Three years exploring longevity science

Longevity science had been a hobby for me for a long time and about 3 years ago I decided to pursue it as a new full-time career.  I put the first version of my treatise Anti-Aging Firewalls – The Science and Technology of Longevity online in May 2008 and started this blog in January 2009.  This blog entry is about how my some of thoughts relating to longevity science have evolved during that period.

These thoughts are in addition to those in the January 21 2010 blog entry The evolution of this blog.  At that time I was logging 700 to 1,000 unique visits a day, different people who stayed to read 2 or more web pages.   Now, 6 months later, I am typically logging between 1,100 to 1,800 unique visits a day.  Interestingly, I have recently been getting a lot of visits from Russia.

From the onset I was determined to take a broad view of longevity science rather than to focus on one or the other of the many pet theories out there.  I was also interested in identifying any actionable steps older people like me could take to live longer and more healthily.  So, I set out in my treatise to examine the main theories of aging.  My initial approach was logical.  I would identify what the major theories of aging are and then, for each theory, identify to the extent possible a “firewall” of lifestyle, dietary and dietary supplement steps that would be protective against aging according to that theory.  My information would come from perusal of published research information and I would avoid repeating unsubstantiated information or opinions from non-professionals or commercial sites.

By the time I first went online with the treatise in May 2008, I had pursued this approach for the first 12 theories of aging dealt with in my treatise:

1.     Oxidative Damage

2.     Cell DNA Damage

3.     Mitochondrial Damage

4.     Tissue Glycation

5.     Lipofuscin Accumulation

6.     Chronic Inflammation

7.     Immune System Compromise

8.     Neurological Degeneration

9.     Declines in Hormone Levels

10.                        Susceptibility to Cancers

11.                        Susceptibility to Cardiovascular Disease

12.                        Telomere Shortening and Damage

Within the next six months I realized that to these classical theories of aging I needed to add two newer theories:

13.                        Programmed Epigenomic Changes and

14.                        Stem Cell Supply Chain Breakdown

I have continued to refine my description of these as time progresses and believe that the Stem Cell Supply Chain Breakdown theory of aging is original with me.  Later I went on to identify an additional six possible “candidate” theories of aging:1.     Incorrect protein folding, 2.     Accumulation of progerin, 3.     Gene mutations leading to hellicase abnormalities, 4.     Increasing mTOR signalling, 5.     Declining hypoxic response, and 6.     Micronutrient triage with aging.

Further I developed few key insights about the theories:

1.  it is possible to keep on adding more theories of aging; the next two could be    Metabolic degradation affecting the expression of sirtuins(ref)(ref), and Decline in effectiveness of autophagy(ref), 

2.  beyond anti-aging interventions for the first 12 theories, there seemed to be few if any additional interventions I could suggest for the other theories, and

3. The “theories” of aging might better be called corollaries or concomitants of aging because with the exceptions of 13 and 14 they are far too specialized and incomplete to describe aging.  Each of the theories relates to phenomena that can and often do happen during aging and that can accelerate aging when they occur.  However, aging itself is a systems process involving the processes of all of the theories. 

Think of it this way.  If one asks “What causes an automobile to move?” valid answers could include “The tires, the wheels, the transmission, the engine, the internal combustion of gasoline, the gear train” and many others.  All are valid answers but if you are really concerned about how an automobile works you have to look at it as a complex system where each part has its own function and all are needed.  The same holds for the body and aging, a system vastly more complex than an automobile.

After launching this blog in January 2009 I started writing about gene-activation pathways, molecular activator and co-activator substances, types and properties of stem cells and other topics that I previously knew nothing or next to nothing about.  It became apparent that there was a growing list of complicated topics related to molecular biology, genetics, epigenetics and other advanced sciences that have a lot to do with longevity.  So, I started to research and write about these.  The list of these advanced topics is already long staring with NF-kappaB, P21,  P16/ink4a and mTOR, DHMEQ,  Nrf2, ALPHA-msh, DNA repair strategies the NRG1 gene  and moving on to include iPSC stem cells, SIRT-1 and DNA methylation and histone actetylation.  In recent weeks advanced topics have included the ghrelin and humanin proteins, the AMPK pathway and the HSP70 heat shock protein family. 

New bodies of science highly relevant to aging have been assuming importance during my three years of study: epigenetics, epigenomics, proteomics, transcriptomics, nutrigenomics, and many others.  I have also reported from time to time on these.   

So, as time has progressed I have been learning and sharing a lot more about advanced topics in longevity science.  At the same time I have explored deeper into the original theories of aging and practical anti-aging interventions.  I have written posts on the benefits of blueberries, spices, extra-virgin olive oil and other foods and on exercise, for example.  I have written posts on age-related diseases such as Alzheimer’s, auto-immune diseases, cancers like melanoma and lymphoma, and HIV for example.  I have described the growing number of new association studies that are linking genetic and epigenetic states to disease susceptibilities.  The list goes on and on.  As of now this blog includes 296 substantive posts and 512 comments. 

To put it simply, I have been learning a lot about the sciences behind aging. I have devoted thousands of hours to studying the literature of aging science, thinking about various topics and writing these blog posts.  And recently I have been going to conferences on aging and I have had personal discussions with some of the giants in the field.

How have my viewpoints changed as a result of that intensive educational process?  Here are some observations: 

·        Aging is a much more complicated process than I thought it would turn out to be and still very poorly understood.  Multiple interacting body systems are involved and the areas of science that will really help aging are just barely getting off the ground: epigenetics and epigenetic-epigenomic regulation and the life-cycle of the stem cell supply chain(ref).   

·        What we have learned we don’t yet know relating to these areas has grown exponentially compared to what we have actually learned.  I personally know a great deal more now about aging science than I knew three years ago.  But I now see there are vast relevant areas where knowledge is scanty or nonexistent, like the vast areas on ancient maps marked “Hic sunt dracones” (Here there be dragons).  Three years ago I was oblivious to the existence of these areas.   And I am sure that as those areas are explored, the presence of even vaster relevant areas beyond them will be discovered. 

·        There is no simple “magic bullet” in sight for radical life extension, a pill or process that will allow even a few of us humans to live beyond the 122 years known life-limit for humans.  There is not even speculation about what such an approach would look like in the aging research literature.  This has been a disappointment to me since when I started out I thought telomere extension via telomerase activation might do the trick.   I was quite naïve at the time and currently question whether telomerase activation is of any lasting value.  See the recent post on Stress, exercise and telomere lengths.  Nonetheless I have not given up on the idea of radical life extension and remain keenly on the lookout for research clues as to how it might be created.  I expect something new and basic relating to this possibility to show up in the next 3 years.

·        On the other hand, I have learned that there is solid evidence that a few known genetic pathways and possible intervention strategies might conceivably allow us to extend our average lifespans and healthspans by as much as 15% to 20%.  These strategies include inhibition of mTOR, activation of AMPK, activation of SIRT1, activation of telomerase, and possibly combinations of these. 

·        Life extension seems to be the same as extension of healthspan when considering these strategies.  In animal models of life extension the same diseases and problems of old age still occur but they occur later in life.

·        Life extension can occur through postponing or curing diseases of old age, so the science of Alzheimer’s disease, of diabetes and of the other killer diseases of old people is part and parcel of the science of longevity.  Predictive, personalized proactive medicine based on early identification of disease biomarkers is likely to have a strong positive impact on lifespans in the coming two decades.

·        Surprising benefits in healthspan and life extension can probably be realized via adopting healthy conventional-wisdom lifestyle patterns, diet and taking dietary supplements – again, perhaps 15%.  See for example Stress, exercise and telomere lengths, Back to blueberries,  Calorie restriction mimetics – focus on avocado extract, Extra-virgin olive oil.  And of course, see the lifestyle regimen section of my treatise.

·        Even a 15% increase in healthspan and lifespan across the population in an advanced country like the US would be of incredible value, worth trillions of dollars in increased productivity(ref).

·        Additional ways in which my thinking about aging has changed are described in the recent blog post What are aging, life-extension and anti-aging? In that post I comment on the difference between interventions that extend lives and ones that combat the biological process of aging.  Healthier diets that lead to less obesity, for example, can extend lives without tinkering with the intrinsic aging process.

·        I plan to continue writing blog entries on complex topics relating to aging, at least until I feel sure I have covered all the important ones.  I will report on current research amplifying or extending our understanding of topics I have written about before.  And I will sometimes delve deeper into topics already discussed.  So, the tendency of the blog to become more technical may well continue.

·        You can count on me always to write in a context respecting scientific integrity.  As always I will frequently quote directly from research citations and make sure that, when I am expressing my own opinion, that is clear.  I have no commercial affiliations and do not accept advertising.

·        This blog and my treatise are already well on their way to being a comprehensive and constantly updated compendium of knowledge, research information and citations regarding the science of aging.  I want to continue on that track.

A speculation on a chain of future developments

One very bright area related to longevity science is the development of infrastructure such as capability for genome sequencing and genomic/epigenomic databases.  Improvements in sequencing (genomic, epigenomic, proteomic, etc.) technology have followed Moore’s Law – price-performance doubles every two years.  These infrastructure elements allow continuing acceleration in the rate of new discoveries relevant to aging.  

I suspect sequencing will continue to follow a path like the computer industry did.  When I started this journey three years a, I compared the field of aging science to the field of computer science in 1955.  Now the sophistication of longevity science and engineering is perhaps up to about the levels for computers in 1958, when the very-first large mainframe computers were coming on the market.  These massive 10-million dollar computers were orders of magnitude more powerful than 1952 computers, but had only a very tiny fraction of the power and capability of the Blackberry smartphone I carry everywhere on my belt. 

Today, powerful advanced “next-gen” tabletop gene sequencers are available while formerly they filled entire rooms like early computers did. Today it costs about $6,000 to sequence the entire genome of an individual and the figure will soon be less than $1,000, down from a cost of over a hundred million dollars only about 10 years ago.   

What can happen if sequencing continues to go the way computers did?  Here is a speculation.  Before 2017, personal multifunction sequencers will become available – small units the size of PCs that will allow members of a family not only to sequence their personal genomes but also to some extent monitor the states of their epigenomes.  By then a large number of genomic/epigenomic markers should be available indicating increased susceptibilities to many diseases that worsen with aging.  The early warnings will allow corrective actions to be taken before actual disease states set in.  Like having a radar in an airplane, the sequencer will allow people to see the storm clouds of a disease coming and in many cases fly around them.  By 2020 the software in these units will allow more sophisticated testing and offer day-to-day monitoring  of problems and suggest corrective actions.  The units will link online to large genomic/epigenomic databases and to people’s physicians and health providers.  People will start buying these units in large quantities like they were buying PCs in the early 1990s. 

By 2025 the sequencer-monitor units will be far more capable, will be smaller than a hearing aid, will be unobtrusive and routinely worn, and will offer hour-to-hour monitoring of a large number of body conditions as well as epigenetic state.  The unit will communicate wirelessly with health resources and, in case of emergencies the unit will signal wirelessly for help indicating the nature of the emergency. 

While this speculative scenario may seem a fantasy, it is just a replay of what has been happening with smart cell phones and computers.  The microtechnology required for all of this to happen basically exists.  What is needed to get this process going is the development of an initial product, starting to build a market, ever-better biomarkers, personal-sequencer software and constant lowering of cost that can only come with economy of scale.

Many hoped-for approaches to longevity have not turned out to be going as well as I hoped they would be, but other unforeseen developments are quite positive.  Armed with ever-increasing sophistication, I am continuing on the journey and quest to learn more about aging and how to retard or reverse it.  I will document all possibly relevant discoveries in this blog.  So please stay tuned.  I most value your feedback.

The evolution of my own health during the last 3 years is another issue I will take up in a different blog entry.