A recently published report from last year's Biomedical Innovation for Healthy Longevity conference, held in Russia, serves as a sampling of ongoing work in the field of aging research; a wide range of views on theories of aging are represented. One thing that strikes me from a review of the topics is that few of the people involved are working on anything related to rejuvenation, or, setting aside the much-needed consideration of biomarkers of biological age, any other projects with near term practical applications likely to significantly extend life. For the most part this is a field concerned with investigation, development of drugs that produce small effects on aging, and little else. The primary thrust is to map the cellular biochemistry of aging in as great a detail as possible, one small step at a time, with a sideline in finding drug candidates that might somewhat alter that biochemistry. Insofar as fundamental research goes, this is indeed the goal of science as a whole, to achieve greater understanding of the complex systems of the natural world. It has been argued that this is not the right focus for those groups that aim for the more rapid production of effective therapies capable of greatly extending healthy life spans, however, given the present state of knowledge.
Regular readers will know the argument already. The research community knows enough about the root causes of aging to strike out and build effective therapies even if the full details of the biochemistry involved have yet to be mapped out. Take senescent cells, for example. Their involvement as a cause of aging has become increasingly clear over the past thirty years of investigation. It is now demonstrated that removing senescent cells reliably reverses aspects of aging and extends life in mice. Yet at the level of cell mechanisms and signals, there lies ahead at least another decade or two of further work to catalog all of the relationships and interactions responsible for the harms caused by these cells. Scientists will undertake that work, of course. But it should not be the focus for clinical research, given that the basis for an effective therapy exists today in the form of destroying these cells, an approach that cuts through the unknown mechanisms, fixing them just as effectively as it fixes the problems that are known and understood.
Cellular senescence is but one example of many. Researchers in general do a very poor job of identifying and addressing root causes in aging, however. Because they are primarily engaged in mapping and discovery, they tend to focus on late stages of aging, working backwards from a state of dysfunction step by step and protein by protein in long and complex chains of cause and consequence. When they propose therapies as a result of their findings, these therapies necessarily take the form of tinkering with the already malfunctioning operation of metabolism - altering the downstream consequences of fundamental damage, rather than repairing that damage. The outcomes are inevitably marginal. Trying to keep a damaged engine effective by changing the oil or running it hot, while failing to replace the worn and damaged parts that are the cause of the issue, is a futile endeavor. This is just as true of our biology. So while there are many interesting items in the full report, just a few of which are quoted below, remember that interesting doesn't necessarily mean useful enough to justify the expenditure of a great deal of effort and funding.
Blanka Rogina (University of Connecticut Health) "Indy reduction maintains fly health and homeostasis". Indy (I'm not dead yet) encodes the fly homologue of a mammalian transporter of the Krebs cycle intermediates. Reduced Indy gene activity has beneficial effects on energy balance in mice, worms and flies, and worm and fly longevity. In flies, longevity extension is not associated with negative effects on fertility, mobility or metabolic rate. Others and we show that Indy reduction extends longevity by mechanism similar to calorie restriction (CR).
Vladimir Skulachev (Moscow State University) in his lecture "Naked Mole Rats and Humans: Highly Social Creatures Prolonging Youth by Delay of Ontogenesis (Neoteny)" considered some physiological mechanisms responsible for longevity of eusocial mammals, i.e. a rodent (naked mole rat) and a primate (human). It is concluded that both naked mole rat and human are no more affected by dynamic natural selection due to specific organization of the socium (naked mole rat) and substitution of fast technical progress for slow biological evolution (human). Since aging is supposed to be a program stimulating evaluability by increasing pressure of natural selection upon an individual, such a program became a harmful atavism for naked mole rat and human. This is apparently why aging as a reason for death is very rare in naked mole rats younger than 30 years and humans younger than 55 years. Such an effect is achieved, at least partially, by prolongation of youth (neoteny). The numerous facts are described indicating that The Master Biological Clock responsible for timing of ontogenesis is retarded both in naked mole rat and in human. In these species, numerous traits of youth do not disappear (or disappear enormously slowly) with age.
David Gems (University College London) spoke on "The origins of senescent pathology in C. elegans". The biological mechanisms at the heart of the aging process are a long-standing mystery. An influential theory has it that aging is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species (ROS) produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair and turnover) protect against aging and increase lifespan. However, recent tests of the oxidative damage theory, some using the short-lived nematode worm C. elegans, have often failed to support the theory. This motivates consideration of alternative models. One new theory proposes that aging is caused by the non-adaptive running on in later life of developmental and reproductive programmes. Such quasi-programmes (i.e. that are genetically programmed but non-adaptive) give rise to hyperfunction, i.e. functional excess due to late-life gene action, leading via dysplasia to the age-related pathologies that cause the late-life increase in mortality. Here we assess whether the hyperfunction theory is at all consistent with what is known about C. elegans aging, and conclude that it is.
S. Michal Jazwinski (Tulane University Health Sciences Center) presented "Metabolic and Genetic Markers of Biological Age". Biological and chronological age are not the same, as individuals depart in health from the average. Taking a systems approach, we developed an objective measure of healthy aging, a frailty index (FI34) composed of 34 health and function variables. FI34 is a much better predictor of mortality than is chronological age; therefore, it directly reflects biological age. It increases exponentially with chronological age, but it does so more slowly for offspring of long-lived parents. FI34 is also heritable. Thus, it can be used in genetic analyses. The patterns of aging described by the variables in FI34 are very different for offspring of long-lived and short-lived parents. We have examined the association of the components of energy metabolism with FI34 in the oldest-old. Surprisingly, there is a positive association of FI34 with resting metabolic rate (RMR). This points to the rising cost of maintenance of integrated body function with declining health during aging.
Daniel Belsky (Duke University) presented "Quantification of biological aging in young adults". Population aging threatens to bring a tidal wave of disease and disability. Strategies to prevent or treat individual diseases will be inadequate to contain costs and preserve economic productivity; interventions that address the root cause of multiple diseases simultaneously are needed. We studied aging in 954 young humans, the Dunedin Study birth cohort. To quantify biological aging in these individuals, we tracked multiple biomarkers across three time points spanning their 20s and 30s. We devised a longitudinal measure that quantifies the pace of coordinated physiological deterioration across multiple organ systems. This measure, the "Pace of Aging," showed substantial variation in young, healthy adults who had not yet developed age-related disease. Young adults with faster Pace of Aging were, by midlife, less physically able, showed cognitive decline and brain aging, self- reported worse health, and looked older.
Tamas Fülöp (University of Sherbrooke) presented "Are there any reliable biomarkers for immunosenescence?". Aging is accompanied by many physiological changes including those related to the changes in the immune system. These changes are called immunosenescence which is accompanied by the inflammaging phenomenon. Many biomarkers have been proposed to describe these age-associated changes in the immune system. One of the most consistent is the chronic Cytomegalovirus infection. Most of the elderly are affected in developed countries which about 70% and in developing countries about 100% at the age of 80. Despite the numerous studies there is no consensus which role the recurrent CMV infections play in the alterations of the immune system namely in the inflammaging process and in the more consistent phenotypic alterations of T cells.
Alexander Kulminski (Duke University) reported "Can age-specific genetic effects be relevant to biological age?". Living organisms are getting older and eventually die at a certain age. The actual time an organism has been alive refers to chronological age (CA). However, not all organisms die at the same chronological age even if they are of the same species. The idea of biological age (BA) is that the differences in lifespan of these organisms can be due to an internal clock. For humans, BA refers to how old that human seems. A problem, however, is how to quantify BA. A promising approach could be to express BA in terms of measurable phenotypes such as biomarkers. As phenotypes, biomarkers represent endpoints of a cooperative work of genes in an organism. Accordingly, BA could readily have a genetic origin. Does it necessarily imply that there should be specific genes regulating BA? The answer is not straightforward.
Ksenia Lezhnina and colleagues presented "Signaling pathways signature of sarcopenia identified by iPANDA algorithm." Sarcopenia is a losing muscle mass and function with aging. Decreased strength and power of muscle function may contribute to higher risks of accidents among older people and affects quality of life. Until recently sarcopenia was not even considered as a pathological condition and as a consequence clinical definition and diagnostic criteria is poorly developed. Mechanisms underlying sarcopenia are extensively investigated but still not fully understood. In order to study this we compare transcriptomic profiles of muscle tissues from young and old people, both women and men. We assume that aging process starts from the fourth decade of life. We apply a new algorithm in silico Pathway Activation Network Decomposition Analysis (iPANDA) to transcriptomic data to find signaling pathway signatures of aging in muscle tissues. Common pathway signatures can be considered as a target for development of new approaches for sarcopenia treatment.
Matt Kaeberlein (University of Washington) presented "Effects of transient mid-life rapamycin treatment on lifespan and healthspan". The FDA approved drug rapamycin increases lifespan and improves measures of healthspan in rodents. Nevertheless, important questions exist regarding the translational potential of rapamycin and other mTOR inhibitors for human aging, and the optimal dose, duration, and mechanisms of action remain to be determined. Here I will report on studies examining the effects of short-term treatment with rapamycin in middle-aged mice and dogs. We find that transient treatment with rapamycin is sufficient to increase life expectancy by more than 50% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodelling of the gut microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine, along with a dramatic shift in the cancer spectrum in female mice. In dogs, we have defined a dose of rapamycin that is well tolerated, and initial results are consistent with improvements in age-associated cardiac function similar to those observed in rapamycin-treated mice. These data suggest that a transient treatment with rapamycin may yield robust health benefits in mice, dogs, and perhaps humans.
Maxim Skulachev (Mosсow State University) presented "Development of mitochondrially-targeted geroprotectors: from the molecular design to clinical trials and marketing strategy". Research and development of geroprotectors is always challenging when the project passes from theoretical and laboratory work to routine drug development (preclinical and clinical trials and medical authority approvals). In this talk, we present an example of an anti-ageing RnD project aimed on creation of geroprotector drugs on the basis of rechargeable mitochonrially-targeted antioxidants. Our strategy is to get the potential geroprotector approved as a drug against a certain age-related disease, and then to expand the list of indications for this pharmaceutical to other traits of ageing. We synthesized a series of novel organic compounds, derivatives of plastoquinone. Our first pharmaceutical was designed for local administration (in the form of eye-drops) to speed up the process of clinical development and to get the clinical data faster. At the current stage of the project our first drug Visomitin (Rx eye drops with antioxidant SkQ1 helping in such age-related diseases as dry eye syndrome and cataract) has been approved and marketed in Russia and successfully passed phase II clinical trials in US. Systemic oral form of SkQ1 has entered clinical trials in Russia and completed preclinical program in US and Canada. We consider our project to be a valuable attempt to slow down human aging by a mitochondrial approach.