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What Animals Can Teach Us About Longevity

Dean Pomerleau

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From this new article from the BBC:


"Across mammals alone, expected lifespan can vary 100-fold, from shrews that live for no longer than 1.5 years to the bowhead whales that can live for more than 200. It is as if, for various reasons, natural selection has somehow pushed certain creatures to evolve their own elixir of life."


The writer goes on to talk to scientists studying genes and gene expression in whales, bats and naked mole rats, in hopes of discovering how they live so long, and in particular avoid cancer.  The article talks about the possibility of using gene therapy to replicate some of the longevity-promoting genetic changes observed in these long-lived animals in people someday.


One of the researchers talks about a study I'd sign up for - comparing bowhead whale gene expression to the gene expression of people practicing CR!  It reminds me of the study [1] Luigi Fontana did on our muscle tissue - namely comparing our gene expression to that of CRed rats.


Note: This is yet another example of a post that would be fit better on a "Science of Health & Longevity" forum, rather than here on the "CR Science & Theory" forum. How about it Brian/Tim?





[1] Mercken, E. M., Crosby, S. D., Lamming, D. W., JeBailey, L., Krzysik-Walker, S., Villareal, D. T., Capri, M., Franceschi, C., Zhang, Y., Becker, K., Sabatini, D. M., de Cabo, R. and Fontana, L. (2013), Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell, 12: 645–651. doi: 10.1111/acel.12088. Full Text: http://onlinelibrary.wiley.com/doi/10.1111/acel.12088/full

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A possible explanation might be that animals which live less long evolve/adapt more quickly - more generations per century - whereas those that live for a very long time are likely to be overtaken (outwitted and eaten) by the more rapidly reproducing/evolving predators.  So all the longer living species eventually became extinct as they were outwitted/outgunned by the shorter lifespan, but faster-evolving, competition?  

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A possible explanation might be that animals which live less long evolve/adapt more quickly - more generations per century - whereas those that live for a very long time are likely to be overtaken (outwitted and eaten) by the more rapidly reproducing/evolving predators.  So all the longer living species eventually became extinct as they were outwitted/outgunned by the shorter lifespan, but faster-evolving, competition?  


I think you've identified half the equation - there are niches where short lifespan and rapid evolution are advantageous. It seems some micro-organisms and cancer cell lines follow this strategy.


But there are other niches where competition isn't so fierce, so individuals can take their time and have multiple generations of offspring - e.g. whales, bats or naked-mole rats (vs. common rats). In these species, it is evolutionarily advantageous to develop better metabolic maintenance and repair machinery, to facilitate longer lives. 



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  • 3 weeks later...

There were two new articles out addressing the topic of what we can learn from animals about longevity, and particularly cancer. The first focuses on sea anemones, which don't appear to age or get cancer. But it doesn't say much more then "Huh - it would be nice to know how they do it, since they share many genetic pathways with people. Scientists are trying to figure it out."


The second article is much more interesting, both because it focuses on elephants, which are terrestrial mammals and therefore much more similar to humans than are anemones, and because it has actually experimental results about how elephants are able to avoid cancer, the second-leading cause of human mortality in developed countries. The article is in reference to a new study [1] from the Journal of the American Medical Association.


The researchers looked at cancer rates in a bunch of different animals, and found the mortality rate from cancer in elephants was much lower than in humans (5% for elephants vs. 11-25% for humans) despite the fact that elephants live lives not much shorter than people (50-70 years) and have 100 times more cells than the human body. With all those extra cells, you'd expect elephants to have many more rogue cells that turn cancerous, but exactly the opposite happens - elephants get less cancer than people rather than more.


So researchers looked at cells cultured in the lab from elephants, normal humans, and unfortunate people suffering from Li-Fraumeni Syndrome (LFS) who have a 90 per cent chance of developing cancer over their lifetime. They exposed them to ionizing radiation to induce genetic mutations and then observed how many of the damaged cells underwent apoptosis (programmed cell death) to clear out the potentially cancer causing cells. Sure enough, damaged elephant cells self-destructed much more readily (~15% of damaged cells) than damaged human cells (~7% of damaged cells), and the LFS patients were worst of all, disposing only 2.7% of the potentially cancerous cells.


And the mechanism they identified was even more interesting. The rate of apoptosis in the three groups of cells was directly proportional to how much of the p53 gene they expressed: 


In search of an explanation, the scientists combed through the African elephant genome and found at least 40 copies of genes that code for p53, a protein well known for its cancer-inhibiting properties. DNA analysis provides clues as to why elephants have so many copies, a substantial increase over the two found in humans [and only one found in the LFS patients - DP]. The vast majority, 38 of them, are so-called retrogenes, modified duplicates that have been churned out over evolutionary time.


So basically, natural selection appears to have resulted in elephants possessing many more copies of the apoptosis-inducing p53 gene, which enables them to kill off damaged cells before they can become malignant cancer. One can easily imagine someday using the new CRISPR technology (or its descendents) to edit human DNA to insert extra copies of the p53 gene, and thereby hopefully increase apoptosis of damaged cells in people and reduce the incidence of all types of human cancer. But that is still a long way off.


In the meantime, we may be able to ramp up our apoptosis to more "elephant-like" proportions, through, you guessed it, CR. It doesn't appear that CR increases apoptosis via the same p53 pathway as elephants, but instead via its effects of IGF-1 and SIRT-1. Here is a simplified schematic from [2] (note: Autophagy is another form of programmed cell death, closely related to apoptosis):



In fact, several studies of cancer-prone p53-deficient mice, which are used as an animal model of LFS as well as the study of cancer in general, have shown that both CR [3,4] and intermittent fasting [3] reduce IGF-1 and delay onset of cancer, even when started relatively late in life (with CR > IF in terms of effectiveness).


Study [4] in particular was interesting. They exposed cancer-prone p53-deficient mice to a bladder cancer carcinogen and then divided them into three groups - ad lib fed (AL), 20% dietary restriction (DR) and 20% dietary restriction + exogenous IGF-1 to restore IGF-1 level to "normal" in calorie-restricted mice. Here is what they found:


Although tumor progression was decreased by DR, restoration of IGF-I serum levels in
DR-treated mice increased the stage of the cancers. Furthermore, IGF-I modulated
tumor progression independent of changes in body weight. Rates of apoptosis in the
preneoplastic lesions were 10 times higher in DR-treated mice compared to
those in IGF/DR- and ad libitum-treated mice. Administration of IGF-I to DR-treated
mice also stimulated cell proliferation 6-fold in hyperplastic foci.
In conclusion, DR lowered IGF-I levels, thereby favoring apoptosis over cell proliferation
and ultimately slowing tumor progression. This is the first mechanistic study
demonstrating that IGF-I supplementation abrogates the protective effect of DR on
neoplastic progression.
So if you want to live long like an elephant, and avoid cancer by killing off rogue cells, CR seems like a pretty good way to go, at least until more effective gene therapy comes along!  Furthermore, to gauge the effectiveness of your CR practice on your risk of getting cancer, it's a good idea to get your IGF-1 level tested.


[1] JAMA. Published online October 08, 2015. doi:10.1001/jama.2015.13134


Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans

Lisa M. Abegglen, PhD1; Aleah F. Caulin, PhD2; Ashley Chan, BS1; Kristy Lee, PhD1; Rosann Robinson, BS1; Michael S. Campbell, PhD3; Wendy K. Kiso, PhD4; Dennis L. Schmitt, DVM, PhD4; Peter J. Waddell, PhD5; Srividya Bhaskara, PhD6,7; Shane T. Jensen, PhD2,8; Carlo C. Maley, PhD9,10; Joshua D. Schiffman, MD1,7 


Importance:  Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology.
Objective:  To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS).
Design, Setting, and Participants:  A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015.
Exposures:  Ionizing radiation and doxorubicin.
Main Outcomes and Measures:  Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes.
Results:  Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95% CI, 0%-5%]; African wild dog, 8% [95% CI, 0%-16%]; lion, 2% [95% CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% [95% CI, 1.93%-3.48%] vs human controls, 7.17% [95% CI, 5.91%-8.44%] vs elephants, 14.64% [95% CI, 10.91%-18.37%]; P < .001; doxorubicin exposure: human controls, 8.10% [95% CI, 6.55%-9.66%] vs elephants, 24.77% [95% CI, 23.0%-26.53%]; P < .001).
Conclusions and Relevance:  Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.


[2] Aging (Albany NY). 2012 Aug;4(8):525-34.

Caloric restriction: is mammalian life extension linked to p53?

Tucci P(1).

Author information:
(1)Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1
9HN, UK. paola.tucci@unical.it

Caloric restriction, that is limiting food intake, is recognized in mammals as
the best characterized and most reproducible strategy for extending lifespan,
retarding physiological aging and delaying the onset of age-associated diseases.
The aim of this mini review is to argue that p53 is the connection in the
abilities of both the Sirt-1 pathway and the TOR pathway to impact on longevity
of cells and organisms. This novel, lifespan regulating function of p53 may be
evolutionarily more ancient than its relatively recent role in apoptosis and
tumour suppression, and is likely to provide many new insights into lifespan

PMCID: PMC3461340
PMID: 22983298



[3] Carcinogenesis. 2002 May;23(5):817-22.

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in
p53-deficient mice.

Berrigan D(1), Perkins SN, Haines DC, Hursting SD.

Author information:
(1)Division of Cancer Prevention, National Cancer Institute, Bethesda, MD
20892-7105, USA.

Heterozygous p53-deficient (p53(+/-)) mice, a potential model for human
Li-Fraumeni Syndrome, have one functional allele of the p53 tumor suppressor
gene. These mice are prone to spontaneous neoplasms, most commonly sarcoma and
lymphoma; the median time to death of p53+/- mice is 18 months. We have shown
previously that juvenile-onset calorie restriction (CR) to 60% of ad libitum (AL)
intake delays tumor development in young p53-null (-/-) mice by a p53-independent
and insulin-like growth factor 1 (IGF-1)-related mechanism. To determine whether
CR is effective when started in adult p53-deficient mice, and to compare chronic
CR with an intermittent fasting regimen, male p53+/- mice (7-10 months old, 31-32
mice/group) were randomly assigned to the following regimens: (i) AL (AIN-76A
diet), (ii) CR to 60% of AL intake or (iii) 1 day/week fast. Food availability on
non-fasting days was controlled to prevent compensatory over feeding. Relative to
the AL group, CR significantly delayed (P = 0.001) the onset of tumors in adult
mice, whereas the 1 day/week fast caused a moderate delay (P = 0.039).
Substantial variation in longevity and maximum body weight within treatments was
not correlated with variation in growth characteristics of individual mice. In a
separate group of p53+/- mice treated for 4 weeks (n = five mice per treatment),
plasma IGF-1 levels in CR versus AL mice were reduced by 20% (P < 0.01) and
leptin levels were reduced by 71% (P < 0.01); fasted mice had intermediate levels
of leptin and IGF-1. Our findings that CR or a 1 day/week fast suppressed
carcinogenesis-even when started late in life in mice predestined to develop
tumors due to decreased p53 gene dosage-support efforts to identify suitable
interventions influencing energy balance in humans as a tool for cancer

PMID: 12016155


[4] Cancer Res. 1997 Nov 1;57(21):4667-72.

Dietary restriction reduces insulin-like growth factor I levels, which modulates
apoptosis, cell proliferation, and tumor progression in p53-deficient mice.

Dunn SE(1), Kari FW, French J, Leininger JR, Travlos G, Wilson R, Barrett JC.

Author information:
(1)Laboratory of Molecular Carcinogenesis, National Institute of Environmental
Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.

Diet contributes to over one-third of cancer deaths in the Western world, yet the
factors in the diet that influence cancer are not elucidated. A reduction in
caloric intake dramatically slows cancer progression in rodents, and this may be
a major contribution to dietary effects on cancer. Insulin-like growth factor I
(IGF-I) is lowered during dietary restriction (DR) in both humans and rats.
Because IGF-I modulates cell proliferation, apoptosis, and tumorigenesis, the
mechanisms behind the protective effects of DR may depend on the reduction of
this multifaceted growth factor. To test this hypothesis, IGF-I was restored
during DR to ascertain if lowering of IGF-I was central to slowing bladder cancer
progression during DR. Heterozygous p53-deficient mice received a bladder
carcinogen, p-cresidine, to induce preneoplasia. After confirmation of bladder
urothelial preneoplasia, the mice were divided into three groups: (a) ad libitum;
(b) 20% DR; and © 20% DR plus IGF-I (IGF-I/DR). Serum IGF-I was lowered 24% by
DR but was completely restored in the IGF-I/DR-treated mice using recombinant
IGF-I administered via osmotic minipumps. Although tumor progression was
decreased by DR, restoration of IGF-I serum levels in DR-treated mice increased
the stage of the cancers. Furthermore, IGF-I modulated tumor progression
independent of changes in body weight. Rates of apoptosis in the preneoplastic
lesions were 10 times higher in DR-treated mice compared to those in IGF/DR- and
ad libitum-treated mice. Administration of IGF-I to DR-treated mice also
stimulated cell proliferation 6-fold in hyperplastic foci. In conclusion, DR
lowered IGF-I levels, thereby favoring apoptosis over cell proliferation and
ultimately slowing tumor progression. This is the first mechanistic study
demonstrating that IGF-I supplementation abrogates the protective effect of DR on
neoplastic progression.

PMID: 9354418

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  • 2 weeks later...



Al Pater posted this review [1] (thanks Al!) of what animals can teach us about longevity. The two most interesting points I took away from the full text are about naked mole rats (NMRs), which live 8x longer than similar-sized mice:


* NMRs have elevated expression of the P53 stress-response gene, just like we saw above in elephants.


* To quote the full text: "Finally, although NMR are glucose intolerant, their glycated hemoglobin levels are low and they are naturally insulin deficient and insulin sensitive (57)."


That second, glucose-related characterization of naked mole rats sounds exactly like several of us serious, long-term CR practitioners.


You know you're out on a limb when you take comfort in your similarities with one of the ugliest creatures on the planet. :-)





[1] Curr Opin Clin Nutr Metab Care. 2015 Oct 20. [Epub ahead of print]


Nutrients and ageing: what can we learn about ageing interactions from animal biology?


Stenvinkel P, Kooman JP, Shiels PG.


PMID: 26485336






Many prevalent clinical conditions, such as chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary, and cardiovascular disease associate with features of premature ageing, such as muscle wasting, hypogonadism, osteoporosis, and arteriosclerosis. Studies on various animal models have shown that caloric restriction prolongs lifespan. Studies of animals with unusual long or short life for their body size may also contribute to better understanding of ageing processes. The aim of the present article is to review what we can learn about nutritional modulations and ageing interactions from animal biology.




Caloric restriction is a powerful intervention that increases longevity in animals ranging from short-lived species, such as worms and flies, to primates. As long-term studies on caloric restriction are not feasible to conduct in humans, much interest has focused on the impact of caloric restriction mimetics, such as resveratrol, on ageing processes. Recent data from studies on the long-lived naked mole rat have provided important novel information on metabolic alterations and antioxidative defense mechanisms that characterize longevity.




Better understanding of the biology of exceptionally long-lived animals will contribute to better understanding of ageing processes and novel interventions to extend lifespan also in humans.




biomimicry, caloric restriction, naked mole rat, oxidative stress, premature ageing, resveretarol





-- > Energy excess is a main cause of accelerated ageing

of mammals and caloric restriction prolongs lifespan in

mammals ranging from flies to primates.


-- > As long-term caloric restriction is not feasible in the

majority of humans, the potential antiageing effects of

caloric restriction mimetics deserves further studies.


-- > Better understanding of the biology of exceptionally

long-lived animals, such as naked mole rats, will

contribute to better understanding of ageing processes

and novel interventions to extend life.

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  • 6 months later...
The below papers are pdf-availed.  Nuances to the story may be considered.
TP53 Gene and Cancer Resistance in Elephants.
Casola C.
JAMA. 2016 Apr 26;315(16):1788-9. doi: 10.1001/jama.2016.0440. No abstract available.
PMID: 27115383
To the Editor
Dr Abegglen and colleagues proposed that
the occurrence of multiple copies of the TP53 gene in
elephants may be an evolutionary innovation associated
with cancer resistance in pachyderms.1 These extra TP53
copies have been described as alleles of the “ancestral”
TP53 gene. However, according to the Genetics Home Reference
curated by the US National Library of Medicine, the
word allele refers to “one of the alternative versions of a
gene at a given location (locus) along a chromosome.”2 Copies
of a given gene, such as the multiple TP53 copies found
in elephants, should be referred to as paralogous genes, or
paralogs.3 Alleles represent the range of biological variation
of a gene in a species, including deleterious alleles responsible
for mendelian disorders, whereas most paralogs perform
separate biological functions, are expressed in different
tissues or at different developmental stages (for
example, the genes encoding globin proteins4), or both.
Therefore, suggesting that African elephants possess “40
TP53 alleles”1 is not only semantically incorrect but also biologically
To add confusion, these extra TP53 copies are often referred
to as “retrogenes” in the article. Retrogenes are proteincoding
copies of other genes that originate through a process
known as gene retroposition.5However, new copies of the African
elephant TP53 appear to have lost the ability to encode a
complete p53 protein and thus represent pseudogenes or,more
appropriately, retropseudogenes.5
In the article, Dr Abegglen and colleagues proposed 2
mechanisms for a potential role of TP53 copies in the p53-
dependent apoptosis response to DNA damage despite their
limited coding capacity. First, retropseudogenes could
encode p53 fragments that act as decoys for protein repressors
of the full-length p53 protein. The finding that one of
these fragments binds to mouse double minute 2 homolog
(Mdm2) seems to support this mechanism. However, this
has been shown only for the retropseudogene 9 construct
expressed in transfected human HEK293 cells. The binding
of peptides encoded by TP53 retropseudogenes to Mdm2
has yet to be demonstrated in vivo in elephant cells, and the
expression of any TP53 retropseudogene peptide in vivo
remains unproven. The second mechanism points to the
possible action of TP53 retropseudogene mRNAs as decoys
for micro-RNAs targeting transcripts of the ancestral TP53
gene and is entirely speculative. Although the discovery of
multiple TP53 retropseudogenes in animals with apparent
cancer resistance is intriguing, evidence of a causal link
between extra TP53 copies and cancer suppression is yet to
be offered.

TP53 Gene and Cancer Resistance in Elephants.
Pessier AP, Stern JK, Witte CL.
JAMA. 2016 Apr 26;315(16):1789. doi: 10.1001/jama.2016.0449. No abstract available.
PMID: 27115385
To the Editor
The study by Dr Abegglen and colleagues
affirmed the Peto paradox and suggested that elephants are
cancer resistant by virtue of multiple TP53 gene copies and
enhanced responses to DNA damage.1 This study epitomizes
a “One Health” approach to solving important disease problems
shared by humans and animals.2 However, from our
experience working in a large zoo-based veterinary pathology
program, we were surprised by the results because,
unlike in the notoriously cancer-resistant naked mole rats,3
we have diagnosed cancers in several elephants.
The authors used historical necropsy data from our zoo
(1964-1978)4 to compare cancer prevalence in 36 zoo mammal
species to a lay database of elephant mortality. However,
estimates derived from this database are likely biased
by using voluntary nonmedical reports of mortality. Furthermore,
the prevalence estimates in other species were
underestimated or overestimated by including perinatal
mortalities within the at-risk population and by combining
incidental benign neoplasms with malignancies. Although
the authors corrected for missed diagnoses in the lay database,
we wondered if elephants would still appear to be cancer
resistant using only recent necropsy data from San Diego
Zoo Global. During this time (1987-2015), comprehensive
necropsies were performed on all animals that died.
Using these data, we repeated the study by Abegglen
et al but excluded animals younger than 1 year and separated
benign and malignant neoplasms (complete data
available from the authors on request). Cancer was diagnosed
in 4 of 12 elephant necropsies (estimated lifetime
prevalence, 33.3% [95% CI, 9.9%-65.1%]). If benign neoplasms
(eg, uterine leiomyoma) were included, the prevalence
was 66.7% (95% CI, 34.5%-90.1%). Two geriatric
elephants (16.7%) died of cancer. Instead of cancer resistance,
these findings suggest that elephants acquire cancer
in proportions similar to the 11% to 25% human cancer mortality
cited by Abegglen et al. Of course, cancer is not a
single disease, and notably, several elephant neoplasms
occurred in the uteri of aged nulliparous animals, in which
uninterrupted hormonal cycles are known contributors to
endometrial proliferative disease.5 Although the small
sample size limits the generalizability of our results, we
hope these results illustrate potential pitfalls in the design
of comparative studies. Research of this kind captures the
imagination and helps professions come together to
improve the health of all living things. To ensure the validity
and repeatability of future studies, we encourage using
only reliable databases, well-defined at-risk populations,
and strict case inclusion criteria.

TP53 Gene and Cancer Resistance in Elephants.
Perez RP, Komiya T.
JAMA. 2016 Apr 26;315(16):1789-90. doi: 10.1001/jama.2016.0446. No abstract available.
PMID: 27115384
To the Editor
Dr Abegglen and colleagues1 confirmed a low
cancer incidence in elephants and hypothesized that this
relates to increased genomic protection by p53, possibly due
to high copy numbers (20-40) of transcribed p53 pseudogenes.
Also, peripheral lymphocytes and fibroblasts in
elephants showed greater apoptotic sensitivity to ionizing
radiation or doxorubicin than similar cells from humans.
Apoptotic sensitivity was attributed to increased p53
protein levels. In Figure 6 in the article, levels were modestly
elevated in elephant lymphocytes at 0 hours. However,
p53 levels of both species varied over time in the
absence of treatment, with human p53 levels comparable or
higher at 5 and 24 hours. These variations complicate quantification
and interpretation of interspecies differences.
Humans and elephants showed equally robust p21
responses to ionizing radiation, suggesting similar p53 function.
Meanwhile, apoptosis increased over time in both species,
with or without treatment (Figure 3 in the article):
elephant cells always showed greater apoptosis, even at
times (eg, 24 hours) when p53 levels were higher in
Still unanswered is how elephants tolerate elevated p53
levels. Overexpressed p53 was generally lethal in mouse embryos
and Xenopus models.2,3 Although the authors offered a
possible partial explanation (eFigure 12 in the Supplement),
the ability of elephants to survive and grow despite sustained
high p53 protein levels suggests that compensatory mechanisms
must be present in this species.What these are and how
they might affect apoptosis or other p53 functions remains to
be determined.
Taken together, these observations suggest that the
relationship between p53 and apoptosis is complex and the
extent to which p53 might contribute to observed differences
in cancer risk is unclear. Changes in other apoptotic
(BCL2/BH3 or IAP) or DNA damage response (BRCA1/2,
ATM/ATR/Chk1/Chk2) proteins could possibly explain some

TP53 Gene and Cancer Resistance in Elephants--Reply.
Schiffman JD, Schmitt DL, Maley CC.
JAMA. 2016 Apr 26;315(16):1790-1. doi: 10.1001/jama.2016.0457. No abstract available.
PMID: 27115386
In Reply
We agree with Dr Casola that we may have misused
the term allele in reference to the additional elephant TP53
(ep53) genes. We also agree, as highlighted in our article,
that the exact role of ep53 remains to be determined. Ep53
appears to originate from ancient reverse transcription of
TP53 mRNA, followed by a large number of gene duplications.
A retrotransposed gene can still encode a protein
even if not identical to the ancestral protein, as indicated by
our experiments with ep53 retrogene 9. It is unclear if the
additional ep53 genes should be called retrogenes or retropseudogenes.
Laboratory experiments to answer these questions
are ongoing.
One of the limiting factors in comparative oncology
is the lack of good data on cancer in both wild and captive
animals. As Dr Pessier and colleagues describe, the lay database
of elephant deaths that we used may contain biases,
and we welcome the extensive expertise and careful data
curation by the San Diego Zoo for elephants and other
animals. Pessier and colleagues report that 2 (16.67%) of
their 12 San Diego Zoo elephants died of cancer (95% CI,
0%-37.75%), consistent with our estimate of 4.81% (95% CI,
3.14%-6.49%) based on 644 elephant deaths. They highlight
the large number of benign uterine leiomyomas and
malignant uterine tumors in their elephants; this high
prevalence of uterine tumors has been correlated with nulliparous
status in captive elephants,1,2 rhinoceroses,2 and
even ovariectomized guinea pigs.3 Disrupted life history
strategies in humans also have been associated with
increased reproductive cancer risk (eg, reduced parity and
limited breastfeeding with estrogen-positive breast cancer4
and nulliparity, regardless of fertility, with endometrial
cancer5). Genomic analysis for TP53 mutations or deletions
in the San Diego Zoo elephant cancers would be informative.
The true elephant cancer mortality rate may be higher
than our estimates from 644 elephant death reports, partially
due to nulliparity, but it remains clear that elephants
do not develop 100 times more cancer than humans and
that the Peto paradox remains a real and important problem
to answer.
We concur with Drs Perez and Komiya that analysis of
p53 protein levels in elephant cells is important. Unfortunately,
available elephant reagents remain limited, so we
used a human p53 antibody that cross-reacts with ep53 to
demonstrate global p53 protein expression. This antibody
does not recognize activated p53; therefore, comparisons of
functional p53 protein levels cannot be made using Figure 6
in the article. Furthermore, elephant and human proteins
were not run on the same gel and membrane. To address
these issues, we repeated experiments on the same Western
blot comparing p21 protein expression (a direct target of
p53) with an antibody that detects both human and
elephant p21 (eFigure 10 in the Supplement). We found
greater p21 protein expression in elephant cells compared
with human cells, suggesting more robust p53-mediated
apoptosis in response to DNA damage. These assays should
be repeated when antibodies to activated ep53 become
available. Perez and Komiya also discuss apoptosis in
elephant cells with or without treatment, which we
addressed through varying lymphocyte wash conditions
reported in the supplementary content. The apoptosis we
described accounted for baseline differences between
elephant and human cells, including increased cell necrosis
due to cell wash conditions. The finding of increased apoptosis
in elephant cells regardless of treatment exposure may
reflect a heightened sensitivity and response to the DNA
damage inherent to cell culture growth, potentially mediated
by ep53 amplification.

Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.
Abegglen LM, Caulin AF, Chan A, Lee K, Robinson R, Campbell MS, Kiso WK, Schmitt DL, Waddell PJ, Bhaskara S, Jensen ST, Maley CC, Schiffman JD.
JAMA. 2015 Nov 3;314(17):1850-60. doi: 10.1001/jama.2015.13134.
PMID: 26447779

-- Al Pater, alpater@SHAW.ca
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Thank you to anyone positing at this site (all four of you) who signed! It received more than 150,000 petitioners signing to help end this disgusting practice that kills elephants. And if you haven't yet signed, do cuz it still ain't too late!



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