Across a wide range of organisms, levels of the key metabolite NAD+ decline with aging, with undesirable consequences at multiple biological scales: In our cells, reduction in NAD+ decreases the activity of the sirtuins, a well-characterized family of pro-longevity proteins. At the systems level, the changing NAD+/NADH balance interferes with the communication between our brains and adipose tissues, resulting in further metabolic dysregulation.

Consequently, a fertile and active area in the broad field of longevity enhancement is the concept of NAD repletion: the idea that, by supplementing the body with molecules that help cells make more of this compound, we can restore (or at least maintain) a more metabolically youthful state, from the cellular level on up.

At present, NAD repletion lies at a busy intersection between basic research, the nutraceutical industry, and translational medicine: A growing number of fundamental studies have demonstrated that supplementation with NAD precursors extends lifespan (and boosts its cellular- and tissue-level correlates) in mice; related compounds are being marketed direct to consumers without FDA regulation; and the first clinical trials are beginning to assess whether we can safely and sustainably increase NAD+ levels in humans.

Because the human data are so preliminary, much of our belief in the potential for NAD repletion relies on results from animal models. Accordingly, it behooves us to keep abreast of the most recent developments. This is especially true when the latest results are partially, but not completely, consistent with previous findings; such discrepancies can reveal cracks in our models and blind spots in our understanding of critical biology.

In the most recent issue of Cell Metabolism, Mitchell et al. report that administration of nicotinamide (NAM), a precursor of NAD+, confers a variety of benefits. In a mouse model, the authors demonstrated that NAM treatment decreased oxidative stress, improved glucose metabolism, and prevented age- and lifestyle-related deterioration of the liver. The supplemented mice benefited at a functional level as well, exhibiting improved coordination and locomotor activity. Thus, NAM (like other NAD+ precursors) increased the ‘healthspan’, that is, the proportion of the adult lifespan free of age-related disease.

Despite these benefits, and in contrast to other NAD repletion studies, NAM treatment had no effect on mean or maximum lifespan, implying that the improvements observed in functional studies occurred in pathways that are not limiting for lifespan, at least in this strain of mouse. Moreover, while there was some evidence that sirtuins were activated, tissue levels of NAD+ did not measurably rise.

This is surprising, given that other NAD precursors have been shown to both extend lifespan (and, for that matter, boost NAD+ levels as expected)— raising the question of why NAM, an orally bioavailable NAD precursor, does not have the same effect. One possible explanation, supported by the authors’ findings in this study, is that NAM administration suppressed uptake of NAM and altered expression of NAD biosynthetic enzymes, although it remains less than clear why this would yield some, but not all, of the previously observed benefits of NAD repletion. Alternatively, high doses of NAM could be inhibiting sirtuin activity, as they do in yeast—but given that NAM is itself produced by enzymes that consume NAD, it is not clear why all methods of NAD repletion would not run afoul of this type of end-product inhibition.

For me, the key point is that there was a strong prior reason to believe that NAM supplementation would have the same healthspan- and lifespanextending benefits as other NAD precursors…but it didn’t, which means that we still have a good bit left to learn about the biology of the NAD pathway, even at the fairly simple level of how to inject material into the system to adjust relative concentrations of compounds of interest in a safe, salutary, and sustainable way.


Mitchell et al. “Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice.” Cell Metabolism 27(3):667–676 (2018). DOI: 10.1016/j.cmet.2018.02.001


I recently had the opportunity to give an Ignite talk at the 20th Anniversary Summit of the Long Now Foundation. The talks were intended to convey the broad interests of the membership of this organization, which is devoted to long-term, planetary-level thinking.

I elected to speak about the coming era of anti-aging medicine, first giving some short background on the fundamental biology of aging and then talking about some of the challenges and opportunities presented by clinical progress in this field.


the presentation went off without a hitch, and I got a tremendous amount of feedback from Long Now members about the talk. It was especially exciting to find out about the topics that non-scientists wanted to learn more about, and this will inform my research on future projects on this topic.

At some point I’m going to put a transcript and all the slides on Medium, but that won’t happen for another week or so.

P.S.: Notwithstanding the MC’s pronunciation, my last name rhymes with “hill,” not “eel”. 😉

From the mailbag, news of a new aging-related peer-reviewed journal, currently in its first issue: Pathobiology of Aging & Age-related Diseases. I haven’t had to check it out yet, but it looks like it will be of broad interest to biogerontologists from a variety of disciplines. The editorial board includes quite a few luminaries of the field, so it seems promising.

In their own words:

Aims: Pathobiology of Aging & Age-related Diseases (PBA) is a new peer reviewed journal serving as a forum for researchers to communicate pathology data as a primary scientific focus of aging; data that might be of less interest in other journals more focused on generic aging or specific scientific disciplines. We are especially interested in developing a focus for advancing the pathological basis of aging in mammalian systems, in particular the mouse and humans.

Scope: Pathobiology of Aging & Age-related Diseases is interdisciplinary in nature and covers all aspects of pathology of aging related to disease phenotypes including cancer, cardiovascular disease, neurological disorders, metabolic dysfunction, renal and gastrointestinal disorders, endocrine dysfunction, musculoskeletal conditions and skin disorders. The underlying theme is based on the sound scientific principles of the pathogenesis of aging and age-related diseases as well as intervention data with resolution of pathological endpoints. The emphasis will be on preclinical studies as well as clinical studies related to strategies developed in animal models and will be image intensive. Papers on the basic biology of aging in invertebrates will not be considered unless comparative mammalian data is also included.

We welcome Research papers, Review articles, Brief reports, Case reports, New animal models, Technical reports, Images, PhD thesis Summaries, and Commentaries.

Target groups: Anatomical and molecular pathologists, gerontologists, geriatricians, transgenic mouse geneticists, toxicologists, and scientists, veterinarians and physicians focused on basic and clinical research in cardiovascular disease, cancer, gastrointestinal disease, endocrine disorders, metabolic dysfunction, renal disease, neurological disorders including Alzheimer’s disease, skin disorders, and musculoskeletal disease.

PBA is open-access; the publisher, Co-Action Press, is a relatively new entity whose small but growing stable consists entirely of open-access journals spanning a wide range of fields.

My personal feeling is that there are probably already too many journals, mostly because I don’t think I or my colleagues actually interact with journals as entities. Mostly we just do literature searches, and choose papers to read based on titles and abstracts. The exception is when we’re submitting papers, but then the diversity of formats and author requirements creates obstacles to rapid submission (and re-submission, if necessary).

I wouldn’t mind seeing individual journals be replaced by a robust tagging system on a relatively laissez-faire neo-journal such as PLoS ONE (to allow scholars to create communities and filters on the firehose of new papers), and a little time spent teaching everyone how to set up PubMed RSS feeds. That said, if we’re going to start new enterprises, this is probably the right way to go, so good luck to PBA.

From the mailbag:

You are kindly invited to the Baltic Sea, for the

*RoSyBA: Rostock Symposium on Systems Biology and Bioinformatics in Ageing Research*
15th-17th September 2011 (Rostock, Germany)

Confirmed speakers: Stuart Kim (Stanford), Ann Brunet (Stanford), Jan Hoeijmakers (Rotterdam), Günter Lepperdinger (Innsbruck), Aubrey de Grey (Cambridge), Joao Pedro de Magalhaes (Liverpool), Thomas von Zglinicki (Newcastle), ….


Early Registration: until June 15, 2011 – Save up to 100%
Call for Contributions: deadline June 1, 2011

From the mailbag:

I am writing to inform you that June 15th is the deadline for
discounted registration and abstract submission for the fifth
Strategies for Engineered Negligible Senescence (SENS) conference, to
be held at Queens’ College, Cambridge, England on August
31st-September 4th 2011. After the deadline, all registration fees
rise by £150.00. Also, after that date, we cannot guarantee that
submitted abstracts will be considered for oral presentation or that
they will be included in the conference abstract book.

All details of the conference, including forms for abstract submission
and online registration, are at the conference website:

The conference program features 33 confirmed speakers so far, all of
them world leaders in their field. As with previous SENS conferences,
the emphasis of this meeting is on “applied gerontology” – the design
and implementation of biomedical interventions that may, jointly,
constitute a comprehensive panel of rejuvenation therapies, sufficient
to restore middle-aged or older laboratory animals (and, in due
course, humans) to the physical and mental robustness of young adults.
The list of sessions and confirmed speakers is as follows:

SENS Lecture:
Caleb Finch, ARCO/Keischnick Professor of Gerontology and Biological
Science and Director, Gerontology Research Institute, U. Southern
Decellularised organs for tissue engineering
Shay Soker, Laura Niklason
New advances in stem cells
Xiao-Dong Chen, Mariusz Ratajczak
Gut rejuvenation
James Wells, Graca Almeida-Porada
Brain aging
David Rubinsztein, Einar Sigurdsson, Charles Greer, Rodolfo Goya
Combating mitochondrial mutations
Matthew O’Connor, Michael Teitell
Genetic dysregulation in aging
Silvia Gravina, James Kirkland
Minoru Ko, Bill Andrews, Dan Kaufman, Michael Lisanti
Novel treatments for atherosclerosis
Pedro Alvarez, Alexandr Kharlamov
Crosslink accumulation in the extracellular matrix
Daniel Nyhan, Paul Thornalley, David Spiegel
Novel antibody technology
Kenneth Shea, Michael Sierks
Janko Nikolich-Zugich, Doren Melamed
Bioinformatics in aging
Alex Zhavoronkov, Pat Langley, Maria Konovalenko
The long-term context of truly effective medicine aginst aging
Max More, Dana Goldman

In addition, there will be at least twenty short talks selected from
submitted abstracts, as well as poster sessions each evening. Authors
of short talks and posters will, like the invited speakers, be invited
to submit a paper summarising their presentation for the proceedings
volume, which will be published in the high-impact journal
Rejuvenation Research early in 2012.

Please note that registration fees are fully inclusive of
accommodation and all meals. Those not requiring accommodation,
journalists wishing to obtain free press passes (not including
accommodation), and those who are unable to register using a credit
card are asked to contact me by email (

I hope to welcome you to Cambridge in August!

Cheers, Aubrey

Aubrey de Grey
Organiser, SENS5
Chief Science Officer, SENS Foundation
Editor-in-Chief, Rejuvenation Research

(^ Index)
(<– Previous session)

Talks in this session:

  1. Sagi: Engineering a long-lived worm
  2. Suchanek: The germline and somatic reproductive tissues influence C. elegans
  3. Stanfel: Ribosome Function and Aging

Dror Sagi (Stanford; Kim lab) — Engineering a long-lived worm

If aging is an engineering problem, then we should be able to solve the engineering challenges more easily in simple systems.

By introducing genes from a long-lived organism into the genome of a short-lived organism, it should be possible to add pro-longevity functions – in effect “upgrading” the short-lived animal so that it lives longer. Sagi has set out to do just that, by transferring genes from the long-lived zebrafish (4-year lifespan) to the short-lived work (4-week lifespan).

The first gene he described was the UCP2 gene, the subject of an earlier talk. Expressing fish UCP2 in the worm lowers overall ATP, and extends worm lifespan. As an important control, expressing an additional copy of the worm UCP2 under the same promoter control does not extend life.

Likewise, fish lysozyme results in lower daf-16 activity, and also extends lifespan. The fish enzyme appears to act by decreasing the pathogenesis from E. coli, an unnatural food source for the worm that causes health problems in late life.

Overall, Sagi characterized 5 well-characterized longevity pathways, testing 16 genes and getting 7 hits.

The next obvious question: Can “upgrade” genes be combined to further increase lifespan? Indeed they can: several pairwise combinations of genes combined to extend lifespan longer than either single gene alone. At some point it worked a little to well: the lifespan of the worms started getting long enough that the survival curves became unwieldy.

  • Staying with the worm…

Monika Suchanek (UCSF; Kenyon lab) — The germline and somatic reproductive tissues influence C. elegans

Classically, it had been assumed that there is a tradeoff between lifespan and the number of progeny produced over the lifespan. We now know that this isn’t necessarily true; there are several examples of long-lived mutants that have a normal number of progeny (though the kinetics may be slower, which poses an issue with respect to fitness: if I live twice as long as you and have the same number of progeny but half as quickly, I will probably lose the evolutionary race).

Suchanek began by reviewing old data (like, from when I was a rotation student in the Kenyon lab: old) demonstrating that removal of the germ cells results in lifespan extension, but that this longevity enhancement requires the presence of the somatic gonad. This loss of the germline causes nuclear accumulation of the DAF-16/FOXO protein in the intestine. It is clear from several diverse pieces of data that the somatic gonad and germ line exert their effects on longevity somewhat independently.

Two other genes, daf-9 and daf-12 are required for the extended longevity of germline-deficient worms. DAF-9 is an enzyme that makes dafachronic acid, the ligand of a receptor encoded by DAF-12. Addition of dafachronic acid has no effect on lifespan of germ-cell-deficient, somatic-cell-competent cells, but it does extend the lifespan of animals that lack both germ cells and the somatic gonad.

How does the intestine know that the germ line is gone? To answer this question, Suchanek screened a “signaling sublibrary” of 1304 genes, and got 115 unique hits including several components of the Wnt pathway. Two components, mom-2 and wrm-1 (ß-catenin), are required for nuclear accumulation of DAF-16/FOXO and for the extended lifespan of germline-deficient worms. Suchanek favors a model in which germ line cells emit Wnt inhibitors.

  • Finishing on a strong note…

Monique Stanfel (Buck Institute; Kennedy lab) — Ribosome Function and Aging

The Kennedy lab is interested in identifying longevity/aging genes that are conserved in yeast and worm, and then testing these in the mouse.

In both yeast and worm, deletion/knockdown of many ribosomal proteins (RPs) can extend lifespan. In yeast, most if not all of the RPs with a role in lifespan are components of the large subunit (60S). In worm, knockdowns of both small and large subunit components can increase lifespan. Three of the genes conserved between worm and yeast can be knocked down in mice.

In order to characterize translation in mouse mutants, Stanfel ran polysome gradients on liver tissue. She analyzed the fractions in two ways, looking at both ribosome-associated RNAs and at the ribosome-associated proteins.

Surprisingly, the Rpl22 gene can be knocked out and has very little effect on global translation in the mouse liver. This may be because a homologous gene, Rpl22L (“-like”) is compensating for the loss of the major species.

Knockout of another gene, Rpl29, has a larger effect on global translation, decreasing the levels of 80S ribosomes. When fed a high-fat diet, Rpl29 knockouts were protected against weight gain, and their blood glucose also remained low; furthermore, the animals were leaner than wildtype. They also resist developing cardiac hypertrophy in another assay – thus, they meet all the preliminary criteria for the time and resource investment of a lifespan study.

(^ Index)
(<– Previous session)

Talks in this session:

  1. Choy: Intracellular trafficking and processing of amyloid precursor protein
  2. Kown: Age-associated decline in immune function; new role of SIRT1 in regulatory T cells
  3. Pan: Regulation of p53 and ageing by SnoN
  4. Grueter: Disruption of the lipid synthesis gene, DGAT1, extends longevity

Regina Choy (Berkeley; Shekman lab) — Intracellular trafficking and processing of amyloid precursor protein

The talk began with a review of the proteolytic processing of amyloid precursor protein (APP) into Aß peptides. Choy emphasized that it is important to have a balance between the amyloidogenic and non-amyloidogenic pathways – a bias toward amyloidogenesis places one at risk for Alzheimer’s disease (AD).

The big question: Where is Aß being produced inside the cells? (What are the possible intracellular sites of Aß peptide production? Where is it actually happening). The approach: study of APP trafficking. The goal: Insights into regulation of Aß production and its relationship to AD.

Building on evidence that the primary site of Aß is the endosome, Choy performed RNAi knockdowns of the endosomal sorting machinery (ESCRT complexes as well as the ATPase VPS4). Knockdown of early components in endosomal sorting result in decreased Aß production, but knocking down the later components or VPS4 results in an increase in Aß production. Together with immunofluorescence results, these findings suggest that Aß production happens after APP leaves the early endosome. Surprisingly, however, APP does not colocalize with early endosome markers in the VPS4 knockdown – in fact, it ends up getting rerouted to the TGN. This raises the possibility that Aß production may happen after APP recycles through the TGN.

More beautiful immunofluorescence data followed, bolstering the recycling hypothesis and leading Choy to conclude in favor of a model in which the primary site of Aß production is in the TGN.

  • Yet another role for SIRT1, coming right up…

Hye-Sook Kown (Gladstone; Ott lab) — Age-associated decline in immune function; new role of SIRT1 in regulatory T cells

Regulatory T cells (Treg) maintain immune tolerance, i.e., they stop the rest of the immune system from attacking the body. They accomplish this by suppressing differentiation of naive cells and the activation of effector cells. This, in turn, helps to prevent autoimmune disease and graft rejection. However, Treg cells increase their activity during aging, which might make elderly people more susceptible to infection.

Treg activity is regulated by FoxP3, which is in turn modified by acetylation that is regulated by SIRT1. Kown used mass spec to identify the specific acetylation sites on FoxP3; she found three, and raising specific antibodies against the acetylated peptides.

Inhibition of SIRT1, a deacetylase, enhances acetylation of FoxP3 at a specific site in both Jurkat T cells and mouse inducible Treg (iTreg) cells. The acetylated protein is stabilized and active, promoting Treg differentiation and survival in a variety of cell culture and in vivo assays.

Thus, by downregulating the activity of Treg cells, SIRT1 promotes a more active immune system: lower iTreg activity promotes increased differentiation of naive T cells and activation of Th1, Th2 and Th17 effector cells. In older people where SIRT1 levels are lower, higher Treg activity may result in a less responsive immune system and higher susceptibility to infection.

In questions, I asked whether SIRT1 inhibition could therefore be used to prevent autoimmune disease – the short answer is “yes”; this has advantages over expanding Treg populations ex vivo, which sometimes results in loss of FoxP3 expression.

  • More mammalian regulatory biology…

Deng Pan (Berkeley; Luo lab) — Regulation of p53 and ageing by SnoN

Starts off with a review of the cancer-aging hypothesis, i.e., the idea that the anticancer activity of tumor suppressors like p53 have a cost: apoptosis and senescence of damaged cells ultimately reduces the regenerative capacity of tissues, contributing to age-related decline in tissue function.

Pan has focused on SnoN, an inhibitor of TGFß/Smad signaling, using a knock-in mouse in which SnoN can no longer bind the Smad promoter. Using this system, he demonstrated that SnoN can function as a tumor suppressor by activating p53-dependent senescence.

SnoN can interact with the PML-p53 pathway; the SnoN protein is a component of PML-nuclear bodies, which in turn activate p53. There are several ways to activate p53: stabilization (i.e., preventing ubiquitination); antiprepression, and promoter-specific activation. How specifically is SnoN activating p53?

Using pulldown assays, Pan showed that SnoN can directly bind to p53, in a manner that does not depend on PML. This binding stabilizes p53, probably because SnoN competes with Mdm2 (which ubiquitinates p53, targeting it for destruction). The working model is that SnoN is a stress transducer that communicates information about cellular stress to the p53 pathway.

The knock-in mice showed premature aging-related phenotypes, including kyphosis and hair loss, as well as higher levels of senescent and apoptotic cells.

  • The final speaker of the session is clearly working on a novel organism…:-)

Carrie Grueter (Gladstone; Farese lab) — Disruption of the lipid synthesis gene, DGAT1, extends longevity

Given how much we know about fat and lifespan, it is perhaps surprising that very few longevity studies have focused on mice with modified lipid metabolism. To remedy this omission, Carrie Grueter has been studying the effect of the DGAT1 (diacylglycerol O-acyltransferase) knockout on phenotypes including lifespan. (DGAT is involved in triglyceride synthesis.)

Hypothesis: Leanness, with a concomitant improvement in metabolism, will extend longevity.

DGAT-deficient mice use more oxygen than wildtype siblings, but do not consume proportionally more food. The knockout mice are protected from the age-related increase in fat mass, as well as age-related increases in inflammation. (Not surprising since abdominal fat is associated with chronic inflammation.) The knockouts exhibit decreased serum IGF-I levels.

The payoff: DGAT knockouts live 25% longer than wildtype. There’s a cost: according to Grueter’s data, DGAT-KO have trouble lactating and therefore have decreased fecundity. Furthermore, the knockouts are bad at surviving short-term calorie restriction: half the mice fail to survive a 48-hour fast, probably because their core body temperatures plummet in the absence of stored fat to burn – the lethality can be rescued by group-housing the mice with wildtype animals or by raising the temperature to 30°C.

So in sum, the hypothesis enumerated above seems to hold, at least when calories are abundant – but when times are tough, it’s nice to have a little bit of extra padding.

(Next session –>)