This is a progress report on the changing state of human longevity during the five-year lifespan of this blog. It reviews major trends and forces impacting on our lifespans, both scientific and social. Longevity can be viewed either from the societal viewpoint or the personal viewpoint. It is impossible to comprehend one fully without considering the other. From a personal viewpoint, enhanced longevity may come from taking a supplement or a “longevity drug” or pursuing a certain lifestyle practice. And it also can come about as a result of background happenings in our society such as public health measures: cleaner air and water, availability of bike and walking paths, and less tobacco smoke. I review some important trends here that are manifest today, and discuss how I see them to be interacting so as to create longer and healthier lives. Five years ago, I speculated that the efficacy of practical interventions for life extension can be expected to double every seven years, proposing this as “Giuliano’s Law.” At the end of this blog entry I look again at that speculation.
So, this is a “big picture” blog entry looking mainly at the interaction of multiple factors impacting on longevity, how they relate, and how they are unfolding. It is a progress report, a snapshot from today’s view. The main content of this blog is a summary review of trends with links to many (but by far not all) of the some 460 blog entries we have generated.
Jim Watson and I have published blogs of “Top-12 things I have learned about aging in 2013(ref)(ref),” This blog goes further back and offers a five-year view, one that combines objective developments and personal opinion.
1. SOCIETIES ARE AGING. As a general trend, in all healthy societies in the world we are living longer and longer. This is an observed and unmistakable phenomenon, a trend since before the beginning of history that continues to accelerate. The trend is widely recognized by international agencies and has resulted in new commercial initiatives to address the needs of aging and retiring “baby boomers.” We have written about it extensively(ref)(ref)(ref)(ref).
Here is one graphical look at the history of human lifespans and projecting where they are headed:
Image source, The line for the United States in 1970 has moved to the right to where it is now close to the leftmost dotted line, The authors of the source article project human longevity increase in humans based on animal studies if calorie restriction mimetics can be found which effectively control inflammation and inflammatory-related diseases. I am quite sure that achieving radical life extension will require addressing many additional biological pathways in addition to inflammatory ones, but that the projected extension of human lifespans may well be possible.
2. SCIENCE OF AGING KEEPS EXPANDING: There have been significant advances in scientific understanding of fundamental biological processes and how they impact on aging
- One field hardly visible to me five years ago but now of major proportions is epigenitics. DNA Methylation, histone acetylation and chromatin remodeling are the classical areas of epigenetics. The new frontier in epigenetics appears to be understanding the roles of the multiple species of non-coding RNAs and understanding what particular RNAs impact on gene regulation in which particular circumstances. Of particular interest are long non-coding RNAs, micro RNAs, and other RNA species such as circular RNAs. We have written several blog entries about these topics(ref)(ref)(ref)(ref)..
- Of great interest also is what happens to DNA and RNAs with aging. Concern includes age-related global and local DNA methylation, proliferation of long repeat DNA sequences and circular RNAs, and changes in the DNA repair machinery as it is impacted by various molecular processes and aging(ref)(ref)(ref)(ref)(ref)(ref)(ref)
- Another area where there has been an immense swelling of research during the last five years has to do with molecular pathways that can regress cells to earlier age states, particularly all the research related to induced pluripotent stem cells (iPSCs). There is a burgeoning field of research in regenerative medicine involving the use of iPSCs as more and more stem cell therapies are coming into actual use (ref)(ref)(ref)(ref)(ref)(ref).
- The period has seen deepening of understanding as to the functioning of key molecular pathways related to life and aging and how these pathways interact. We see that we can start with any key biological system in the cell whether this is the nucleus, the mitochondria chromosome telomeres or other organelles, and trace interacting pathways to essentially all other important biological systems and organelles. One of several ways to start looking at aging, for example, is in terms of REDOX states(ref). Another perspective is identified in the blog entries on the view from the end of the chromosome(ref)(ref)(ref). Autophagy is another key process related to both health and longevity(ref). Also, we can start with any key longevity related molecule like SIRT1, IGF-I, Nrf2 or Klotho and trace how these impact on key longevity pathways which in turn impact on multiple other important pathways. In summary, we are continuing to discover the complete systems nature of biology which consists of numerous interacting control and homeostasis–maintaining loops. (ref)(ref)(ref)(ref)(ref)(ref)(ref).
3. NEW DISCOVERIES CAN COME FROM THEORY OR OBSERVATIONS. Observed longevity phenomena are leading to theoretical understanding as well as the other way around. These in turn inform interventions which can enhance health spans and lifespans. Not all science starts with a theory and works towards practical results. In many cases an observation leads to a whole body of theoretical understanding. This is the case, for example for the mTOR pathway, where suppression of this pathway is a proven way to extend longevity in a number of animal models. mTOR stands for mammalian target of rapamycin a substance that was discovered in the soil of Easter Island and later refined into the drug rapamycin, So first came the observation of what rapamycin did and after that came understanding of the mTOR pathway which is suppressed by rapamycin. Examples of discoveries during the last five years and being very much discussed today include:
- Heterochronic parabiosis and GDF 11. It was observed that when the bloodstream of an older mouse is crossed with that of a paired younger mouse, the older mouse experiences rejuvenation in numerous dimensions, while the younger mouse appears to get older. This has led to a search for the factor or factors in the blood involved in this rejuvenation. One of the factors has been recently discovered, GDF 11. This factor is known to produce rejuvenation effects in the heart, cardiovascular system, brain and nervous system and possibly other systems as well. Some key publications related to the discoveries appeared only this month(ref)(ref)(ref)(ref)(ref).
- Mitochondria. There have been a series of research discoveries associated with mitochondrial health, On the one hand, these discoveries involve understandings of key molecular biological pathways, such as how events in a cell nucleus can impact what goes on in mitochondria, how dysfunctions in telomere-maintenance pathways can lead to problems in DNA repair and mitochondrial respiration and redox state. Also there is increased understanding about the possibility of practical interventions to enhance mitochondrial health and possibly longevity: NMM, NR, mitoQ, and buckyballs (ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref).
- Diseases. There has been increasing understanding of the processes involved in age-related disease processes, not only cancers (ref)(ref)(ref)(ref)(ref)(ref) but also many others including Parkinson’s disease(ref), sarcopenia(ref), MRSA(ref), lymphoma(ref)(ref), lupus(ref), and infectious diseases(ref).
- Interspecies interdependencies. Another area of increasing both theoretical and practical interest relates to bacterial biomes, interspecies signaling, quorum sensing and high degree of interspecies interdependency(ref)(ref)(ref). There has been particular interest in the gut biome, for example(ref).
- Circadian rhythms, These profoundly affect and are affected by gene expression(ref)(ref)(ref).
- Neural and brain health and neurogenesis, and muscle health, all in relationship to aging (ref)(ref)(ref)(ref).
- Pathway links between inflammation, aging and cancers, There may be interventions that serve to minimize all three of these(ref)(ref)(ref))(ref)(ref).
- Key molecules. We have often returned to certain molecules, particularly ones that serve key signaling functions, including P53, NF-kappaB, IGF1, species of ROS, sirtuins, Nrf2, heat and cold-shock proteins, and key gasses(ref)(ref)(ref)(ref)(ref).
- Some findings have been negative. For example, telomere extending supplements are unlikely to work(ref)(ref) and you can forget about 1-a-day multivitamin supplements(ref). The old free radical theory of aging is dead(ref) and is replaced with a much more sophisticated version involving mitochondria.
- Systems biology and quantum biology offer new and alternative perspectives on biological phenomena(ref)(ref),
- Klotho-related results. There has been a steady increase in the perceived importance of Klotho for longevity, mental health, and retaining full cognitive capability in aging. For background, you can check out my 2011 review article on Klotho. There have been many important subsequent results and I plan to publish an updated blog entry on the subject soon. In the interim, you may want to check out a few relevant research publications(ref)(ref)(ref)(ref)(ref).
- Key cell components. We have looked at additional key cell components beyond those in the nucleus and mitochondria, and the roles they play in health maintenance disease processes and aging. An example is microtubules(ref). Another is the endoplasmic reticulum(ref)(ref).
- There is exponential growth in the sciences related to aging. Publication rate provides a measure. For example, consider items indexed in PUBMED, the general medical-related literature:
PMID publications in PUBMED
|YEAR NUMBER||ENTRIES||NUMBER ADDED||% INCREASE|
So, the cumulative impact for seven years would be around 45% and growth is more or less exponential. However the growth rates for medium-hot area of research related to longevity are much greater. For example, for sirtuin, there were 16,286 publications in 2006 and seven years later there were 69,936, an increase of 329% For klotho there were 43 publications in 2006 and 192 in 2013, an increase of 347%. For iPSC there were 47 publications in 2006 and 434 in 2013, an increase of 823%. For ncRNA there were 47 publications in 2006 and 168 in 2013, an increase of 257%. These numbers suggest far more than doubling of knowledge in key longevity-related topics over a 7 year period.
- Grand Unified Theory of biology, Health and Aging (GUT). As we have been studying more and more biological pathways and phenonena and integrating our knowledge gleaned from diverse disciplines, I believe the outlines of a comprehensive GUT are starting to emerge, as well as new insights into the process of evolution (ref)(ref)(ref)(ref). I believe Jim Watson joins me in this perception.
- The last five years have, for me at least, seen the emergence of a number of new and practical health and antiaging interventions, ones soundly grounded in research and that can be widely adopted today. These interventions can involve approaches such as stress pathway activation to generate hormetic stress signaling, overcoming age-related restraints on gene activation such as DNA promoter site methylation, and promoting mitochondrial health.
- Uses of specific phytosubstances to promote health via specific and sometimes multiple pathways, neuroprotection and protection against cancer, microglial activation and other disease processes. Exploitation of xenohormetic substances and plant-based RNAs. (ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref).
- Practical applications of hormesis and conditioning approaches as well as improved understanding of stress-response pathways and how to use them to promote health(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref).
- Uses of liposomal and nano-formulations of healthful substances to greatly enhance their bioavailability and increase effective doses without incurring side effects(ref)(ref)(ref).
- There has been a stream of new findings relating to health properties of food substances. Also, we have published original articles in this blog related to stressing fruits and vegetables to increase their healthfulness. (ref)(ref)(ref)(ref).
- Longitudinal observations of centenarians and super-centenarian population cohorts have also been yielding a wealth of observations relating to genetics, lifestyles, diets and the stresses encountered(ref)(ref)(ref)(ref)(ref). The results of these observational studies can be correlated with molecular biology studies of centenarians(ref). In my opinion, they lend credibility to suggested practical interventions we have identified for longevity such as use of hormetic stresses as well as careful attention to diet.
In summary with respect to science, there has been an increasing rate of breakthrough discoveries and upwards integration of knowledge. We have already identified and are increasingly testing novel longevity-enhancing strategies. And we may be getting closer to discovering even more-powerful anti-aging interventions
- There have been steady improvements in engineering technologies related to research, biotechnology and practices. These include better and lower cost diagnostic tools and techniques, more and better predictive biomarkers, more economic abilities to do large scale scanning, extension beyond genome scanning to include epigenetic indicators, methylome’s, transcriptomes, improved bioreactors and other bioproduct manufacturing techniques and equipment, etc, Genetic Engineering and Biotechnology News is a definitive biotechnology sector trade publication which announces a variety of new approaches, innovative and lower-cost biotech technology every month.
- Big Biotech is a powerful economic engine propelling life sciences innovation. The world biotech industry had sales of $47 billion in 2006 and estimated $133 billion in 2013. A 7-year increase of 183%. This industry thrives on innovation. I believe it plays a similar role in the 21st century life-sciences revolution that the semiconductor industry played in the 20th century information and communications revolution.
- “Big Data” and bioinformatic tools are allowing a variety of studies leading to levels of understanding hitherto impossible. One application is determining biological pathways common to multiple disease processes as well as aging(ref); another is to accelerate drug discovery(ref). Another application is targeted repurposing of already-approved drugs and their use in personalized medicine(ref). There are additional applications of big data for personalized medicine(ref) and for improving the effectiveness of healthcare(ref).
- There is increasing consciousness on the part of the population of the importance of maintaining wellness(ref)
- new campaigns focusing on diet, particularly with respect to obesity and type 2 diabetes
- increasing public sophistication with regard to diets
- acceleration of focus on fitness
- new focus on disease prevention in the Affordable Care Act(ref)
- Personal electronic activity and biomarker tracking. More small sophisticated wearable devices, “smart scales” and other personal health-indicator measuring devices are coming on the market, ones that constantly or daily monitor health indicators and communicate them wirelessly to a central personal “health and fitness” database. Marketed as health and fitness devices instead of medical devices, they are available to all consumers. The market for these devices is becoming highly competitive, there being a large number of “activity trackers” now being sold. Fitbit sells tiny gadgets that measure steps, flights of stairs climbed, estimates calories burned daily and tracks sleep patterns. Using the fitbit Aria scale, the measurements also include weight, body lean-to-fat ratio and BMI. Performance charts and records are automatically uploaded and available on computers and mobile devices anywhere. The Withings devices measure the same indicators plus pulse rate, blood pressure and blood oxygen. I expect we will see more and more biomarkers included in the list as time goes on, a relatively easy picking being blood glucose for example. I expect there will be evolution to the point where hundreds of health biomarkers will be automatically tracked and sophisticated software will provide interpretations, daily health guidance and medical alerts.
- Health and wellness apps. The Apple iTunes Store (iOS) and Google Play (Android) each offers hundreds of Health and Fitness apps(ref)(ref)(ref) for smart cellphones and tablet devices. Most are free or cost less than $4. In 2009, these did not exist. Last week there was news that Apple is focusing on health and fitness in iOS 8 with its new ‘Healthbook’ App(ref).
- The maturation of the Baby Boomer population. Large numbers of people are entering the range where they are susceptible to age-related diseases but wish to maintain their own health and wellness. The size and affluence of the Boomer market provides a major incentive for entrepreneurial innovation related to health and wellness. Social innovations may have major health impacts. Examples include bike lanes in cities, subsidized exercise and wellness services, and public health campaigns. A large number of commercial organizations are mobilizing to support the Boomer population and have increased their focus to the affluent retiring boomer population. Traditional organizations concerned with elders, like the AARP, have shifted their focus to the health wellness and vitality of those over 50.(ref)(ref)(ref)(ref).
- Innovations in wellness and health care are supplementing the existing highly-institutionalized health care system. There is ongoing expansion in the numbers and scopes of employee wellness programs(ref). AARP just sponsored a LivePitch event in Boston on May 9, 2014, where innovators-entrepreneurs pitched their health innovations for people 50 and over. Videos of the pitches can be linked to here.
- Walking and biking for health. Many progressive city and local governments are building bike lanes and paths, closing streets to auto traffic, enhancing public transportation options, implementing rail-to-trail paths and taking other steps that encourage walking and biking exercise while reducing auto emissions(ref).
- Shifts in medical practice paradigms. These are evolving slowly but definitely towards being more science-based. For example, there is closer tying of cancer therapies to biomarker indicators of specific kinds of cancers. This is part of a long-term shift to personalize health and medicine(ref)(ref).
- New public health initiatives like ones to further curtail smoking, to control childhood obesity by getting harmful sugars, starches and fats out of school lunch menus, and for getting kids moving. There is greater focus on air and water quality, automobile safety, product safety, workplace safety, etc.(ref)
- Market for healthier foods. There is slowly growing appreciation for basic rules of nutrition. Along with this, immense markets have emerged for organically grown fruits and vegetables, free-range meats, cage-free chickens, and low-calorie and low fat products. Supermarket shelves feature increasing numbers of products which claim to be “all-natural” “fat-free,” “sugar-free” or “gluten free.” In many cases, such health claims associated with packaged foods are misleading or irrelevant. For example, a number of sugar-laden breakfast cereals feature on their boxes in giant print that they contain vitamins and minerals. Other products announce that they are “fat-free” but in fact contain large amounts of sugar and are hardly good for you. However, food labels are more stringent than they used to be, allowing aware consumers to discover packaged food contents if they take time to read the fine print.
- Rules associated with medical reimbursement. Some changes in these mitigate towards a greater focus on health and wellness. An example is the Hospital Re-admissions Reduction Program, which reduces government payments to hospitals which have too many re-admissions. Thus, hospitals have a financial incentive to emphasize the importance of wellness measures to patients being discharged(ref). This is one example of how the runaway costs of the current healthcare system in the United States is creating powerful incentives for wellness. The results will be enhanced longevity
- Wellness is emerging as a major thrust of large institutions who have played major roles in conventional health care delivery including health insurance companies and HMOs. Johnson and Johnson, United Healthcare and Kaiser Permenente are examples of such organizations.(ref)(ref)(ref)(ref).
From the broadest perspective, a combination of better scientific knowledge, social trends and initiatives, industry and engineering developments are already propelling the general populations in our country and in other advanced societies towards greater health and enhanced longevity. It is not just that science will do this in the future; it is already happening by the interaction of science, social and commercial developments and engineering developments. Extending human lifespans is not just something that is going to be in the future. It is something very much with us in the fabric of what is happening right now.
From a personal perspective, I believe that the swelling stream of scientific knowledge about health and longevity is increasingly enabling earlier adapters to live lives that are longer, healthier, and more productive than the lives experienced in the general population. Enhanced life extension is increasingly available for those willing to learn about how to pursue it and who are willing to modify their lifestyles and habits to bring it about.
Is such a projection reasonable? Many highly reputable scientists think so. “Earlier this year, researchers at the U.K.’s University of Cambridge and the Medical Research Council reported that people who exercise regularly, don’t smoke, limit their alcohol intake and eat five servings of fruit and vegetables a day live, on average, 14 years longer than people who didn’t.(ref)”
Reviewing Giuliano’s Law
How do I assess all the above in terms of effectiveness of practical longevity interventions? In March 2009, I posted a blog entry identifying what I called Giuliano’s Law (I must admit, a rather immodest naming act). As originally stated:
Starting now, every seven years will see the emergence of practical age-extension interventions (ones that have a potential of leading to extraordinary longevity) that double the power of the interventions available at the start of the 7 year period. That is, on an average basis, the practical anti-aging interventions available at the end of a seven-year period will enable twice the number of years of life extension than did the interventions available at the start of the period. Life extension is measured in years of life expectancy beyond those actuarially predicted for a given population starting in a certain base year.
I predicated Giuliano’s Law based on Moore’s Law as a model – the Law for microprocessor chips that stated: every two years, at a given price point, the power of a commercially available chip approximately doubles. That Law had been in operation for four decades in 2009. And it still appears to be operational today. For many of those years the doubling period was only 18 months, though I think it is now somewhat more than two years. I asked myself what were the scientific, engineering, commercial, economic and social factors that were driving Moore’s Law starting in the 1970s. The operation of the Law was and continues to be driven by a combination of such driving forces, not just on any one, but by a synergistic combination of all of them. And then I asked myself if there were equally compelling and interacting driving force factors affecting health and longevity today. The answer was definitely yes, and this was the basis on which I predicated Giuliano’s Law. I published a subsequent blog entries back in 2009: Factors that drive Giuliano’s Law which laid out the driving forces behind the operation of the Law. In a sense, this current blog entry is an update of that one, laying out driving forces for the Law as they appear even more powerfully today, five years later. And, several of the factors listed above were not visible in 2009. Thus, it may be that Giuliano’s Law with its projected 100% increase in effectiveness longevity interventions over a 7-year period is too conservative. Only time will tell.
Of course Giuliano’s Law has to be in the nature of a statistical projection. Time of death for anyone will be a stochastic variable depending on numerous personal and environmental factors and on luck. If you get mashed badly by a bus, a careful history of longevity interventions won’t help.
I strongly suspect that the Law is valid although 8 years may not be the correct doubling period My own anti-aging regimen has evolved considerably from what it was when I generated the Law five years ago and I am doing fine, but I will tell my personal story in a different blog entry..
Acknowledgments. The blog entries referred to here were generated by multiple associate researcher-writers as well as myself: Victor, Dan Campagnoli, Brendan Hussey, Melody Winnig and Mike Giuliano. Jim Watson has been a particularly important contributor for over a year now, not only for his original writings but also for our intense and stimulating phone and e-mail collaborative interactions. Melody Winnig has also served an importance literature surveillance function, bringing important findings to Jim’s and my attention on a daily basis, and as a blog proofreader.