Below you'll find linked a few papers on the biochemistry of extremely old individuals, those who are in the portion of life in which they are heavily damaged by the processes of aging, most of their former peers are dead, and genetic variations become significant in determining quality of life and remaining life expectancy. A great deal of data is arriving on the biochemistry of the aged. The capacity of the research community to accumulate data on molecular biochemistry, in genetics, in epigenetics, and in the growing diversity of "omics" fields, of which genomics was only the first and least specialized, has for years greatly exceeded the capacity to analyze that data. Those fractions of the community concerned with making sense of it all will be playing catch-up for decades, I believe, given the pace of growth in data on the operation of human cellular metabolism - and given that productive and useful analysis is fundamentally a harder, more expensive, and more uncertain problem than collecting the data in first place. The ongoing revolution in biotechnology means that mountains of omics data are assembled today, and there is every sign that tomorrow's mountains will be an order of magnitude larger. So when you pick papers to read from the ongoing river of new studies that build upon human metabolic data, bear in mind that if the influx of new data stopped tomorrow, there would probably still be enough to productively occupy the research community for years yet. It is an interesting situation, to be sure.
When it comes to aging, it all becomes deeper and more uncertain, of course. Researchers still have a long way to go to completely fill in the high level sketch of how human metabolism works in an ordinary, healthy adult, to turn that high level sketch into a comprehensive accounting of living molecular biology at the detail level. The task of understanding how that vastly complex and poorly understood system then changes over time, and how it goes wrong, and how it behaves in the seemingly endless variety of damaged states that accompany aging rather than in its normal, proper modes of operation in youth ... well, that is a much bigger project. The sheer complexity of our biochemistry is why researchers have struggled to produce safe and effective ways to alter cellular metabolism to slow aging, even when the goal is replicate aspects of well-known and easily studied states such as the responses to exercise or calorie restriction. Producing a slow-aging human by following this path is not a project for our era, but something that will require the far greater resources of biotechnology and computation that will emerge much later this century. Even then, why do this? Aging more slowly because you have a better biochemistry is not rejuvenation, and it doesn't much help those already old and damaged.
Thus to my eyes the best way to look upon the study of human longevity and human genetic and metabolic diversity is as an interesting but presently less important field of scientific endeavor. Extension of healthy life will not come from these studies, but rather from efforts to repair and reverse the molecular damage that causes aging. Given therapies that can achieve that goal sufficiently comprehensively, people will not enter the state of being very damaged and frail, and age-related diseases will not arise. The study of the resilience of some older people in the face of frailty will become a historical curio, in the same way as there is little study of the impact of genetic variations on smallpox survival rates today. That is the future we want to see, and it is one that researchers can work towards today, given present knowledge of the causes of aging, sidestepping our ignorance of the intricate chain of cause and effect linking root cause molecular damage to end result age-related disease. Just as the Romans could use engineering and empiricism to build imposing and functional structures that lasted for centuries, without modern materials science and computational modeling, in a state of comparative ignorance, the very same conceptual approach can be applied to rejuvenation therapies: revert the well-known and well-cataloged differences between old and young tissues, and observe the results, adjusting course as needed.
Plasma lipidomic profile is species specific and an optimized feature associated with animal longevity. In the present work, the use of mass spectrometry technologies allowed us to determine the plasma lipidomic profile and the fatty acid pattern of healthy humans with exceptional longevity. Here, we show that it is possible to define a lipidomic signature only using 20 lipid species to discriminate adult, aged and centenarian subjects obtaining an almost perfect accuracy (90%-100%). Furthermore, we propose specific lipid species belonging to ceramides, widely involved in cell-stress response, as biomarkers of extreme human longevity. In addition, we also show that extreme longevity presents a fatty acid profile resistant to lipid peroxidation. Our findings indicate that lipidomic signature is an optimized feature associated with extreme human longevity. Further, specific lipid molecular species and lipid unsaturation arose as potential biomarkers of longevity.
Last year, we managed to recruit 60 longevity families from Hainan province, a well-known longevity region in China, and performed a complete physical examination on all subjects. Based on this population, we found that the thyroid function was associated with longevity and could be heritable. In this study we expanded the study by investigating associations of the rest blood parameters with age, and associations between generations, aiming to seek candidate factors associated with familial longevity. Associations of blood parameters in centenarians (CEN) with their first generation of offspring (F1) and F1 spouses (F1SP) were analyzed.
In this study, using association and further comparison analyses we identified several blood parameters that may contribute to longevity. First, total cholesterol (TC) and triglyceride (TG) increased with age until 80 years, but decreased in centenarians, indicating that lipid metabolism was improved in the oldest old. A similar trend was observed for LDL-C, although it was not associated with age before 80 years. The changes in lipid levels were consistent with that in other studies. Increased TC, TG and LDL-C concentrations are the most important independent risk factors for cardiovascular disease, the leading cause of adult death worldwide. In this regard, we can assume that the CEN may be less susceptible to cardiovascular disease, and hence, live longer. To understand why the CEN have such a favorable lipid profile, we analyzed the expression of genes involved in lipid metabolism and found some differentially expressed genes between the CEN and F1SP. Based on their known functions, they may confer both beneficial and detrimental effect on regulating lipid profiles, suggesting there is a balance in the regulation of the lipid metabolism in the longevity subjects. However, the overall outcome seemed to reduce lipid levels and thus accounted for the favorable lipid profile in centenarians.
More importantly, we observed for the first time that diastolic blood pressure rather than systolic pressure was improved in CEN compared to the elderly. Blood pressure is a well accepted cause for age-related diseases, not only for the cardiovascular disease, but also for cerebrovascular and/or neurodegenerative diseases, such as cerebral hemorrhage and senile dementia. Indeed, a number of studies have noticed that diastolic blood pressure exerts stronger influence than systolic blood pressure on the occurrence and development of cardiovascular and cerebrovascular diseases. Our results expand the knowledge by extending the age range to over 100 years. Likewise, we managed to identify several candidate genes associated blood pressure. Of notice is the CST3 gene, it has the most significant difference between the CEN and F1SP, and it codes a protein called cystatin c which has been positively associated with systolic pressure but inversely with diastolic pressure, which was well consistent with our observation.
Changes in the DNA methylation (DNAm) landscape have been implicated in aging and cellular senescence. To unravel the role of specific DNAm patterns in late-life survival, we performed genome-wide methylation profiling in nonagenarians (n=111) and determined the performance of the methylomic predictors and conventional risk markers in a longitudinal setting.
The consequences of aging-accompanied DNAm alterations for late-life health and functional abilities are largely unknown. A recent epigenome-wide association study (EWAS) demonstrated that the association between age-related DNAm changes and healthy aging phenotypes in individuals 32-80 years of age is negligible. The results of this study also reveal that the DNAm regions associated with aging phenotypes are distinct from those associated with chronological age. These findings suggest that the CpG sites involved in health-related outcomes in later life are largely regulated by sites other than the established age-related DNAm regions. In addition, using an EWAS approach, we have recently demonstrated that the CpG sites that are associated with aging-related inflammation are largely different from the sites associated with age. This phenomenon is also observable in regard to gene expression profiles and old age mortality. We have previously demonstrated that the genes exhibiting aging-related changes in expression levels are predominantly different from those that predict mortality in late life. These findings underscore the complexity and unknown nature of the genomic factors that control the human health span and late-life events.
Nevertheless, the mortality-predicting genes in our previous study were found to be functionally connected to the nuclear factor kappa B (NF-κB) complex, which is a central mediator in immunoinflammatory responses and has been advocated as the culprit in aging and cellular senescence. Aberrant activation of NF-κB has been reported in various age-associated conditions, such as neurodegeneration, immunosenescence, inflammaging, sarcopenia and osteoporosis, whereas studies involving mouse models have observed that NF-κB activation is a key determinant of accelerated aging and longevity. The results of this study corroborate the role of NF-κB in all-cause elderly mortality; the molecular network constructed from the genes harboring the mortality-associated CpG sites displayed the NF-κB complex as a central mediator. We hypothesize that our findings could relate to the recent observation of a programmatic role of hypothalamic NF-κB and IκB kinase-β activation in the control of the life span in experimental mouse models. Adhering to the conclusion of this mouse study that the decisive role of hypothalamic NF-κB is exerted systemically level through immune-neuroendocrine crosstalk, we suggest that our findings on immune cells might represent the peripheral correspondence of hypothalamic NF-κB activation. However, establishing the systemic-level events that connect NF-κB function to all cause-mortality in aged humans will require further research.