Vince Giuliano www.agingsciences.com - PowerPoint Presentation

1. Vince Giulianowww.agingsciences.comV. June 13 2017On the WebBy Vince GiulianoTHE SCIENCES OF LONGEVITYAn overview of what current science tells us

2. I am going to go slow so you can get what I am sayingThis is because it could be extremely important for youIt could possibly impact on how long you live or how healthy you are

3. PART 1 SCIENCES OF AGING(This session)PART 2 – a potential future session Personal actions and interventions for extending healthspan and lifespans – Focus on the personal and practical

4. State of science –The relevant scientific literature is vast Understanding aging takes us into just about every area of human biology and medicineImage sourceGrowth in PubMed.org publicationsNow over 23 million indexed research publicationsMore than a million new publications every year

5. “While physics is infinitely deep,” “biology is infinitely complex”State of the science

6. Aging, like the universe, has no center or single central causeThe human body is the most complex system known in the entire universe.

7. Systems nature of biologyWhat goes on at any network point is ALWAYS a function of multiple interacting feedback loopsDiagrams like these exit for each level of biological organizationThis rather crude one is for aging itself

8. Levels of biological systemsQuantumMolecularCell organelleCellOrganBody systemEnverionmentalSocialLive entities like us consists of multiple interacting systems at each levelAnd there is much interaction between levels tooVery many things at each level can kill youAnd some things at each level can raise the chances of you living longer The interactions are all very finely tunedYou can’t mess too much with what is going on in one system without profoundly affecting many others

9. Differentially expressed enzymes in Purine MetabolismImage source

10. Brain tumor pathways

11. Metabolic pathways

12. Composite network of molecular pathways active in HCV-infected liver tissue.

13. There are tens of thousands of such diagrams to be found in the literature not all consistent, mostly unconnected with other related diagramsThe research tends to be solid but extremely complex.Because of this, researchers in one field usually can’t and don’t follow the literature in possibly-related fields.Purine metabolism – image sourceImage sourceState of the science

14. Systems nature of biologyWhat goes on at any network point is ALWAYS a function of multiple interacting feedback loopsThese feedback loops operate so as to assure dynamic stability, e.g. homeostasisE.g. body temperature. Heart rate, blood oxygen level, blood chemical lecels, and thousands of othersWhile we can draw the diagrams we are generally nowhere near being able to model what goes on in real live organisms

15. Biological systems are inherently complex, redundant, interacting and messySo, despite being able to draw all those diagrams, generally it is impossible to predict how the whole system works or what goes on in real live organismsThe loops are too complicated and the mathematical relationships are generally not known

16. Research is usually reductionist and highly focused E.g.What us the impact of A on B under well defined conditions C, D, E, F, G, H,--- ?. That is on what goes on at one point in a diagram assuming everything else stays the same. So, our research typically provides us with lots of data and relatively little insight about what goes on in real live conditionsNot a matter of blame – mainly a comment on where we are in the history of life sciencesWhich it never does in fact

17. Research is reductionist and highly focusedThe dominant methodology and culture that dominates biological and biomedical research across the entire spectrum of research activities internationally. This traditional strategy has unquestionably led to significant progress and remarkable insightsif we are ever to have a fully developed, fundamental understanding of aging and longevity and their relationship to healthA more integrated approach is needed

18. So, how does science speak with regard to aging?With many tongues Important findings about aging can come from cancer research, Alzheimer’s disease research, genetics and epigenetics research, studies of animals and plants, population health studies, and aging research studies.They can come from just about everywhere in the life sciences.They can be inconsistent, pushing different viewpoints.The contributing scientists mostly do excellent work. But they don’t always talk with each otherA tower of babel!

19. Aging, like the universe, has no center or single central causeWe have all kinds of competing sub-theories in biology but, so far, no Grand Unified Theories, except evolutionIn this respect, biology today is in a similar condition to that of physics in about 1910

20. Where are we in aging research? -AMOUNT AND DEPTH OF DETAIL IS ASTOUNDING – A HUMAN IS BY FAR THE MOST COMPLEX ENTITY KNOWN IN THE UNIVERSELIKE PUTTING TOGETHER A 30 MLLION PIECE MULTIDIMENSIONAL JIGSAW OF AGING AND THE PATHWAYS INVOLVED IN AGING

21. Aging is multilayeredThe aging of a living organism is both a manifestation and a result of complex changes in composition, structure and function across all levels of biological organization from molecular pathways, cell components and cells, to organs and tissues, to whole-body systems. Almost all research investigations have been carried out at a specific single level of organization or from a particular disease in isolation with a relatively narrow focus. It is rarely studied that wayLIMITS OF THE CURRENT CULTURE OF RESEARH

22. Where are we in aging research? WE ARE ASSEMBLING SUB CHUNKS OF THE PUZZLE WITHOUT KNOWING HOW THEY WILL ALL EVENTUALLY FIT TOGETHERWE DON’T HAVE A GUIDING PICTURE ON THE BOX COVERWE HAVE ENOUGH BIG SUBCHUNKS TO MAKE MANY OF US THINK THAT THE PUZZLE WILL BE COMING TOGETHER SOONWE ARE UNDERSTANDING MORE AND MORE ABOUT THE CONSEQUENCES OF AGING AND THE PATHWAYS INVOLVED IN AGING AND WHAT TO DO TO LIVE LONGER HEALTHIER LIVES

23. The context – State of the scienceUnderstanding aging takes us into just about every area of human biology and medicineThe field is incredibly broad and deepIt consists of many disparate areas of studiesMost scientists are only partially aware of what other scientists producing related results are doing, and can be unaware that others have solved part of the problem that they are addressing.So, what is presented here is my own story of what is known about aging

24. Our challenge (AgingsSciences .com)Pulling together important current research results from diverse fields and interpreting them from the viewpoint of agingPublishing in-depth articles on key topics in our blogwww.agingsciences.comA 10-year undertaking, so far, over 500 in-depth articles2,000 – 5,000 daily readers75,000+ registered subsribersEstimated worldwide following of over 200,000 people

25. OKSO, FINALLY, JUST WHAT IS AGING?

26. WHAT IS AGING?What happens with aging that leads us so surely to die? Aging is a species-specific program with random elements. The program starts with conception, devolves lifelong and ends with deathAging is not simply the result of random damage or “wear and tear” Every species has a typical lifespanThe program is extremely complex and we are just starting to understand parts of it We know of some minor hacks on the program that can give us a certain number of good years of life beyond the averageI do not think it will ever be possible for us to live forever in the bodies we haveNature favors preservation of species or evolution of species to more viable alternatives. Renewal of life and sure death of individuals is part of the game for all living species

27. Inevitability?See if this fits for you:“Around me , it has turned that people I know of my age and younger are getting cancers  of all kinds - diabetes - gout - dementias - incurable infections - life-threatening cardio conditions - falls - unable to move – debilitating arthritis - heart, liver and other organ failures,  etc.  Wait a day and I hear about someone else.” I do not believe that such conditions of aging are necessary concomitants of aging for most people in their 60s, 70s or even 80s or possibly 90s. They are largely optional.Sooner or later, however, you can expect some such condition to get you. That is the nature of biological entities. Personally, I have opted for later.

28. II.CONSEQUENCES OF AGINGPersonal and Social

29. We know a lot about the consequences of agingIt is fatalWe are living longerYet, everybody dies by age 122Image sourceSurvival curve is becoming rectangular

30. The life expectancy curve is being rectangularized60Now. Average US life expectancy 80Image source3090120Ancient Rome -Life expectancy 3619502050?1AD4000 BC

31. We know a lot about usual consequences of agingEfficiency and regulation of key body systems declines with advancing ageStem cell senescence and decreased cell differentiation capability lessened immune responses Decline in key hormonesDecreases in numerous key proteins Decreased antioxidant defenses Decreased DNA repair capabilities

32. We know a lot about usual consequences of agingMetabolic pathways less efficient DNA methylation deregulatedHistones get deacetylated Molecular signaling pathways becomes less efficient Activation of key health genes decreases Activation of cancer and other disease-related genes increases More and more DNA damage The list goes on and onIncremental decripitude

33. With declines there is a steep rise in susceptibilities to age-related diseasesCancers, cardiovascular diseases, diabetes, Alzheimer’s Disease, Parkinson’s Disease, etc.Image sourceImage sourceAlzheimer’s DiseaseConsequences of aging

34. Consequences of agingWith aging there is a steep rise in susceptibilities to age-related diseases, e.g. cancersImage source

35. With aging, there is a steep rise in susceptibilities to age-related diseasesConsequences of agingParkinson’s Disease DementiaImage sourceImage source

36. There is also generally a decline in capabilities, e.g. cognitiveImage source

37. Image sourceCost of fall injuries by age groupImage sourceThe aged consume far greater health care resourcesImage sourceA growing world-wide problem

38. The Prevailing view:

39. An emerging view:THE CONSEQUENCES WE USUALLY ASSOCIATE WITH AGING ARE NOT INEVITABLE

40. III.CAUSES ANDPROPERTIES OF AGING

41. What causes aging?There are at least 36 respectable scientific theories of what causes aging Here are a few of them – my top 14 in 2007

42. Aging theories – my 2007 starting listOxidative damageCell DNA damageTissue GlycationLifofuscin accumulationMitochondrial dysfunctionalityChronic inflammationImmune system compromiseNeurological degenerationDeclines in Hormone LevelsSusceptibility to CancersSusceptibility to cardiovascular diseasesTelomere shorteningEpigenomic transformationsCell senescence

43. Discovered or proposed laterDozens of other reasons for aging , e.g16. Age related declines in SIRT, NAD+, PGC1alpha, Nrf2, etc, expression17. Age related increases in NF-kappaB, P66shc, GSK-3 beta expression18. Proliferation of ANRIL DNA repeats and inserted segments19. Mutations in non-coding DNA and micro RNAs20. Age-related changes in microbiomes 21. Proliferation of circular RNAs22. Age-related circadian dysregulation23. Insufficient stress24. Micronutrient insufficiancy25. ---

44. More newer views on the causes of aging include:DNA damage/mutations, Epigenetic dysregulation, e.g. DNA methylationExpression of transposable elementsCellular senescence, Increased IGF or mTOR signaling, Mitochondrial dysfunction, Proteotoxicity, Autophagy failure, Inflammation, inflammation, inflammation 

45. About the theories of agingThey are not independentE.g., oxidative damage can foster tissue glycation which, together with programmed accumulation of INK4a can increase susceptibility to cancersEvery week new research reveals more complex inter-relationships among the theories.They all define important ways for looking at agingFrom the viewpoint of wanting to slow, stop or even reverse aging, we can’t ignore any of them.

46. Aging, like the universe, has no center or central cause

47. Molecular biology study of biology at a molecular level. Overlaps with biology, chemistry, genetics and biochemistry.Epigenetics and EpigenomicsCritical information in DNA but not in the genes themselvesGene activation pathwaysAmazing impacts of non-coding RNAsStress ManagementLessons of long-lived speciesStem cell scienceInduced pluripotent stem cellsAdult somatic stem cells, autologous stem cellsSOME RESEARCH AREAS WHERE THERE HAS BEEN SIGNIFICANT RECENT ADVANCEMENT AND DISCOVERY

48. Cross-species communications and interdependenciesRoles of biomes - Microbes that lie with and affect us; the gut, the skin, in the soil, etc.Lessons of long-lived speciesMetabolic pathwaysCircadian regulationLessons of centenarians, super-centenariansData miningSystems biologyRoles of non-coding “junk” DNA and RNANanotechnologyBiomarkers of agingLiposomal supplement and drug deliveryMORE SCIENTIFIC AREAS WHERE THERE HAS BEEN SIGNIFICANT RECENT IMPORTANT DISCOVERY

49. Some important insights regarding age-related degenerative diseasesALL the animal longevity experiments show that lifespans and healthspans go togetherDouble the lifespan of an animal and they will still die of the same causes and diseasesThey will get the diseases and die of them much later.This leads to a whole different way of thinking about degenerative diseases.Aging now thought to be not only a risk factors for age-related diseases but a causal factor for such diseases.

50. Above-all a change in paradigm is required“Health care” in aging now mainly means trying to repair degenerative diseases and processes after they have happened – cancer, diabetes, dementia, heart disease etc. By the time these are diagnosed it is usually too late to fix themMost such diseases are the results of 10-20 year processes; they can be seen comingIt is far easier and less expensive to slow or stop these diseases from happening than to try and fix them after the fact.

51. A shift in health care emphasis , both in research and in practiceFrom repair-shop focusTo lifestyle design and preventative maintenance focus

52. SNEAK PREVIEW OF PART 2ANTI-AGING INTERVENTIONSFirst: the stakes:

53. From a science view, the challenge is how to put the descriptions of the elephant together so we can fathom the whole beast. This is very tough to do.However, extending human lifespans is an easier challenge- On both the societal an personal levels

54. The stakes: PERSONALDo you want to greatly up the probability of 10-30 extra good healthy and productive life for yourself or a loved one? Worth serious consideration

55. The stakes: SOCIETALIf we could delay aging an average of 10 years the health care cost savings would be immenseEverybody moves back 10 years on the health care cost curvePlus, the economic productivity benefits of everyone working 10 years more could be worth trillions

56. What is a universal characteristic of the degenerative processes of aging?And this provides a very important guide on how to slow aging at all ages“Together our results suggest that suppression of inflammation is the most important driver of successful longevity that increases in importance with advancing age and is amenable to pharmacological intervention.”From E-bio Medicine 2015 Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians - a large Japanese cohort studyThis has to do with an intervention I describe laterIt is CHRONIC inflammation

57. FIRST, A TRUE STORY Of a major breakthrough in life extension I saw it happen -- You possibly did tooEXTENDED HEALTHSPANS AND LIFESPANS BY A FACTOR OF FOUR TO SIX.Happened over a 40 year periodWe can apply the approach personallyWas it in:C-elegans?Drosophila melanogaster?P66shc- knock-out mice?Naked mole rats?