause
Despite its accuracy in the prediction of ovarian reserve and likely response to ovarian stimulation for IVF, anti-Mullerian hormone (AMH) remains an unsuitable marker for predicting age at menopause in everyday practice. This was the conclusion emerging from a cohort study follow-up of 265 ovulating women who were aged 21–46 years at recruitment between 1992 and 2001; 155 were available for analysis and, by the second follow-up in 2013, 88 had become postmenopausal. 1
Initial analysis showed that patient age and ovarian reserve tests (AMH and antral follicle count, AFC) were both significantly correlated with time to menopause, but multivariable analysis, adjusting for baseline age and smoking, showed only AMH as an independent predictor of time to menopause. However, even the predictive effect of AMH became less strong with increasing patient age, such that individual AMH-based age at menopause predictions did not cover the full range of menopausal ages.
The authors note that a reliable predictive test of menopausal age is becoming more and more urgent. An increasing number of women, they write, are seeking expensive fertility treatment for age-related infertility, while the health risks of a premature menopause (premature ovarian insufficiency, POI) are now becoming clearer. Indeed, a systematic review in September of premature or early-onset menopause found a higher risk of coronary heart disease, cardiovascular mortality and overall mortality in women who had premature or early-onset menopause when younger than 45 years. 2
A full European guideline published earlier this year put the definition of POI as loss of ovarian activity before the age of 40, with a prevalence of 1%. 3 With AMH and AFC recognised as relatively inaccurate predictors, the guidelines recommended diagnosis based on ‘menstrual disturbance’ (oligo/amenorrhoea for at least four months) and biochemical confirmation (elevated follicle stimulating hormone (FSH) >25 IU/l on two occasions >four weeks apart). As suggested in the systematic review above, the guidelines warned that ‘untreated POI is associated with reduced life expectancy, largely due to cardiovascular disease’.
However, as the authors of the AMH study note, FSH itself has not been without controversy in its role for menopause prediction. One study found that FSH became non-significant when AMH was added to the prediction model, while another showed that FSH lost its predictive value in a model next to female age. ‘Taken together’, say the authors, the results of the present study and published data strongly suggest that AMH is the better candidate when it comes to providing individual corrections on the general forecast for the occurrence of menopause in women with a normal regular cycle.