1	"Presentation by" Presentation by: Vincent E. Giuliano, PhD Update July 29, 2009
2	"“" “I don't want to achieve immortality through my work. I want to achieve it through not dying.” – Woody Allen
3	Two central questions What does science know about aging at this time? In the light of that knowledge what exactly can be done now by ordinary people to retard, stop, or possibly even reverse aging?
4	The answers are not easy We all know what aging is, a process through we progressively become more vulnerable to diseases and disabilities and eventually die. Aging is growing older. But scientists disagree not only about what causes aging but what about it actually is.
5	The answers are not easy because: There are many theories regarding the causes of aging, each plausible in its own domain, each with its own group of proponents, and each based on credible research evidence. These theories are like the blind men of fable who feel only different parts of an elephant. That is, each aging theory is valid in its own right but presents only a small part of the picture. A larger unified theory of aging is only now starting to emerge.
6	An evolving approach Thoroughly investigate the major scientific theories of aging (14 of them) Find out how they relate to each other, what they say in common Ask the question for each theory “If the underlying assumptions of this theory are correct, then what can be done now to slow, stop, or reverse aging according to this theory?” To combine the answers to determine what can be done now about aging Monitor the research literature of molecular biology, genetics, genomics, etc. on a daily basis with an open mind Continuously update and revise my findings
7	NOTE Underlined items in this color or blue are hyperlinks. They can be clicked to explore the subject in more detail in either my online Anti-Aging Firewalls Treatise or in my Anti-Aging Firewalls Blog.
8	Major theories of aging To see details click on title of theory Oxidative damage The most traditional theory: that aging is due to accumulated tissue damage due to oxidative stress created by free radicals. Cell DNA damage That aging is due to accumulated damage in cellular DNA, leading to cancers, cell senescence or cell death, in turn leading to tissue and organ deterioration.
9	Major theories of aging To see details click on title of theory 3. Mitochondrial damage Mitochondria (energy-producing organells in cells) are critical to the cell reproduction cycle and their DNA, different from the cell’s main DNA, is particularly vulnerable to damage. Tissue glycation With aging, tissues become increasingly damaged and dysfunctional due to cross-linkages with sugar molecules. Lipofuscin accumulation Metabolic product gunk called lipofuscin accumulates in cells and inhibits their functionality.
10	Major theories of aging To see details click on title of theory Chronic inflammation Chronic inflammation appears to be a core condition underlying many if not most age-related disease processes. Immune system compromise Immune systems weaken with age increasing susceptibility to all kinds of diseases. Neurological degeneration Neurological systems weaken with age causing loss of coordination of other body systems.
11	Major theories of aging To see details click on title of theory Declines in Hormone Levels Hormone levels run down with age and so do all of the body systems they regulate Susceptibility to Cancers Risk of cell cancer pathology due to shift in gene expression increases radically with aging Susceptibility to Cardiovascular Disease Cardiovascular diseases are the biggest killers of old people
12	Major theories of aging To see details click on title of theory Telomere Shortening and damage It is thought that most of the diseases of old age come about through cell senescence due to telomere loss. Telomeres are the “caps” found on the end of chromosomes in somatic cells. Programmed Epigenomic Changes Aging is a consequence of programmed shifts in gene expression that happen throughout life. Decline in Adult Stem Cell Differentiation Aging is due to a slowing rate of organ regeneration because of declining differentiation activity of adult stem cells.
13	About the theories of aging They are not independent E.g., oxidative damage can foster tissue glycation which, together with programmed accumulation of INK4a can increase susceptibility to cancers Every week new research reveals more complex inter-relationships among the theories. They all define important ways for looking at aging From the viewpoint of wanting to slow, stop or even reverse aging, I don’t want to ignore any of them.
14	About the theories of aging The newer theories based on genetics, proteomics, molecular biology, stem cells and epigenomics give more powerful ways of looking at aging. Approaches that will enable us to live 150 – 300 years or more will be based on them.
15	Candidate theories of aging In the last year I have identified four more candidate theories of aging, reflecting sophisticated research in progress: Incorrect protein folding Accumulation of Progerin Gene mutations leading to hellicase abnormalities Aberrant mTOR signalling
16	Constructing a science-based anti-aging program Focus on healthy people of any age and be concerned mainly with here-and-now practical approaches: Ask the question for each theory “If the underlying assumptions of this theory are correct, then what can be done now to slow, stop, or reverse aging according to this theory?” Base answers on research Define an anti-aging firewall for that theory consisting of Lifestyle patterns and habits, and Using dietary supplements Combine the firewalls to determine what can be done now about aging
17	Nature of longevity research Macroscopic studies of large populations Like population of Okinawa Large population cohort studies Follow thousands of people for 10-30 years Controlled clinical trials Short, very expensive, specialized for drugs Animal experiments Mice and rats live 2-3 years, very good models In-vitro and in-vivo studies of cell populations Thousands of such studies, very specialized Synthesis and review studies Put together results from many studies in interpretative frameworks
18	Constructing a science-based anti-aging program All the actions and supplements in the anti-aging firewalls are based on one or more of these kinds of research Most are supported by several of these kinds of research For a few firewall elements, supporting research exists on all of the above levels. E.g. value of exercise, impacts of consuming vitamin C, curcumin and green tea New research results are constantly coming in
19	Constructing a science-based anti-aging program Example: For the Oxidative Damage theory of aging: Lifestyle firewall elements would include avoid circumstances that produce large number of free radicals (ROS) in the body like X-radiation, UV exposure, ingesting heavy metals, eating rancid food. Eat blueberries, chocolate. Supplement firewall substances would include Antioxidants of various types which directly quench free radical activities
20	Constructing a science-based anti-aging program Example: For the Tissue Glycation theory of aging: Lifestyle firewall elements would include Minimize eating substances having a high glycemic index, burned or heavily browned foods. Supplement firewall substances would include Supplements that break up or inhibit formation of advanced glycation endproducts like l-carnosine and benfotiamine
21	Constructing a science-based anti-aging program Example: For the Programmed Epigenomic Changes theory of aging: (looking at the role of NF-kappaB in one such theory) Lifestyle firewall elements would include avoid circumstances and activities that trigger activation of NF-kappaB, including many disease, stress and inflammatory processes. Supplement firewall substances would include Substances which inhibit the nuclear translocation of NF-kappaB – 36 of them in the combined firewall program.
22	Constructing a science-based anti-aging program Example: For the Immune System Compromise theory of aging: Lifestyle firewall elements would include Sleep at least seven and a half hours a night on a regular schedule, avoid chronically stressful situations, do mild cardiac exercise at least a half-hour each day, avoid situations likely to lead to infections Supplement firewall substances include Phyto chemicals and hormones which specifically enhance immune system functioning as well as protect against infectious diseases
23	Constructing a science-based anti-aging program Example: For the Telomere Shortening and Damage theory of aging: Lifestyle firewall elements would include Minimize stress, diseases, injuries, follow the general lifestyle regimen. Supplement firewall substances would include Antioxidants, to protect against shortening Astragaloside IV or or cycloastragenol to activate telomerase expression in body cells, possibly immortalizing these cells and conferring longevity to the associated organs.
24	What I have learned First: I started to pull this all together in a draft of a book but I found relevant research discoveries are happening so frequently that in May 2008 I decided instead to create a comprehensive Anti-Aging Firewalls Treatise on the web. And in January 2009 a corresponding Anti-Aging Firewalls Blog I update the blog almost every day and it contains over 134 major postings and 123 reader comments I update the treatise more or less weekly
25	What I have learned Second: Although the anti-aging firewalls for each theory are different, there is great overlap among them so that in combination it was possible to identify an overall anti-aging lifestyle regimen and an overall dietary supplement regimen, both based on the current state of scientific knowledge of aging.
26	What I have learned Third: There is an immense overlap between the research-based anti-aging lifestyle regimen, which can be found online in my treatise, and conventional wisdom concerning a healthy lifestyle in terms of sleep, stress minimization, exercise, mental activity, social participation, good eating, good mental attitude and so on. This conventional wisdom is not only based on theory but is backed up by many long studies involving tens of thousands of people I report frequently on these in my blog
27	Conventional health wisdom
28	What I have learned Fourth: most but not all of the supplements in the overall anti-aging firewall regimen are well known, taken by millions and have excellent safety records e.g., fish oil extracts, curcumin, glucosamine, calcium, magnesium, zink, DHEA, vitamins C, D, and E Some are traditional Indian or Chinese medicinal herbs that have also been extensively researched through Western science e.g. ashwagandha, boswelia, ginger, astragalus A few are based on more recent developments in molecular and cell biology e.g. alpha-lipoic acid, acytl-l-carnitine, astragaloside IV, resveratrol
29	What I have learned fifth: it is clear that radical life extension—to beyond age 100 or 110—must depend on knowledge associated with the newer and more sophisticated ongoing research in epigenetics, molecular biology, and stem cells. Certain substances in the anti-aging regimen may act powerfully toward this end, but what they can actually do for human life extension will not be known for many years.
30	What I have learned Fifth (continued): Substances that might contribute to extending human lifespans beyond the normal 110 year limit include: Use of r-alpha lipoic acid and acytl-l-carnitine to address cell mitochondrial longevity and inhibit unwanted cell apoptosis (self-destruction), and use of resveratrol or resveratrol homologs to activate the SIRT1 and FOXO3 “longevity” genetic pathway, the pathway known to confer life extension due to calorie restriction.
31	What I have learned Fifth (continued): Substances that might contribute to extending human life spans beyond the normal 110 year limit include: Use of astragaloside IV or cycloastragenol to activate telomerase expression in body cells so as to extend their replicative life spans, promote cell renewal through differentiation of stem cells, and thus confer longevity to associated organs, and use of green tea, curcumin, and other phyto-substances for their powerful cancer-preventative effects and cardiovascular benefits that operate through genetic mechanisms.
32	What I have learned Sixth: Research is revealing more and more cross links among the theories of aging, and new theories are cropping up in the process. Like the outline of an immense approaching sailing ship still barely discernable through thick ocean fog, the outline of a unified understanding of aging is starting to emerge as the fog slowly falls away. As this happens, I expect the anti-aging firewall regimens will continue to become more sophisticated and powerful.
33	Where the longevity breakthroughs will be coming from Molecular biology study of biology at a molecular level. Overlaps with biology, chemistry, genetics and biochemistry. Genetics/Genomics Multiple gene interactions Gene activation pathways Epigenetics/Epigenomics Critical information not in the genes themselves Proteomics Protein structures and functions Protein folding Stem cell science Induced pluripotent stem cells Adult somatic stem cells, autologous stem cells
34	Giuliano’s Law: Prospects for breaking through the 122 year human age limit Every 7 years will see a doubling in the effectiveness of practical available anti- aging interventions. Progress being driven by social, economic, scientific and technology streams that are real today. The Law’s consequence is that, taking advantage of today’s anti-aging interventions and the stream of new anti-aging developments likely to come over the years, it may well be possible for a healthy person now under 80 to break through the 122 human age limit and live up to hundreds of years.
35	A personal note When I first got involved with computers in 1951 there were only a few hundred of us in the field. Obtaining one of the first PhDs from Harvard in what was later called Computer Science, I continued to participate in the “information revolution”, making several key contributions over the years. Today, we are in a very early stage of a “longevity revolution,” also of vast importance. The current status of this new revolution reminds me of the computer revolution in 1955—the same excitement, rate of new ideas and discoveries, rate of new people coming into the field, new practical applications, intractable problems being cracked, and incredible promise for the future. .
36	A personal note I am now 79 years old and see longevity science as my main career for at least the next thirty years, perhaps sixty. To help me get there I do my best to follow the suggestions in the anti-aging lifestyle and supplement regimens.
37	Resources Details of he theories of aging and the anti-aging lifestyle and dietary firewall regimens can be found in my frequently updated treatise: ANTI-AGING FIREWALLS - THE SCIENCE AND TECHNOLOGY OF LONGEVITY My companion BLOG can be found on the: ANTI-AGING FIREWALLS WEBLOG I post many interesting items relevant to longevity here on an almost-daily basis
38	"Like my Treatise and Blog" Like my Treatise and Blog, this Presentation is a work-in-progress I will be revising it as time progresses to reflect new research and changing perspectives
39	"Presentation by" Presentation by: Vincent E. Giuliano, PhD Update July 29, 2009