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October 1^st, 2000 at the Children’s Hospital of Oakland Research Institute, Oakland, CA

Co-organizers: Aubrey de Grey, Bruce Ames, Gregory Stock

Moderator: Aubrey de Grey

Host: Bruce Ames

A. Executive overview

This meeting is designed to continue and build upon UCLA’s pioneering "roundtable on aging" convened by Gregory Stock in February, 1999. Like that meeting, this will include only about ten participants and will have a roundtable format with no formal presentations. The major departure from the 1999 meeting is that the focus this time will be somewhat more narrowly defined, as befits a one-day event. We will discuss an aspect of biogerontology research that has been dangerously neglected during the recent spate of interest in genome-related breakthroughs: the active reversal of various aspects of age-related degeneration. This is, more-or-less by definition, an area that cannot be informed by comparative analyses between organisms with different rates of aging, which is the focus of microarray and related studies. We do not belittle the value of comparative work, but we feel that far more attention needs to be drawn to ongoing research with the potential to influence human life histories more dramatically than anything based purely on emulating other organisms.

B. Concept

The term "negligible senescence", defined in 1990 by Finch, describes the life history of organisms whose risk of death does not measurably rise as they get older, but remains the same as when they reached adulthood. Thus, "engineered negligible senescence" means restoring and maintaining, by biotechnological intervention, the health (and consequent resistance to life-threatening diseases) that we possessed in early adulthood.

We regard engineered negligible senescence as the true objective of biogerontology research. This is in contrast to the view of many gerontologists, who prefer to stress "successful aging" as their goal. "Successful aging" means extending healthy life (healthspan) so that the period of ill health at the end of life (frailty-span) is very short, but without substantially increasing maximum total lifespan, since they consider that unrealistic. Our view is that not only is extending maximum lifespan realistic, it is the only realistic way to shorten frailty-span much beyond present levels, because it entails extending healthspan (and thus postponing frailty) indefinitely.

C. End products

It was clear following the 1999 roundtable that a high-profile communiqué summarising the results of the discussions would have nicely complemented the mainstream press coverage of the event and been an effective way to disseminate its results to the scientific community. To ensure that the 2000 roundtable’s conclusions gain the greatest possible exposure among both gerontologists and the scientifically literate community at large, we have secured the interest of Science in publishing such a piece in their "Policy Forum" series. Their enthusiasm is demonstrated by the fact that Dr. Katrina Kelner, the editor responsible for all of Science’s review and comment material ("Science’s Compass"), has asked to attend the meeting. Science Compass is an especially appropriate place for the communiqué to appear, because in addition to the large readership guaranteed by publication in Science, the "Policy Forum" series is specifically targeted at reviewing research issues which have widespread and urgent societal implications.

Additionally, we will build upon the work done by Stock and his colleagues to make the proceedings of the 1999 roundtable available on the Internet. The web site of the Program on Medicine, Technology and Society (which Stock directs) was augmented with pages describing the structure of the 1999 roundtable, the participants, the topics prepared for discussion in advance of the meeting, and a summary of the conclusions. We will produce a similar description of the 2000 meeting, including a more expanded version of its conclusions than the Science article. We will also add to and revise that meeting’s milestones in light of recent developments and the results of this meeting. We stress that the concept of "milestone" in this context does not imply a timeframe or deadline; it is a way to describe goals that are sufficiently short-term to be structured more as engineering projects or critical experiments than basic science. The recommendations that emerge from this meeting will make that clear.

D. Overall structure of the meeting

The meeting will largely comprise a series of half-hour discussions, each led by a different participant who is a world leader in his or her field. The overall moderator of the meeting will be de Grey. Areas to be covered include reversal of cell loss (especially in brain, muscle and various glands), reversal of somatic DNA damage or its effects (including mitochondrial mutations), reversal of decline in cellular proliferative potential (in various cell types, including fibroblasts and osteoblasts) and reversal of accumulation of cross-linked, unrecycled macromolecules (both in the extracellular medium and within lysosomes). All these topics have seen very significant biotechnological advances in recent years, which have attracted too little attention in the highest-profile science media. They lead us to believe that a dramatic extension of maximum lifespan in mammals may be much nearer than many of our colleagues contend.

Each half-hour discussion will revolve around the expertise of a single participant, the discussion leader; they will be the person to whom most of the questions are naturally addressed, and they will also bring ideas and issues of their own into the debate. They will start their discussion with a few-minute introduction. The "product" of each discussion will be a list of projects which (a) are directed to reversing the aspect of aging that was discussed, (b) either are ongoing already (though in need of more exposure/funding) or can be initiated now at a realistic funding level, and (c) could be planned as engineering rather than basic science projects, i.e. it can be stated in detail how they would be seen to completion (though unforeseen pitfalls are recognised to have a chance of arising). The overall result of these discussions will be that the participants will have a good appreciation that not only their own area of expertise, but most other aspects of aging as well, are realistically reversible in mammals by technology that could emerge within 5-10 years.

Following these discussions, the meeting will address the relevance to society of progress in the various research avenues outlined above, and the consequent implications for science policy in the USA and worldwide. Stock will lead the analysis of these matters. Faced with increasing hype about anti-aging breakthroughs in the popular press, the reaction of many professional biogerontologists has long been to declare that any substantial increase in the maximum human lifespan is absolutely unachievable. This has led to promotion of the concept of "successful aging", by which is meant (in the extreme) avoiding all age-related dysfunction until well past the present average lifespan and then dying in one’s sleep while in good health. The desirability of "successful aging" as a goal of biogerontology research has been widely embraced by professionals, but we believe that it is grossly misguided. Not only is it biologically much more implausible than extending maximum lifespan, but it is also very far from what elderly people actually see as desirable—the fitter they are, the more they wish to live, irrespective of how old they are. Thus, the public and professional policy regarding biogerontology research is in severe need of re-evaluation, since it does not presently reflect public aspirations. The urgency of such a re-evaluation is heightened by the fact that reversal of aging in rodents will occur long before such technology can be applied to humans, but will trigger an immediate shift of public perception regarding human aging, with dramatic consequences for society.

E. Participants

The confirmed participants are (in alphabetical order):

Bruce Ames (U. California at Berkeley): co-organiser and host. Winner of the National Medal of Science. Relevant expertise: the anti-aging and anti-cancer role of micronutrients; the dietary reversal of bioenergetic decline.

Julie Andersen (U. Southern California; from 8/00, Buck Center for Research in Aging) Relevant expertise: the cell biology and free radical biochemistry of age-related neurodegenerative diseases, especially Parkinson’s disease; transgenic interventions in such diseases.

Steven Austad (U. Idaho) Relevant expertise: the evolution of interspecies and interpopulation differences in rates of aging; cell biology of negligible senescence in vertebrates.

Andrzej Bartke (Southern Illinois University School of Medicine) Relevant expertise: the role of growth hormone, and other hormones, in determining the rate of aging; interventions to reverse the age-related changes in hormone levels.

Judith Campisi (U. California at Berkeley) Relevant expertise: the pathological significance of replicative senescence in aging, including both the loss of proliferative potential and the intercellular toxicity (especially carcinogenicity) of dysregulated enzyme secretion; the reversal of such pathology by elimination of cells that are approaching or have reached replicative senescence.

Aubrey de Grey (U. Cambridge, UK): co-organiser and moderator. Relevant expertise: the role of mitochondrial mutations in aging; the development of nuclear-coded replacements for the mitochondrial DNA; the elimination of cells containing mainly mutant mitochondrial DNA; the removal of normally undegradable, heavily cross-linked intracellular aggregates.

Christopher Heward (U. California at Los Angeles; Kronos Scientific Director). Relevant expertise: detailed clinical analysis of age-related degenerative changes; dietary and pharmacological interventions to pre-empt and/or reverse these changes.

Roger McCarter (U. Texas Health Sciences Center at San Antonio) Relevant expertise: the mechanisms underlying loss of muscle mass during aging (sarcopenia); therapies to reverse it.

Gregory Stock (U. California at Los Angeles): co-organiser. Convenor of the 1999 Milestone’s Conference. Relevant expertise: the scientific, social, and ethical implications of recent and likely future breakthroughs in molecular biology and genetics.

F. Site

The meeting will be hosted by Bruce Ames at the Children’s Hospital of Oakland Research Institute, where he is presently based.

G. Schedule

08:30 Coffee, fruit, bagels

09:00 Arrival, introductions

09:20 Stock/de Grey: overview of the 1999 meeting and how this meeting builds on it

09:40 Austad: definition of negligible senescence; differences between the physiology and cell biology of negligibly senescent and other vertebrates; progress towards emulating such differences as an approach to regenerative medicine

10:15 Coffee break

10:35 McCarter: physiology of sarcopenia; loss of systemic homeostasis caused by it; proven methods for reversing it; unproven but realistic methods (e.g. satellite cell repopulation)

11:10 Andersen: physiology of neurodegenerative diseases of aging; pharmacological reversal of symptoms; reversal by repopulation of affected cells or precursors; reversal by destruction of extra- and intracellular aggregates

11:45 Lunch

13:00 de Grey: population dynamics of mutant mitochondrial DNA in vivo; mechanisms underlying its pathological effects; reversal of its effects by nuclear complementation and other methods

13:35 Campisi: incidence of replicative senescence (or approach to it) in various tissues; mechanisms underlying its pathological significance (cancer, immune decline etc); reversal of its effects by elimination of such cells; reversal by telomerase manipulation

14:10 Coffee break

14:30 Ames: accumulation of nuclear mutations; pathological significance (cancer and other); capacity for reversal by cell turnover; role of micronutrients in reducing the level of pre-mutagenic lesions; mechanisms of loss and gain of methylation and other regulatory DNA adducts; interventions to reverse the loss of such regulation

15:05 Bartke: hormonal mechanisms for extension of mammalian lifespan; when they extend it and when they shorten it; options for reversal of aging by hormonal manipulation, including stimulation of cell proliferation; deleterious side-effects and their avoidance

15:40 Coffee break

16:00 TBA (or de Grey): intralysosomal and extracellular cross-linking leading to undegradable aggregates; pathological sigificance; pharmacological means to eliminate or un-link such aggregates, e.g. ALT-711; controversies regarding lipofuscin (centrophenoxine etc); transgenic destruction of lipofuscin and/or its equivalent in arterial macrophages and retina.

16:35 de Grey/Stock: summary of the day’s discussions to this point; tentative prioritisation of the specific projects identified and their relationship to the 1999 milestones.

16:55 Heward: practical challenges and technical obstacles; difficulties involved in translating the meeting’s various projects from the laboratory to the clinic.

17:15 Stock: social/ethical/policy implications in the short and midterm (up to 10 years hence)

18:10 Dinner

20:00 Stock/de Grey: Informal continuation of final session

H. Pre-meeting preparations

De Grey will be corresponding with all participants during the coming two months, discussing specific areas that should be covered in the meeting and making sure that each session's leader knows what to expect. Through these consultations, he will develop a master list of specific projects – either already under way or feasible with current technology – whose implementation could bring reversal of some aspect of mammalian aging much closer. This list will be circulated to all participants well in advance of the meeting. The focus of the meeting will be to evaluate, refine, and expand upon these projects.

A provisional list of such topics is as follows:

Cell loss in brain (Andersen’s session). It has been well publicised that neural progenitor cells have been found in various areas of the brain in recent years. Furthermore, symptoms of Parkinson's disease have been successfully reversed by the implantation of dopaminergic neurons. Sample literature reference: Armstrong et al, Cell Transplantation 9:139-152.

Cell loss in muscle (McCarter’s session). Sarcopenia (loss of muscle mass) is now broadly accepted to comprise both loss of fibre volume and loss of fibre number. However, the debate on how such changes can be reversed is presently very active, as a result of remarkable gains in both fibre volume and fibre number reported to result from suitably regimented exercise. Sample literature reference: Fiatarone et al, JAMA 263:3029-3034.

Cell loss in glands (Bartke’s session). The 30% extension of maximum lifespan by loss of genes involved in growth hormone production is well known to the participants; it is a sterling example of a spectacular breakthrough that was given virtually no airtime in the science media. A recent advance of comparable significance was the nearly complete reversal of thymic involution by IGF-7. Sample literature reference: Aspinall et al, Biochem Soc Trans 28:250-254.

Reversal of the effects of mitochondrial mutations (de Grey’s session). Several ways to achieve this have been advocated in the literature uring the past decade; one very promising approach is introduction into the nuclear genome of suitably modified versions of the 13 protein-coding genes of the mitochondrial DNA. Zullo has recently achieved this (for one gene) in both hamster and human cell culture -- see http://tango01.cit.nih.gov/sig/webversion.pdf for a preliminary account. Sample literature reference: de Grey, Trends Biotechnol 18:394-399.

Reversal of the effect of nuclear mutations and dysdifferentiation (Ames’s session). Several innovative approaches to cancer therapy have been unveiled in recent years; the one gaining most attention is angiostasis, particularly the work of Folkman's group (see e.g. Science 284:808), but others also show promise, including generating antibodies to a patient's own tumour (e.g. Semin Oncol 25:646-653) – which shows particular promise for post-metastatic cancer – and identification of tumour-specific shed proteins (e.g. Yantiri et al, Arch Biochem Biophys 385:336) or mtDNA (Fliss et al, Science 287: 2017) in bodily fluids, which promise earlier diagnosis than yet possible. Changes in the regulation of DNA were proposed long ago by Cutler as a major aspect of aging, due to the maintenance of methylation by copying the methylation state of the other strand, but it is now known to be much subtler – the work of Issa (e.g. Curr Top Microbiol Immunol 249:101-118) shows that sometimes methylation rises with age, and that there is potential for controlling this systemically.

Reversal of decline in cellular proliferative potential (Campisi’s session). This topic is often thought to revolve around telomerase manipulation, which is of course being energetically pursued; less conspicuous aspects of it which have seen recent progress are the response to particular growth factors (see Aspinall et al, above) and (in osteoblasts) to carefully-controlled mechanical stress on bones. Sample literature reference: Swezey et al, J Rheumatol 27:1260-1264.

Reversal of accumulation of cross-linked, unrecycled macromolecules in the extracellular medium and within lysosomes (TBA’s session). One intervention deserves the most mention here: Alteon's compound, ALT-711, which breaks cross-links in the extracellular space that are due to glycoxidation reactions (Vasan et al, Nature 382:275). There is preliminary evidence that ALT-711 does not only exert AGE-breaking effects extracellularly, but that it can penetrate lysosomes and contribute to breakdown of lipofuscin. Other approaches include transgenic introduction of hydrolytic enzymes of bacteria, which have now been shown to break down lipofuscin (de Grey and Archer, unpublished).

Revival of regenerative capacity present in other vertebrates, which may underlie their negligible senescence (Austad’s session). The regenerative capacity of certain amphibians has been known for centuries; this, however, has mostly been studied in terms of regenerating complex structures such as limbs. Of more fundamental interest to mammalian aging is the way in which negligibly senescing species such as rockfish avoid the various age-related degenerative changes surveyed above. If, for example, they maintain cellular turnover in tissues where we lack it (such as the heart), that tells us that bringing about such turnover is not nearly as challenging as we might otherwise think, given the extremely slight differences at the gene level between different vertebrates. Projects coordinated by John Guerin and presented at the recent AGE meeting have already taken this line of research forward substantially. Austad will come to SENS a week after the USC meeting on negligible senescence (SOSA, Symposium on Organisms with Slow Aging) and will update us on recent advances.

Implementation challenges will be daunting in reversing aging, even if the various strategies discussed at this meeting lead to breakthrough discoveries (Heward’s session). Repopulating a few dopaminergic neurons in the substantia nigra, for example, would only be one small step towards actually reversing aging in the brain and returning it to youthful functioning. Nor would introducing mitochondrial genes into somatic cells in tissue culture be tantamount to targeted genetic engineering in an adult organism. An intricate system of neuronal, hormonal, and cellular interconnections.maintains our homeostasis and bodily integrity, and clinicians will have to overcome many challenges and contradictions to revitalize human physiology. To seriously contemplate engineering negligible senescence in humans, we will have to chart a difficult path from our current position towards practical solutions.

I. Communiqué

de Grey will compose a draft communiqué during the few days immediately following the meeting and circulate it. This will be developed into a consensus document through several rounds of comments and modification, and it is anticipated that all participants will be willing to sign it. The typical difficulties in achieving such consensus will be partially mitigated by maintaining a strong focus on this document during the entire meeting and attempting to resolve in advance any disagreements that might stand in the way of universal co-authorship. This has a good chance of success, given that all participants have previously expressed generally positive opinions about anti-aging R&D. Far fewer fundamental differences on this topic exist in this group than in that at last year’s conference at UCLA.

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