By Vince Giuliano with comments by James P Watson
We have come to the end of a year and a start of another, and this has led me to musing about what I have learned in 2013. I have been studying the health and longevity sciences for nearly eight years now, so it is interesting for me to ask myself how my views have changed in the course of just the last year. Here, I share 13 items that are particularly vivid for me – a personal list of headlines for health and longevity in 2013. The stories following each of these headlines are either already told in other blog entries or will be told soon. I conclude with four additional items related how to my own personal professional situation is evolving.
Jim Watson comments briefly on a few of these items here. Jim has also drafted a separate blog entry on how his views have evolved in the course of the last year. I expect that we will publish that very soon.
My list is highly personal:
- Major determinants and symptoms of human aging appear to be stoppable and even reversible. This was a strong hunch going into the year. However, research findings published during the year lead me to be considerably more confident that this is so. Jim lists some of these findings below.
- As these proximate determinants of aging become clearer, three key central interventions for drastically slowing aging appear to be a. upregulating expression of the SIRT1 protein expression (via Resveratrol, etc), b. upregulating nuclear expression of NAD+ (via NMN or certain dietary supplements), and c. taking a supplement that acts as a powerful mitochondrial antioxidant (quite possibly, C60-olive oil or MitoQ).
- Jim Watson and I believe we are sneaking up on creating an overall GUT (Grand Unified Theory) of aging and biology, health and aging.. See the recent blog entry of the topic.
- I believe we have already passed Kurtzweil’s “singularity point” (ref) where humans together with computers transcend the limits of our strictly biological systems The rate of accumulation of important biological knowledge already exceeds anyone’s ability to fathom what it all means when it is put together. Internet information storage and searching, electronic communications, databases, sequencing and computer systems modeling are part and parcel of our existing discovery and knowledge integration processes. We could never have gotten this far without them. The true record of our progress is not in anybody’s mind or in any book or sets of books. It is out “in the cloud.”
- The application of life-extending interventions via two or more independent pathways can result in life extension that is greater than that expected by adding the results of the two pathways. As organisms, we are an extremely complex systems consisting of multiple positive and negative feedback circuits. Linear responses are by far more the exception than the rule. A way to evaluate the effectiveness of a set of longevity interventions is to ask whether the resulting benefits of applying them together exceeds what the benefits would be if the results were additive.
- Three key questions remain foremost when assessing biological impacts of substances and health interventions. These are a. dosage. Is it hormetic,sub-hormetic, or supra-hormetic, b. age and disease state of the organism. Interventions that can help sick or elderly people may show no effects in young healthy people, and c. time of day, since the expression of hundreds of response genes are controlled by circadian rhthyms. Clinical trials that do not take these factors into account may be meaningless.
- Many more biological processes take place through interactions and communications among multiple species than I had hitherto appreciated. The theoretical and practical implications of this for our health and longevity are vast.. The gut biome (actually different biomes in different segments of our intestinal track) is being studied intensely but multiple other biomes are also in constant interaction with us (skin biome, mouth biome, vaginal biome, etc). And in biology in general, interdependency of species is more the rule than the exception.
- No single longevity intervention can be expected to have a profound effect. It is probable that any highly effective longevity program requires applying multiple disciplines and interventions including ones of exercise, other induced stresses, diet, taking of selected supplements, rest and sleep, dealing with mental challenges, and social/interpersonal interactions. Forms of dietary restriction may be key. You can’t keep your automobile young and functional by any single mechanical intervention. It is ridiculous to expect that a single intervention would work with something as complicated as the human body.
- Management of multiple stresses to make sure they are actually being experienced and in the hormetic range is an important aspect of any personal longevity program. Exercise remains a key stressor, but there are many other stressors as well that can be used for health maintenance. These include selective applications of heat, cold, hypoxia, and multiple types of molecules.
- Delivery of drugs and health producing phytosubstances encapsulated in nano-sized particles can greatly enhance their biological effectiveness and minimize side effects. Liposomal delivery is likely to be of increasing importance. The pharmaceutical industry recognizes this and is pursuing much research in nanoparticle-encapsulated delivery of drugs. I believe the same is true for health producing dietary phytosubstances.
- Biological processes both within and among individual organisms and among them are all about signaling communications. In this regard I have come to appreciate a. the key roles in evolution and in organisms today of the “Great God Gasses” like nitric oxide, carbon monoxide, ozone and hydrogen sulfide, and b. the key roles of biological nano-sized delivery packages like exosomes and micelles. We can expect to publish a great deal more in this blog about these substances and their roles and communication.
- We are only now beginning to unravel how the benefits of eating fruits and vegetables are conveyed. There is evidence that, in addition to providing health inducing phytochemicals, cells in fresh fruits and vegetables are still alive and deliver exosome-containing plant-based RNAs. These RNAs act in the same ways our own human RNAs do to control gene expression and produce xenohormetic health and longevity benefits in us humans.
- I believe we are approaching a point where most diseases can be prevented or, if caught early enough, their consequences reduced to nuisance status. That is, when faced with the initial signs or threats of any personal disease situation, it is becoming more and more often possible to figure it out well enough to reduce the disease to where it is gone or just a minor nuisance. This point is not yet reached, but I sense that it is coming. Up to now at least, this has been true for me. This is a dream for the future of medicine.
In short, I think we are getting somewhere and that the rate of that getting is significantly increasing.
Some personal shifts in 2013
Speaking about my personal situation, I have a few additional to add:
A. In the course of 2013 I have developed incredible collegial relationships which are furthering the research and publishing capabilities of this blog.
– The first such relationship is with James P Watson, as is clear from the blogs he has written and those we have written together. Jim is multi-dimensionally extraordinary. He is both a practical healer and practicing surgeon and a deep scholar, thinker and communicator when it comes to essentially all the frontiers of the health and longevity sciences. We are constantly communicating via e-mails and often frequent phone conversations as undertakings of sharing and mutual discovery. We have had three such conversations already today. Jim’s understanding of molecular biology and organic chemistry by far outstrips mine, and besides that he seems to have knowledge of contemporary medical practices that exceeds that of most other MDs I have encountered. He has insatiable curiosity, and it seems there is no arcane biological science or medical topic Jim can’t master in a few days. He is the person who has brought many of the items in this list first to my attention. Further, Jim is a passionate and compassionate person . He does not hesitate to bring his superb research knowledge to bear to assist friends with their personal health/medical issues. I am grateful for my relationship with Jim and humbled by it.
– Two other relatively new professional relationships are also of great collegial value to me. The first is with Melody Winnig, my wife of many years. Melody is the research surveillance person in my network, daily surveying the news and bringing relevant new research items to my attention and the attention of key other colleagues. I found six new e-mails this morning pointing to such items, and this is typical. My observation relating to the knowledge singularity point is because of the vast number of new and exciting findings that Melody in particular has been surfacing. Also, Melody’s knowledge of the health/longevity sciences, going back to 2011, is rapidly increasing. She is particularly interested in phytosubstances and their potential, has joined with me in creating our blog entries on the live food stress hypothesis, and she seems to be playing ever more active roles in my professional life. A second such relationship is with my son Michael Winnig Giuliano who has been very helpful to me in managing multiple priorities.
– Finally I need to acknowledge the collegial contributions of the readers of this blog and the emergence of probably powerful new and additional collegial relationships that are developing. In particular I mention Dr. Ed Dratz, Dr. Frank Williams, Chen Hue, and Dan Campagnoli and Victor who writes for this blog, and the increasing group of people who post highly intelligent and relevant comments on the blog and who e-mail me directly. You know who you are.
B. I have been home-experimenting with making and personally testing liposomal preparations of combinations of anti-inflammatory herbal extracts and dietary chemicals intended to enhance weight and metabolic processes. Liposomes are nano-sized particles with lipid outer layers that encapsulate the substances intended to be delivered into body cells There is much research going on in the pharmaceutical industry focused on liposomal drug delivery. These preparations are intended to enhance the bioavailability of the encapsulated substances by a large factor (6 or over) without incurring side effects. We believe the benefits of liposomal delivery can be realized for dietary phytosubstances such as resveratrol or EGCG as well as for drugs. This work has been with my son, Michael. We are in the very-early stages of this initiative and we have much experimental and laboratory analytical work yet to do. I expect to report on this work in this blog in due time.
C Having turned 84, I continue to be “healthy as a horse.” That is problem-free, healthy, strong and capable for the present. But like any horse or other living biological, I recognize that I am facing an inherently uncertain future. My intention and plan is to keep going in this game of life and at the game of science, learning, developing understanding and communicating. And I intend to do that for a very long time more. I want to be around for the process of truly fathoming aging and to contribute to that process until it is mostly complete. For now, this blog will continue to be a major vehicle for doing that.
A few Jim Watson reactions to my list
I sent a preliminary version of this list with Jim Watson, and the following comments are drawn from an email response. I have italicized the points Jim is responding to
1. Major determinants of aging may be stoppable and possibly reversible. Yes, I fully agree with
you! The most exciting things here that show potential in my opinion is the following:
a. GDF-11 for the heart and skeletal muscle, based on heterochronic parabiosis
b. CCL-11 antagonists for brain aging, based on HCPB experiments
c. NAD for activating all 7 Sirtuins and reversing Warburg-type metabolism.
d. IRS1/2 inhibitors for blocking the insulin/IGF-1 pathway
e. Mitochondrial-specific renewable antioxidants that also activate autophagy (I.e. Buttered Bucky balls)
f. Oral absorption of exosomes containing plant RNA or synthetic RNA that counteract many of the noncoding RNA that “screw-up” the Normal Post transcriptional regulation (Ex: circular RNA, linear noncoding RNA, etc)
2. Kurzweill’s singularity point – yes,I think we are getting near, yet when I see how “inept” humans are at taking knowledge and applying it to their own lives, I do not think that 99% of the mass of humanity will benefit. For instance, I have a dear friend who has had access to much cutting-edge knowledge about aging, yet never took it to heart (his lifestyle was atrocious! No exercise, overweight, ice cream diet, lack of sleep, and poor attitudes about life, no laughter, no spirituality, 3 wives, etc.) The problem of disconnect between knowledge and personal behavior will not be solved via any “Singularity”
3, Grand Unified Theory – This is what I am the most excited about! I am beginning to finally get a handle on the gases. I still do not understand the redox system, however. The two are clearly linked. I have been having an intense conversation with Dr. John Sturges about the clinical use of these gases and combining them with heat. Although the obvious gases are CO, NO, and H2S, we are spending just as much time researching ozone.
3. Being able to do something about individuals with diseases – As an example, I really think that we may be able to help a person I know with mild autoimmune disease – a combination of Lupus and Scleroderma with Raynaud’s syndrome, and with a MRSA susceptibility. We would use something called “ozone steam sauna” therapy. We think that the heat can break the cold-induced Raynaud’s vasospasms and also induce HO-1 (I found out that 20 min of 42 C will induce HO-1 for up to 24 hrs, increasing mRNA for HO-1 via a HSF-1 Mechanism. This way you avoid creating more ROS-induced endothelial damage. On the other hand, topically applied ozone in the “ozone steam sauna chambers” will kill all of the MRSA and biofilm organisms on a fairly take care the skin without the need for antibiotics which would ultimately lead to antibiotic resistance. I think ozone steam Sauna therapy may be a good form of preconditioning before surgery that will reduce post-complications, especially Infections.
Thanks to Vincent and all the others who contribute to this site.
Response by points.
1. no comment
2. (a) Upregulating NAD+ using certain supplements. Good, what supplements?
(b) Mitochondrial anti-oxidant. Quite possibly mito-Q or C60-olive oil. James Watson also supported the possible efficacy of C60. I remain astonished by this result. It is so spectacular that it is either an error,or a fraud or it deserves a whole batch of Nobel prizes. As far as I know (please correct if wrong) C60 does not occur in known natural biological systems. How can adding it to the human system do anything good? Its like tossing a rock into the workings of an elaborate conveyor belt and finding that the conveyor belt now works twice as well as before. ??? If adding C60 does extend longevity, I think that it lends considerable support to the idea that aging (and cancer) are the results of a quasi-programmed behaviour. The C60 would then somehow be jamming the quasi-programmed behaviour.
I think that considerable leverage could be obtained by trying to falsify the idea that aging/cancer are quasi-programmed. Any good ideas about how to do it?
3. GUT Doesn’t yet exist for physics. I am skeptical that it might exist for biology. Good luck in your hunt, its always good to “shoot the moon” in research.
4. Nice observation.
5. Linear responses are exceptional. I like to think of the human system as being in quasi-equilibrium with constraints: both internal and external. As long as these constraints do not change then all first order effects are cancelled out; i.e., no linear responses. However, if a major constraint is removed (say bacterial infectious disease are greatly reduced by cleanliness and antibiotics) then a linear response can be expected to move us to the new equilibrium (our current maximum lifespan of between 80 and 120 years). The use of anti-inflammatories and other immune suppressing strategies then allow us to reduce the diseases of affluence. Similarly, if we discover broadly effective antivirals and/or a cure for cancer, then we can expect more linear response type changes as we move to the new quasi-equilibrium.
6. Well said. I think this is key.
7. No comment.
8. Vince on occasion has seemed to voice support for quasi-programmed aging. If quasi-programming is true then, we might might have profound changes due to some relatively small changes that “jam” the program: C60? or NMN?
11. Would like to hear more.
12. Raw food versus whole food. Meat versus vegetables. Whole can of worms here.
13. Good and good luck.
In the personal comments, paragraph C is scrambled.
Thanks again for your work and your ability to communicate in language suitable for those of us who are “lay people” in this area.
First of all Jim, thanks for this and the other intelligent comments you have contributed to this blog. Let me counterpoint your points:
“2. (a) Upregulating NAD+ using certain supplements. Good, what supplements?
(b) Mitochondrial anti-oxidant. Quite possibly mito-Q or C60-olive oil. James Watson also supported the possible efficacy of C60. I remain astonished by this result. It is so spectacular that it is either an error,or a fraud or it deserves a whole batch of Nobel prizes. As far as I know (please correct if wrong) C60 does not occur in known natural biological systems. How can adding it to the human system do anything good? Its like tossing a rock into the workings of an elaborate conveyor belt and finding that the conveyor belt now works twice as well as before. ??? If adding C60 does extend longevity, I think that it lends considerable support to the idea that aging (and cancer) are the results of a quasi-programmed behaviour. The C60 would then somehow be jamming the quasi-programmed behaviour.”
I wish I knew for certainty which supplements are best but I am not sure.
Your comments about C60-olive oil reflect my sentiments – I am fascinated and cannot wait for the other shoe to drop either validating or discrediting the rat longevity experiment. Last week I started to write a second blog entry on C60-EVOO but found there is not enough new yet to justify doing this. However, above and beyond the pivotal life-extending experiment is other published evidence that C60 is a powerful mitochondrial antioxidant that can quench the ROS that is downstream of scarcity of NAD+ as outlined in Sinclair’s latest pivotal publication. And personally, I do think that aging is a stochastically-mediated quasi program.
“I think that considerable leverage could be obtained by trying to falsify the idea that aging/cancer are quasi-programmed. Any good ideas about how to do it?”
Not really, except to modify or add subroutines to the program which impact aging. Do you have any?
“3. GUT Doesn’t yet exist for physics. I am skeptical that it might exist for biology. Good luck in your hunt, its always good to “shoot the moon” in research.”
True, a complete GUT unifying all of the forces is still elusive in physics despite the brane and 13-dimensional string theories nobody can fathom. However I like to think of quantum theory and relatively theory as key GUT hypotheses that served as scaffolds for physics for over 100 years, never mind that they now have big holes in them. And I do think we are now in a phase of finding more and more unifying principles in biology.
“4. Nice observation.”
“5. Linear responses are exceptional. I like to think of the human system as being in quasi-equilibrium with constraints: both internal and external. As long as these constraints do not change then all first order effects are cancelled out; i.e., no linear responses. However, if a major constraint is removed (say bacterial infectious disease are greatly reduced by cleanliness and antibiotics) then a linear response can be expected to move us to the new equilibrium (our current maximum lifespan of between 80 and 120 years). ”
Why a linear response? Removing one constraint will change values of other variables in the feedback loop where that constraint applies. This in turn will affect many other arelated feedback loops which will reflect back on that one until a new equilibrium applies. The net results are inherently non-linear.
“The use of anti-inflammatories and other immune suppressing strategies then allow us to reduce the diseases of affluence. Similarly, if we discover broadly effective antivirals and/or a cure for cancer, then we can expect more linear response type changes as we move to the new quasi-equilibrium.”
Agreed, except for the linearity aspect. Reducing just a single disease affects many body systems and feedback loops and I expect non-linearity to be the rule not the exception. Yes, we will settle down to new states of quasi-equilibrium. So as we remove constraints to use your terminology, we live longer, and other things may start killing us.
“6. Well said. I think this is key.”
“7. No comment.”
“8. Vince on occasion has seemed to voice support for quasi-programmed aging. If quasi-programming is true then, we might might have profound changes due to some relatively small changes that “jam” the program: C60? or NMN?”
Yes, yes, yes Jim. If the C60-EVOO 90% rat life expectancy is valid (I agree it is either Nobel prize material or a hoax), then we have a case in point. This is exactly the point of non-linearity. As I see it in a nutshell, NMN blocks nuclear pseudo-hypoxia which allows SIRT1 expression, which means nuclear signaling does not tell the mitochondria to turn off mitochondrial protein production, which means that mitochondria run as they should so excessive quantities of ROS are not generated in the electron transfer chain. All of those things would happen with aging because PARP for DNA damage repair competes for SIRT1 so there is not enough to help the mitochondria. If my hunch is right, even if all of those bad things gos on with aging without NMN administration, you might be able to block the positive feedback and damage of the ROS in the mitochondria using C60-EVOO. To be confirmed or not as time progresses,
“11. Would like to hear more.”
I expect there will be lot more. Some aspects of inter and intra-species signaling were covered in by blog entries on quorum sensing. Jim has rough drafted a lot of materials on the Great God Gasses and on exosome communications that have not yet made it into blog entries, so there is a lot more to say. My personal bandwidth as a researcher/writer/editor has been a limitation to what we have been able to get out.
12. Raw food versus whole food. Meat versus vegetables. Whole can of worms here.
Yes but I think there is much yet to be said and sorted out. Have you seen our blog entries on the xenohormetic live food hypothesis?
“13. Good and good luck.”
Thanks, we need it.
“In the personal comments, paragraph C is scrambled.”
That is straightened out now, thanks. Problem was my voice recognition being active and listening when a phone call came in just before publication.
“Thanks again for your work and your ability to communicate in language suitable for those of us who are “lay people” in this area.”
You are welcome, and thanks for the comment which contributes to the vitality of the blog.
Vince is gonna love this. Another ‘Take your vitamins’ (in this case B3) paper. 😉
J Biol Chem. 2007 Aug 24;282(34):24574-82. Epub 2007 Jun 29.
Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells.
Hara N, Yamada K, Shibata T, Osago H, Hashimoto T, Tsuchiya M.
“Together, we conclude that NA elevates cellular NAD levels through NAPRT function and, thus, protects the cells against stress, partly due to lack of feedback inhibition of NAPRT but not NamPRT by NAD. The ability of NA to increase cellular NAD contents may account for some of the clinically observed effects of the vitamin and further implies a novel application of the vitamin to treat diseases such as those associated with the depletion of cellular NAD pools.”
“In conclusion, our findings indicate that NA is a better substrate
for elevating cellular NAD levels than Nam in human
cells with endogenous NAPRT and that elevating NAD levels
via the NA pathway protects the cells against injury such as by
oxidative stress. Our findings, thus, document critical roles of
the NA pathway in modulating cellular NAD levels and cell
functions in human cells.”
@Bruce: Thx, for the Niagen hint.
@Vince, Jim, et al. Keep up producing the most exciting blog on the interwebs.
Forgot the link to the paper above.
Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells.
Have a look at Nicotinamide Riboside (NR). A naturally occurring NAD+ precursor and probable NMN precursor. Mouse experiments indicate that NR offers the health benefits of a low-calorie diet and exercise.
NR became available as a supplement called Niagen several months ago.
We have a blog stuck in the works on the latest David Sinclair publication related to NAD+, pseudo hypoxia, SIRT1, NMN, etc. My quick impression is yes, NR might indeed do the trick of creating NMN and producing its benefits. Stay tuned!
Would like to make two very personal comments. 1) finding, or better yet stumbling on this incredible web site has renewed my faith once again in the human race
And 2) Vincent I was amazed at discovering your age. From your writing I thought you in your 20s. You write with such youthful vigor !!
Keep up this amazing and inspiring work all!
I too am in the process of very similar pursuits. One example: Diaphragmatic breathing-where the belly pops out on the inhale needs to be explored. Not only for it’s increase in oxygen with each breath, and stress-relief, but making the diaphragm muscle itself act as a ‘second heart.’ But getting back to topic, please keep up your insanely wonderful posts for at least the next 100 years. By then we will be middle aged and almost ready to begin to slow down!
Positive feedback like your is very important for me – it keeps me going.
I do attribute much of my good health and vitality to practical application of what I have been learning about aging. Other factors are 1. A wonderful family, physical, social environment, 2. Willingness to experiment with myself, 3. The powerful stimulation of my longevity research work, my excitement about beginning to decode the basic processes of aging, and feedback such as yours.
Response to Vince’s reply.
Finding tests for stochastic programmed aging:
(a) For some mammals (maybe most) the survival curve with respect to time becomes more and more rectangular with better living conditions. As I think you remarked once, this shape of the survival curve is hard to reconcile with aging simply being a compounding of uncorrected errors. One research program would try to quantify this intuition and see if the shape of the survival curve can be used to exclude theories other than stochastic programming. We probably could get some leveage from this but probably not enough.
(b) Look at the evolution of the mammals and try to show that the germ line has better survival if the soma perishes after some time. What is the optimum life span for a given niche? This sometimes goes under the rubric of evolution of evolvability. This optimum lifespan might be set by how long the germ line can be maintained in nearly perfect condition in a given body and by inter generational competition for resources as well as other factors. At too great an age, the mutations begin to mount and women, at least, have menopause, which tends to protect them from having children with birth defects (a high personal and social cost in previous times).
(c) The best way to test stochastically programmed aging would, as you suggest, be to find some intervention that allows one to vary the rate of aging. This would allow us to begin to take the system apart and understand it. I think hints are at hand as you and Dr. Watson have indicated for extending lifespan: heterochronic parabiosis may be a highly fruitful line of research; Sinclair’s work on NAD+ metabolism is also very likely to give considerable insight; and, we have the great shot in the dark, C60. Finally, we may find out a lot by studying the progerias.
Linear response and quasi-equilibrium:
You are right, I was sloppy with my use of words. I meant to distinguish between first and second order response or at least between very small and relatively large responses. I am unsure about how to perturb a quasi-stationary state in a dynamical system. For an equilibrium system, I would be talking about the response to infinitesimal perturbations. If the perturbation is finite then non-linear effects need to be considered — i.e. stock market crashes, population explosions as well as birth and death.
Physics: Unification of forces and the dissolution of the anthropocentric point of view have been two over-riding trends in the development of theoretical physics. In large part, unification is what we mean when we say that we understand the behavior of previously disparate observation. Even if a complete unification of all forces is possible — the result will still have great limitations since the universe is inherently random at the quantum level — and at the classical level most problems of dynamics are chaotic and ill-posed.
Xeno-hormesis. Yes I read the post and it makes me think. For one thing, I have been cooking and eating berries (thickened with tapioca) every night since the early 90’s. I also like my vegetables cooked – with maybe a small salad. Your post, makes me wonder if perhaps I should forgo at least some of the cooking. On the other hand, the invention of cooking was of apparent capital importance in the evolution of the human race.
Mirochondrial anti-oxidants: Bruce Ames has promoted alpha lipoic acid for decades as a mitochondrial anti-oxidant. I have briefly looked at mitoQ but I have not taken the time to assure myself that this is legitimate. With you, I wait for the results on C60.
Thanks again for all your work. Jim Rose
Jim Rose – reply to your reply
“Finding tests for stochastic programmed aging:
(a) For some mammals (maybe most) the survival curve with respect to time becomes more and more rectangular with better living conditions. As I think you remarked once, this shape of the survival curve is hard to reconcile with aging simply being a compounding of uncorrected errors. One research program would try to quantify this intuition and see if the shape of the survival curve can be used to exclude theories other than stochastic programming. We probably could get some leveage from this but probably not enough.”
This has been my basic argument all along. Random damage would be consistent with a Poisson Distribution curve which has an indefinitely long tail for large numbers of events. But there appears to be a fixed human age limit of around 122. Given the immense population of the world, there would be a few individuals out there 200 or 300 years old, but they have never existed as far as I can tell except in mythology. But you are right, mathematical arguments like this don’t cut much ice with most biologists.
” (b) Look at the evolution of the mammals and try to show that the germ line has better survival if the soma perishes after some time. What is the optimum life span for a given niche? This sometimes goes under the rubric of evolution of evolvability.”
We know that there may be something to this since species if transported to a new and different environment may evolve different features as well as lifespans. It is as if the lifespan and major events during life like offspring-bearing is one more parameter to be adjusted when evolution happens. My theory is that as a species, we are rapidly evolving to live longer because this favors the requirements of society.
“This optimum lifespan might be set by how long the germ line can be maintained in nearly perfect condition in a given body and by inter generational competition for resources as well as other factors. At too great an age, the mutations begin to mount and women, at least, have menopause, which tends to protect them from having children with birth defects (a high personal and social cost in previous times).”
I strongly suspect that neither germ-line survival nor rates of mutation are fundamental in determining how long we can live now or in the past. These factors have not gotten in the way of longer human lifespans in the past. The history of homo sapiens has been one of longer and longer average lifespans, with total change of average lifespan being by a factor of 4 or greater. These factors could be limiting in the future, however, if our life spans became much longer yet. .
“(c) The best way to test stochastically programmed aging would, as you suggest, be to find some intervention that allows one to vary the rate of aging. This would allow us to begin to take the system apart and understand it.”
The progeria diseases and many stress interventions give us models for speeded-up aging, but we don’t have many models for slowed-down human aging, CR being the main one.
” I think hints are at hand as you and Dr. Watson have indicated for extending lifespan: heterochronic parabiosis may be a highly fruitful line of research; Sinclair’s work on NAD+ metabolism is also very likely to give considerable insight; and, we have the great shot in the dark, C60. Finally, we may find out a lot by studying the progerias.”
Yes. Well said.
“Linear response and quasi-equilibrium:
You are right, I was sloppy with my use of words. I meant to distinguish between first and second order response or at least between very small and relatively large responses. I am unsure about how to perturb a quasi-stationary state in a dynamical system. For an equilibrium system, I would be talking about the response to infinitesimal perturbations.”
If the system is in fairly stable but dynamic equilibrium, then any minor perturbation will result in a restorative response which may be a function not only of displacement but also of rate of displacement and other dynamic state variables. So linearity is not guaranteed.
” If the perturbation is finite then non-linear effects need to be considered — i.e. stock market crashes, population explosions as well as birth and death.”
“Physics: Unification of forces and the dissolution of the anthropocentric point of view have been two over-riding trends in the development of theoretical physics. In large part, unification is what we mean when we say that we understand the behavior of previously disparate observation.”
Yes. Perhaps that is the best that science can do and that is what we are looking for in biology. We probably can never completely “wrap it up,” just like we can’t completely wrap up physics.
“Even if a complete unification of all forces is possible — the result will still have great limitations since the universe is inherently random at the quantum level — and at the classical level most problems of dynamics are chaotic and ill-posed. ”
And since biological systems are too subject to quantum effects, what you say holds a-fortiori for them too
“Xeno-hormesis. Yes I read the post and it makes me think. For one thing, I have been cooking and eating berries (thickened with tapioca) every night since the early 90′s. I also like my vegetables cooked – with maybe a small salad. Your post, makes me wonder if perhaps I should forgo at least some of the cooking. On the other hand, the invention of cooking was of apparent capital importance in the evolution of the human race.”
A good topic to dialog on in the future. Remember, that the contents of beneficial phytochemicals can be significantly enhanced in some fruits and vegetables. On the other hand, cooked fruits and vegetables are no longer live and capable of stress responses.
Mirochondrial anti-oxidants: Bruce Ames has promoted alpha lipoic acid for decades as a mitochondrial anti-oxidant. I have briefly looked at mitoQ but I have not taken the time to assure myself that this is legitimate. With you, I wait for the results on C60.
I recently emailed you with a few questions and you encouraged me to log on and begin posting.
So this is my maiden post.
First, Vince is to be congratulated for his superhuman efforts in organizing this website and bringing his unparalleled insights to the rest of us. I am a 61yo physician who has been interested in antiaging since having been exposed to the books of Durk and Sandy (whatever happened to them?) about 30+ years ago, and have been taking supplements ever since. I am perfectly healthy. I also happened to be doing some research back then at Wistar Institute where there was an active professor who researched antiaging, Dr. Adelman. I even attended a lecture given by Hayflick!
At any rate, I am nowhere near as erudite in many of the domains discussed on the website as many of the contributors, but I am learning day by day by reading. I actually read quite a lot of science, but on a broad range of subjects.
I notice that some of the comments regarding hormesis and stressors jive remarkably well with principles set forth in the book “Antifragile” by Nassim Taleb, that I am currently reading. I think that his insights into how natural systems function throughout multiple domains apply to the realm of biology and aging as well. I wish he were an active participant in your website!
There has been some discussion of the so called singularity of Kurzweil. I have read his book “How to Create a Mind.” I am not so sure about computers developing as a biological substitute for the brain any time soon. The brain (as well as the body) is a biological nanomachine and computers are not designed with those same properties, although the hierarchical aspects of neural processing are beginning to be replicated, and machines are being designed as implants to supplement and enhance biological abilities. But the brain works not only on the neuronal level but also with regards to the biochemical milieu and the anatomic functionality. I would recommend a fascinating book called “The Physics of Consciousness” by Walker. It delineates in shocking ways how the structure of the brain including its pigmentation literally can facilitate quantum tunneling effects, and how the time intervals of thought processes are now explainable! Finally, “The Tell-Tale Brain” by V. S. Ramachandran explains how the brain helps to create the world around us by combining sensory input with memory. It is surprising to learn that memory is not actually stored but is recreated (or reconstructed), and thus can be modified or confabulated, each time we “recall” something. How mental machinery works is further explained in: “Sleights of Mind: What the Neuroscience of Magic Reveals about Our Everyday Deceptions.”
As to a physics GUT, there are major cracks in current physics models. Books like
“Farewell to Reality: How Modern Physics Has Betrayed the Search for Scientific Truth” and “Not even Wrong” are starting to expose the “emperor has no clothes” moments.
A very interesting book by a pioneering physicist Milo Wolff called “Schroedinger’s Universe” is starting to create a unified theory that, while incomplete, can already explain electrons, charge, spin, relativity, gravity, antimatter, inertia, etc. and derive all of this from just a few basic principles. Spacetime is a wave medium and particles are not singularities but are standing wave center resonances that interact with all other matter in visible universe. Whether this theory turns out to be correct, I think it points in the right direction.
Now Vince, you had asked me to post my questions and comments that I emailed to you, so here goes (edited):
One question on aging is this:
Does the signal or program controlling aging originate within each cell, which may therefore keep its own biological clock, perhaps programmed in some sense by DNA, or is aging a result of each cell receiving in some fashion a hormonal or other signal directed from some master location, such as within the brain? Or, is it a reduced ability of adjacent cells to interact and communicate that leads to aging? (I think this was well-addressed in your comments above)
We know that in early life there are genes encoded in the DNA that are activated in appropriate sequences, as well as cell-surface markers that develop in response, that direct growth and differentiation. Hormonal signals from more specific locations also help coordinate changes. Is aging just such a continuation of this, or does a different mechanism control it?
I would also refer you to this link:
Any plastic surgeon can tell you that we wrinkle due to loss of tissue volume. This is due to both changes in the connective tissue matrix, losing thickness and elasticity, and thus making it more prone to sink with gravity, as well as the loss of cellular volume. Loss of cell volume can have profound effects on normal cell functioning, and may crowd cellular elements, reduce the effectiveness of antioxidants, affect protein synthesis and gene expression, and perhaps cell to cell communication, etc. Even the brain shrinks.
It would seem that any program to oppose aging must have as a result the restoration of cellular volume and connective tissue structure.
It also might be fruitful to study the mechanism of reduced cell volume and trace the problem back to its origin, be it due to an internal or external signal.
I also enjoyed your discussion of C60, but would also like to also hear your opinion on TRH (Abaris or injection form), epitalon (or epithalon) (recommended by Thierry Hertogue), and Melanotan II. (I like the idea that C60 might somehow serendipitously “jam” the aging mechanism. I am also monitoring the bodybuilding websites, as I find there are some who are starting to experiment with this stuff there!)
And lastly, many people take supplements, like you and me, and we take them based on a rational idea of what we expect them to accomplish in our bodies. Yet, ironically, as we age, one of the problems is that our absorption of nutrients may decline. Further, the bioavailability of a given supplement may vary from source to source, depending on among other things, its form, its associated inactive ingredients, the care taken in its creation in the supplement factory, any contaminants, etc. Further, there may be interactions amongst the supplements themselves when taken in large quantities together. do chelating substances reduce mineral absorption, for instance? (I like the new stuff about Niagen. Here is a link I found: http://www.tigerfitness.com/HPN-N-R-Niagen-BOGO-p/niagenbogo.htm?scpid=9&scid=scsho4108077)
So, we decide on a regimen of supplements and a dosage, we swallow them, yet we have no way of knowing just how much is actually being absorbed vs passing through. Certainly, as you eloquently describe, liposomal delivery systems might be helpful in the future.
i also have read some reports that excessive intake of concentrated tea extracts have caused liver damage, even needing a liver transplant. so, we also have the issue of how all these supplements, taken together, are metabolized, and whether our kidneys and livers are up to the task, or could become overloaded.
I don’t know if it has been looked at, but I do not think there are any centenarians that say they got there based on taking supplements, as opposed to just having good protoplasm. I do not think supplements are enough but would also think a top-down approach, to alter the hormonal milieu in positive ways is needed, as to restoration of youthful hormonal levels. I think that one should also incorporate weight-training, which I do, as a key biogical stressor that promote antifragility in our bodies. According to the ideas of Taleb, keeping our bodies antifragile is the mechanism to promote positive hormesis. To that add a modicum of cardiovascular exercise and healthy diet, as well.
Otherwise, I appreciate the editorial comments you and others have made, and I look forward to learning a lot and contributing if I can here or there! Here’s to 2014!
I salute you for the grate work you are doing. I discovered this website few years ago and have been following since.
Seeing new scientific research coming out in the last years make one excited about the prospectus for big improvements in people’s health and longevity. Put all the new discoveries together in the form of a GU Theory is a noble goal. I do not however see it’s practical application even remotely as clear as GUT in physics.
In physics a handful of fundamental equations along with a set of the boundary conditions is all it takes to solve a physical system. And a hard work of thousands of scientists over couple of centuries, of course.
Biological system, I believe, is enormously more complicated. It is possible to postulate fundamental principles of human biological system. To reduce it to practice and prove that it works is the ultimate challenge.
I am optimistic though. One can compare solving biological system to solving meteorological system (i.e. predicting weather). It takes a supercomputer and complicated software to predict weather. Meteorologists become better and better on this. Perhaps some days doctors will use similar tools.
Speaking of practical applications: it has been almost three years since you updated your supplement regimen. Would be interesting to see how new ideas changed you take on the anti-aging firewall.
Please keep you good work.
It is good to hear from another regular follower of the blog.
“Biological system, I believe, is enormously more complicated. It is possible to postulate fundamental principles of human biological system. To reduce it to practice and prove that it works is the ultimate challenge.”
Quite correct in my book. An economical set of fundamental principles that are consistent, work together and explain each other, whose evolutionary origins can be identified, and that point to useful practical applications is what we are looking for. And I think we are getting to them. This set of principles will be our GUT. They are unlikely to last forever since nothing in science ever does.
I think your comparison of practical biology to practical meteorology may be a good one. We know that practical prediction of local weather is impossible for long time periods but that next-day and even next-week forecasts are getting better and better. If we get sufficient handles on pathways and biomarker measurements we may get to where we can make short-range health forecasts for individuals. And these could be accompanied by dietary and other health programs that are aimed to correct any observed deficiencies.
As to my outdated firewall regimen – yes it needs updating. Some, not a lot. I have hesitated to do that because I wanted first to observe medium range-impacts of certain supplements I am taking now on myself before I published anything about them. The whole treatise can stand a thorough ground-up updating as well. I will make a redoing and a recontextualization of the supplement part a priority for the next several weeks.
Vince and James, it has been fantastic to start corresponding with such knowledgeable researchers in the field and to contribute to the blog here. There is always so much to learn, first slowly working through the massive amount of current knowledge, then keeping up with the latest development and piecing together what to investigate further.
I’ve finally completed a new shorter post on what I’ve learnt and looked into over the end of last year and into this new year at http://danielcampagnoli.com/a-new-year-new-insights.
Thanks for the great words. The feeling is mutual. Your first blog entry combines insight with the results of hard work and careful formulation – reaching to the quality level we are striving for in our blog. I will have a look at your shorter piece referenced, and we are looking forward to your Part 2 entry here.