Biomimetics - Nature's roadmap to insights and solutions for burden of lifestyle diseases
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Review Symposium
doi: 10.1111/joim.12982
Biomimetics – Nature’s roadmap to insights and solutions
for burden of lifestyle diseases
P. Stenvinkel1 , J. Painer2, R. J. Johnson3 & B. Natterson-Horowitz4,5
From the 1Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden;
2
Research Institute of Wildlife Ecology, Department of Integrative Biology and Evolution, University of Veterinary Medicine, Vienna, Austria;
3
Division of Renal Diseases, University of Colorado Anschutz Medical Campus, Aurora, CO; 4Department of Human Evolutionary Biology, UCLA
Division of Cardiology, Harvard University, Cambridge, MA; and 5Evolutionary Medicine Program at UCLA, Los Angeles, CA, USA
Content List – This is an article from the symposium: “Bioinspirational medicine”.
Abstract. Stenvinkel P, Painer J, Johnson RJ, environments and with different resources have
Natterson-Horowitz B (Karolinska Institutet, been recognized to provide not only insights into
Stockholm, Sweden; University of Veterinary disease but also novel means for developing treat-
Medicine, Vienna, Austria; University of Colorado ments. Here, we provide an overview of two related
Anschutz Medical Campus, Aurora, CO; Harvard and overlapping approaches (biomimetics and
University, Cambridge, MA; Evolutionary Medicine zoobiquity), which are turning to the natural world
Program at UCLA, Los Angeles, CA, USA). for insights to better understand, treat and prevent
Biomimetics – Nature’s roadmap to insights and human ‘burden of lifestyle’ pathologies from heart
solutions for burden of lifestyle diseases (Review- disease and cancer to degeneration and premature
Symposium). J Intern Med 2020; 287: 238–251. ageing. We suggest that expanding biomedical
investigation beyond its decades old conventional
There are over 8 million species in this world that practices to new approaches based on a broad
live in widely varying environments, from hot awareness of the diversity of animal life and
thermal fissures to cold arctic settings. These comparative physiology can accelerate innovations
species have evolved over millions of years and in health care under the motto ‘Nature knows best’.
vary markedly in how they have adapted to their
environments. In the last decades, studies of how Keywords: biomimetics, evolution, environment, ox-
species have succeeded in surviving in different idative stress, hypoxia, Nrf2.
Look deep into nature, and then you will nature’) and biomimetics (‘inspiration by nature’)
understand everything better – Albert in many disciplines, such as robotics, tissue engi-
Einstein neering, architecture and material design, its
development in the biomedical sciences has been
Biomimetics is the study of nature and natural limited [1]. Recent developments within the biomi-
phenomenon geared towards creating similar metic field in industry [2] include innovations,
structures, devices, materials or processes for the such as Velcro inspired by the tendency of the burr
benefit of humans. It is based on several principles; of the fruit to stick to dogs hair, novel architectural
at first, all biology represents evolved adaptations, designs with improved thermoregulation inspired
secondly, within the multitudes of these adapta- by termite mounds [3], stable building structures
tions in animals and plants may be ‘solutions’ to inspired by the backbone of turban shells, bionic
challenges facing human beings, and thirdly, by cars inspired by boxfish, fluid-drag reduction
studying the natural world, humans can leverage swimsuits inspired by the structure of shark’s
these evolved solutions to innovate and solve skin, design of airplanes inspired by birds, design
problems. Biomimetics has the potential to accel- of the Shinkansen train inspired by kingfisher
erate innovation in many fields including engineer- birds, explosive chemical jet inspired by Bom-
ing, architecture, synthetic chemistry and bardier beetle [4] and robotics inspired by motor
medicine. Although the past 10 years has wit- mechanisms of insects [5]. Unlike engineering,
nessed a surge of interest in biomimicry (‘copy material sciences and product design, the field of
238 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
medicine is only beginning to leverage the power of health. Our bodies possess limited physiologic
biomimetics to accelerate biomedical innovation responses to short periods of hypoxia, dehydration,
and find novel approaches to fight human dis- starvation, infections and trauma [6]. However,
eases. To enable the coexistence of humans, ani- amongst the millions of other species on Earth
mals and plants on a planet that face many facing the same challenges, we find countless other
problems such as global warming, pollution and strategies (adaptations). Some of these may be far
shortage of water [6, 7], we believe biomimetics will more effective than those that have evolved in Homo
be a field increasingly in demand since it has the Sapiens. Thus, the magnitude of opportunity is
potential to provide many answers. staggering.
Animals have evolved unique mechanisms for
Evolution and selection of survival benefits
organ regeneration and tissue repair, for pathogen
The enormous diversity of species and the diverse resistance, for protection from UV rays, for protec-
biology contained within each of these is one of the tion of hypoxia and from senescence. Furthermore,
most striking aspects of life on our planet. With each species has evolved unique adaptive mecha-
about 8.7 million species (6.5 million species on land nisms to these challenges. This means that, con-
and 2.2 million in oceans) in the world [8], medical tained within the natural world, are not just a
scientists have yet only scratched the surface of handful of solutions, but likely countless strategies
inspirations that can be provided from nature. In we might adapt to solve our physiologic needs or
fact, it has been suggested that 91% of species in the treat pathophysiologic diseases. To state it simply,
ocean and around 86% of existing species on Earth the concept that ‘Nature knows best’ is based on
still await description [8]. Animal life emerged at 650 the fact that over evolutionary time natural selec-
million years ago [9]. Every individual since that tion has acted on countless species resulting in the
time has survived, or not, based largely on whether emergence of life forms possessing a wide range of
their adaptations have been beneficial or not. At adaptations to the challenges of life. These provide
least five major mass extinction events have alternative, and potentially superior strategies to
occurred over the last 450 million years, such as those human bodies naturally possess, and inspire
global cooling, volcanic activity (i.e. massive Siber- therapeutic approaches with greater efficacy than
ian volcanic traps 250 million years ago), asteroids those used today.
and changes in atmospheric gases [10]. In the
aftermaths of mass extinctions, ecosystems were The massive release of oxygen from photosynthetic
restructured and long-term evolutionary trajecto- cyanobacteria in oceans to the atmosphere about
ries were set that often accelerated the evolutionary 2.3 billion years ago altered the course of evolution
process, often resulting in ‘ingenious’ adaptations completely and was the fundamental driver for the
facilitating survival in animals. During evolution, development of complex multicellular life and aer-
the genes responsible for adaptations that were obic respiration. The genes required for photosyn-
successful are passed onto subsequent generations. thesis were acquired rather late in the evolution of
Those that do not work are not successful. Failure to cyanobacteria [12]. Exposure to oxygen drove
evolve adaptations which aid survival may lead to divergence of the transcription factor, nuclear
extinction of species. Humans are responsible for factor-erythroid-related factor 2 (Nrf2) [13], which
the ongoing 6th mass extinction, driven by climate promote the transcription of a battery of hundreds
change, overexploitation and habitat loss [11]. To of anti-inflammatory and anti-oxidative genes. The
survive well in a rapidly changing world, adaptation evolution of cysteine-rich kelch-like ECH-associ-
would be very slow; hence, it requires us to make use ated protein 1 (KEAP1) provided mammals with a
of biomimetic tools to maintain our health. The more sophisticated way to adjust Nrf2 activity in
multiple essential physiologic challenges of life on higher organisms [14]. The activity of Nrf2-KEAP1
the planet – oxidation, respiration, temperature may have major implications for a cluster of
control, obtaining sufficient food and water, meta- burden of lifestyle diseases that we today encoun-
bolism, reproduction, infection, predation, trauma – ter [15].
are common to all species. In nature, multitudes of
adaptive strategies to these common challenges
Biomimetics – a novel strategy to conduct medical research
have evolved. Contained within these countless
adaptations, evolved over hundreds of millions of The need for a novel strategy for identifying models
years may be strategies with salience for human relevant to human health is staggering. The
ª 2019 The Association for the Publication of the Journal of Internal Medicine 239
Journal of Internal Medicine, 2020, 287; 238–251
Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
classical approach to solving medical problems is occurring in settings where environments are
to use a combination of basic and clinical research extreme, such as living in hot thermal vents or in
into a translational approach. However, the basic Arctic regions, can provide important lessons.
science is often delegated to cell culture and Today, much basic medical research relies on
murine and rat models, using an approach that studies of a small number of primitive model
may bridge molecular biology and physiology. organisms including invertebrates that lack stem
There is a need to broaden our approaches to cells, such as the worm Caenorhabditis Elegans
solving medical diseases, and Benner et al. [16] and fruit fly Drosophila melanogaster, and estab-
suggested that we should implement a ‘planetary lished vertebrate animal models, such as mice
biology’ approach that includes evolution and (mus musculus) and rats (rattus rattus). This tradi-
history. Biomimetics have emerged as a powerful tional approach neglects the enormous diversity of
tool for innovation as scientists recognize how adaptations that have evolved in nature (Fig. 1).
powerful evolution’s massive ‘trial and error’ has Moreover, since the health of laboratory animals is
been in optimizing structures, substances and poor and standard control mice and rats are
physiologies. As nature never cheats, the quality metabolically morbid, these animal models may
of solutions identified in nature is sustainable, be inadequate for preclinical studies relevant to
offering enduring long-term outcomes exceeding humans [17]. This may in part explain why trans-
those developed through any artificial means. lation of findings from laboratory animals to
Animals have evolved their genome over millions humans often fails. With the advent of novel
of years. Moreover, rapid epigenetic changes techniques that target genes, such as classical
Tr al approach Bio-inspired approach
Ocean quahog
Blue fin tuna
Add drug, malady or a knockout to a laboratory animal
(such as mice, rat, rabbit)
Seals Colibri
Novel Bear
treatment Understand pathology
strategies Elephant
Naked mole rat Greenland shark
Turquoise killifish Tasmanian devil (a) Identify animals that during
evolution have developed traits to
(b) Identify animals that are suscep avoid senescence and age-associated
tible to ageing and/or disease burden of lifestyle diseases
Fig. 1 The classical approach to solving medical problems is to use a combination of basic and clinical research into a
translational approach. However, the basic science is often delegated to cell culture and/or murine and rat models using an
intervention, such as knockout, to better understand pathogenetic mechanisms. A problem with this approach is that
translation of findings from laboratory animals to humans often fails. By using the biomimetic approach, we instead identify
species that during million years of evolution have adapted mechanisms to protect themselves during extreme
environments. Such species include extreme ageing, such as ocean quahog, naked mole rat and Greenland shark or
species that are protected against burden of lifestyle diseases, such as hibernating bears, colibris, elephants and elephant
seals. Other species, such as blue finned tuna, have evolved mechanisms to adapt to extreme metabolic demands. An
alternative or complementary approach is to identify species that are more susceptible to disease, such as the Turquoise
killifish and Tasmanian devil. As nature never cheats, the quality of solutions identified in nature is likely to be sustainable,
offering enduring long-term outcomes exceeding those developed through than any artificial means.
240 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2020, 287; 238–251Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
CRISPR gene editing, DNA repair and regenerative opportunities does not yet exist. Nevertheless,
medicine, it will be easier to explore a larger there has been some progress in the medically
diversity of species and not only rely on a few focused biomimetics. Bio-inspired products
established animal models. intended for medical application are being devel-
oped including tenacious biological glues with anti-
We trust that a biomimetic approach has a vast proliferative, anti-inflammatory and anti-microbial
potential value for biomedical investigation but activity based on sticky proteins (natures glue)
remains tremendously underleveraged in medicine secreted by the bivalve mussel species [18] micro-
[1]. We propose/challenge the field of medicine to probes for brain surgery based on mosquito skin
turn to the natural world specifically focusing on penetration [19], the red sweat of the hippopota-
the evolved physiologic adaptations of nonhuman mus that have antibiotic and sunscreen activity
animals living in the natural world. This may [20], and development of anti-microbial surfaces
improve our understanding of and approach to modelled after the diamond-like architecture of
high impact burden of lifestyle diseases. Using shark skin [21].
examples from a wide range of burden of lifestyle
diseases that accumulate with age and link with However, biomimetic efforts focused on complex
persistent low-grade inflammation, such as human pathophysiology have been limited. In
dementia, coronary heart disease, cancer, conges- some cases, the identification of natural animal
tive heart disease, chronic kidney disease, obesity, models has been more serendipitous than strate-
type-2 diabetes and nonalcoholic fatty liver dis- gic. A shift to a more strategic and proactive
ease, we offer a roadmap for leveraging the natural approach to identifying these models and creating
world’s multitudes of solutions to benefit human environments in which experts from the worlds of
health [15]. To fully understand the underlying human and veterinary medicine, zoology and wild-
causes of the cluster of burden of lifestyle diseases, life biology can collaborate is clearly needed. To
medical researchers should take advantage the counter the lack of communication and collabora-
possibility to learn from nature and the dramatic tion between the fields of human and veterinary
changes that occurred during evolution. As an medicine and to accelerate biomedical innovation,
example, two mutations (the blockade of vitamin C the Zoobiquity conferences were launched in 2011.
synthesis and silencing of the uricase gene) that Zoobiquity – from the Greek word ‘zoe’ (animal) to
occurred during periods of mass extinction may the Latin word ubiquitare (everywhere) – describes
have had major effects on the current panorama of the continuity of animal and human life including
burden of lifestyle diseases since these mutations our shared physiology, vulnerability to pathology
enhanced the activity of fructose to generate fat and common challenges [22]. These research-fo-
and, thus, predispose modern sedentary man to fat cused collaborations between veterinarians and
mass accumulation and metabolic diseases [6]. physicians have been an early step in bringing
physician–investigator communities into contact
with experts in animal physiology and the natural
The Zoobiquity concept – medical doctors can learn from
world – the source of insights for bio-inspired
veterinarian medicine and zoology
medicine. Since that time yearly conferences in
Embedded within biological diversity of life on the United States and internationally are helping to
Earth are many insights with salience for human expand awareness of the opportunities presented
health. However, these insights remain largely by bio-inspired medicine and the necessity for
undiscovered and their impact unrealized. Several transdisciplinary engagement and collaboration.
factors contribute to this [1]. First, physicians have In response to global warming’s threats to human
insufficient knowledge of the nonhuman animal life health, Zoobiquity conferences, along with One
and the diversity of physiologies found in nature. Health [23, 24], a global movement connecting the
Training in human medicine focuses on Homo health of the environment to the health of humans
sapiens and a few model species used for investi- and animals, have increasingly focused on learning
gation. Secondly, opportunities to interact with from animals that have already developed means
experts in veterinary medicine and wildlife biology for surviving in hostile, heated environments where
have been limited, decreasing opportunities for water resources are limited. Other approaches
collaboration and innovation. Finally, a systematic include emerging collaborations between physi-
methodology for identifying evolved adaptations, cians, basic scientists, biologists, ecologists, zool-
studying them and finding translational ogists and veterinarians that identify and together
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Journal of Internal Medicine, 2020, 287; 238–251Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
Burmese python (Python molurus)
Congestive heart failure
Giraffe (Giraffa)
Hypertension Brown bear (Ursus arctos)
Greenland shark (Somniosus microcephalus)
Type 2 diabetes
Jellyfish (Turritopsis nutricula)
Obesity Rockfish (Sebastes)
Burden of life style diseases
Turqoise killifish
(Notobranchius furzeri)
Neurodegenerative diseases
Osteoporosis
Chronic kidney disease Ocean quahog
(Arctica Icelandica)
Ageing Tasmanian devil (Sarcophilus harrisii)
Cancer Elephant (Proboscidea)
Naked mole rat (Heterocephalus glaber)
Nonalcoholic fatty liver
Hummingbird (Trochilidae)
Ischaemic diseases
Elephant seal (Mirounga leonina)
Alcoholism Pen-tailed treeshrews (P ocercus lowii)
Fig. 2 Examples of species that already have been identified as being of interest for finding novel targets for ‘burden of
lifestyle’ diseases that accumulate as we get older. Amongst a number diseases that often tend to cluster (diseasome),
studies of some species in nature have already provided some clues for better treatment of congestive heart failure,
hypertension, type 2 diabetes, obesity, neurodegenerative diseases, osteoporosis, chronic kidney disease, ageing, cancer,
nonalcoholic fatty liver, ischaemic diseases (such as acute kidney injury) and alcoholism.
study species whose physiology may contain gap between lifespan and health span will expand
insights for human health [25]. Below we discuss and place a tremendous pressure on healthcare
some specific areas in which bio-inspired medicine costs, which in USA are expected to reach a total of 47
with lessons from the animal kingdom may benefit trillion USD over 2010–2030 [27]. Our life expec-
medical research and help us to better understand tancy at birth has increased markedly since the
how we can combat ‘burden of lifestyle’ diseases emergence of Homo sapiens five hundred thousand
(Fig. 2). years ago. Since industrialization started at about
1800, lifespans have doubled, largely due to
improvements in nutrition, public health (such as
Longevity in the animal kingdom – novel insights benefit
vaccinations and improved hygiene) and directed
gerontology research
medical treatments (such as antibiotics) that have
Ageing is by far the biggest risk factor for human minimized mortality at young ages. For the first time
disease and as we become older ‘burden of lifestyle’ in human history, four generations are likely to
diseases increase, possibly as a consequence of coexist.
common features that cluster in a ‘diseasome’,
including persistent inflammation, oxidative stress, Unfortunately, the extension in health span (i.e.
mitochondrial dysfunction, metabolic imbalances, years of healthy living) has not kept pace of the
tissue hypoxia and senescence [15, 26]. As the increase in lifespan (Fig. 3). Lifestyle factors have a
prevalence of ‘burden of lifestyle’ diseases increases major influence on our health span. During indus-
with age, and the proportion of the world population trialization, humans have been exposed to a num-
>60 years old will rise from 20% to 40% by 2050, the ber of new environmental and lifestyle risk factors,
242 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2020, 287; 238–251Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
Burden of life style diseases
100 Premature ageing
Clinically overt disease Biological age > chronological age
Large gap between health span and lifespan
Quality of life
Biological age (years)
80 Cost of health care
Average life course
Biological age = chronological age
Moderate gap between health span and lifespan
Subclinical
organ damage
60
Burden of life
style diseases
40 Healthy
Ideal life course
Biological age < chronological age
20 No gap between health span and lifespan
20 40 60 80 100
Chronological age (years)
Fig. 3 The extension in health span (i.e. years of healthy living) has not kept pace of the increase in lifespan. Lifestyle
factors, such as smoking, environmental toxins, air pollution, chemicals, water shortage, sugar rich-Western diets, excessive
calories and salt, processed food products and sedentary lifestyle have a major influence on our health span and promote a
gap between chronological and biological age. Three trajectories are depicted: (1) ideal life course when there is no long
gap between life and health span and patients die at an old age without significant debilitating chronic diseases, (2) the
average life course with a period of chronic disease before death and (3) premature ageing with an exceedingly long
period of one or several chronic ‘burden of lifestyle’ diseases(s) decrease the quality of life for the patient and associated
with high healthcare costs. Studies of nature provide us with novel approaches to target the whole cluster of burden of
lifestyle diseases that often is associated with persistent inflammation.
such as smoking, environmental toxins, air pollu- this may decrease their risk of nonparasitic dis-
tion, chemicals, water shortage, sugar rich-Wes- eases. A survey of 109 plants of the Vernonia family
tern diets, excessive calories and salt, processed (Asteraceae) revealed that Vernonia amygdalina
food products and sedentary lifestyle; factors to holds promise for development into a nutraceutical
which our genome never had the chance to adapt to against diabetes and malaria and Vernonia cinerea
during evolution. Since we lack robust solutions to has potential against inflammatory conditions and
prevent the whole diseasome of burden of lifestyle cancer [31]. Self-medication against parasite infec-
diseases [15], studies of nature give us an oppor- tions is also observed in animals without learning
tunity to identify mammals with limited senes- abilities, such as ants, fruit flies and moths; thus,
cence [28]. this behaviour seems innate and adapted to the
environment [30]. Since chimpanzees in captivity
Humans have the longest lifespan amongst pri- have a lower incidence of ischaemic heart disease,
mates; for example, great apes rarely age beyond cancer and neurodegeneration than humans [29],
50 years. Like our foraging–farming forefathers the gap between lifespan and health span is lower
with no access to modern medicine, infections are compared to humans who commonly suffer from
the major killer in chimpanzees in the wild [29]. burden of lifestyle diseases for prolonged periods
Chimpanzees have learned to identify herbs with before death.
anti-parasitic activity that they use for self-medi-
cation when they suffer from parasitic infections An extraordinary diversity in the lifespan is seen
[30]. Since chimpanzees often tend to select the across different taxa [32], ranging from 1 to 2 days
bitter leaves of the Vernonia family for chewing, (mayfly) to >500 years (ocean quahog). Thus,
ª 2019 The Association for the Publication of the Journal of Internal Medicine 243
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comparative studies provide a golden opportunity Although multiple metabolic alterations contribute
to increase our understanding of causal mecha- to animal longevity, it is evident that outstanding
nisms that drive senescence [28]. A problem in stress resistance linked to robust mitochondrial
animal ageing research is that most of the existing functions and maintenance of protein homoeosta-
longevity data for animals consist of single obser- sis are major pro-longevity factors. Accumulating
vations of maximum lifespan. However, life expec- data support the mitochondrial theory of ageing;
tancy estimates for 330 animal species exist, based that is, biochemical damage in mitochondria plays
on data from North American Zoos and aquariums an important role in ageing and that treatments
[33]. Although the size of the animal has been that target the transcription factor Nrf2, the ability
considered, a main factor that determine longevity to withstand protein modification and upregulation
a number of other factors, such as telomere short- of matrix antioxidants may decrease the gap
ening rate [34], resting heart rate [35], DNA repair between life and health span. Since down-regu-
capacity [36], protein methionine tissue content lated Nrf2 expression is a feature of Hutchinson
[37] and serum phosphate levels [25] correlates to Gilford Progeria syndrome [48] – a rare progeroid
species lifespan. Studies of animal species that syndrome – and a cluster of inflammation-related
exhibit a high longevity quotient (actual longevity/ ‘burden of lifestyle’ diseases [15], human data
expected longevity), negligible senescence and support a role of depressed Nrf2 in premature
superior resistance to age-related diseases, such ageing. As both Nrf2 deficiency [49] and hypoxia
as naked mole rats (Heterocephalus glaber) [38], [50] exacerbate senescence the interrelationships
little brown bats (Myotis brandtii) [39], ocean between hypoxia, repressed Nrf2 activity and
quahog (Arctica Icelandica) [40], rockfish senescence deserve attention in burden of lifestyle
(Sebastes) [41], bowheads whale (Balaena mystice- diseases. Better understanding of the biology of
tus) [42] and Greenland shark (Somniosus micro- exceptionally long-lived animals with negligible
cephalus) [43] are of special interest for biomimetic senescence may contribute to better understand-
studies since they have adapted beneficial changes ing of ageing processes and lead to novel interven-
during evolution that make them exceptionally tions that extend human health span.
long-lived [28]. Detailed molecular studies of a
jellyfish (Turritopsis nutricula) – the only docu-
Biomimetic secrets found in deep oceans
mented immortal organism in the animal kingdom
– may shed further light on ageing biology, and this The marine environment is a rich source of both
knowledge could applied to biomedical sciences biological diversity and chemical diversity, and
especially foraging-related disorders [44]. plankton and microalgae are affluent in bioactivity.
Since complex marine field samples can be used to
So far, experimental gerontology research in verte- investigate bioactivities from otherwise inaccessi-
brate models has been limited by the relatively ble sources [51], this open up for a novel source of
short lifespan of mice (3–4 years) and zebrafish drugs with the conceivable use in human medicine,
(5 years). Thus, studies of the turquoise killifish such as for treatment of obesity [52]. For example,
(Notobranchius furzeri) with an exceptionally rapid marine-derived phoma (phytopathogens widely
timescale of ageing (30–40 days) have provided a distributed in aquatic systems) possess anti-can-
novel and complete genotype-to-phenotype plat- cer, anti-microbial, radical scavenging and cyto-
form that can be used for rapid exploration of toxic properties, and has been regarded as a source
ageing mechanisms [45]. Studies in killifish show of supply for novel bioactive compounds [53]. Fish,
that key ageing genes are under positive selection the most diverse class of vertebrates with >20 000
and that these genes are clustered on sex chromo- existing species, provide a vast spectrum of species
somes, suggesting that differences in lifespan are for bio-inspired research. Fish exhibit an enor-
genetically linked to sex [46]. Indeed, it has been mous range of senescence [54] ranging from rapid
suggested that communication between the gonad (such as eels, killifish and pacific salmon) to
and brain is an accomplished pathway to explore gradual (such as guppy and platyfish) and negligi-
mechanisms that promote longevity [47]. ble (such as sturgeons and rockfish). Fish with
minor signs of senescence could be an avenue to
Specific characteristics in phenotype and molecu- perform comprehensive studies of characteristics
lar adaptations that have been documented in of slow ageing; that is, muscle extracts from fish
selected long- or short-lived species (Table 1) with negligible senescence have protective effects
provide clues for human ageing mechanisms. on senescence induced by oxidative stress [55].
244 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2020, 287; 238–251Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
Table 1. Characteristics in phenotype and molecular mechanisms in selected long- or short-lived species
Naked mole rats (Heterocephalus glaber)
• Subterranean life in eastern Africa • Protein resistance to unfolding
• Lifespan >30 years • High hyaluronan levels
• Low metabolic rate • HIF-1 activation
• Thermoconformer • High proteasome activity
• Survive 18 min of anoxia • High expression of Nrf2
• No age-related changes in body composition • Enhanced immune surveillance
and bone mineral density • High autophagy level
• Protected against age-related diseases, such as cancer, • Sustained levels of oxidation
cardiac disease, muscle atrophy, neurodegeneration
• Superior capacity for mitochondria
to consume H2O2
Ocean quahog (Arctica Icelandica)
• North Atlantic ocean • Low mitochondrial membrane peroxibility index
• Lifespan >500 years • Maintenance of protein homoeostasis
• Low body temperature • Highly efficient mitochondria
• Resistant to multi-stress genotoxicity • High Nrf2 expression
Rockfish (Sebastes)
• Eastern north Pacific • Longevity negatively correlated with mitochondrial DNA mutations
• Lifespan up to 200 years • Limited reproductive senescence
• Low body temperature • Gamete production increases with age
Greenland shark (Somniosus microcephalus)
• North Atlantic and Arctic ocean • Limited reproductive senescence
• Lifespan >400 years • Oxidative damage in red blood cells do
• Low body temperature not correlate with lifespan
Turquoise killifish (Notobranchius furzeri)
• Ephemeral water ponds in Zimbabwe and Mozambique • Accelerated expression of ageing biomarkers
• Transient habitat • Telomere length similar to humans
• Lifespan 30–40 days • Fish deficient for the protein subunit of telomerase
• Develop typical age-dependent phenotypes, such as exhibit the fastest onset of telomere-related
pathologies among vertebrates
sarcopenia and cancer
• Resveratrol prolongs their life span • Key aging genes are under positive selection
• Recolonizing the gut with bacteria from younger fish • Mitochondrial complex modifies their life span
resulted in an extension of their lifespan
Since recent studies suggest that drugs targeting In the animal kingdom, the levels of mitochondrial
senescent cells may arrest human ageing pro- enzymes vary more than 100-fold, from low in fish
cesses [56], comparative studies of fish with rapid white muscle to high in the flight muscles of birds
or negligible senescence would be of interest [54]. [57]. The Atlantic bluefin tuna (Thunnus thynnus)
ª 2019 The Association for the Publication of the Journal of Internal Medicine 245
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is a migratory fish with high metabolic demands Another group of animals that survive periods of
due to a remarkable swimming endurance. This hypoxia are the deep diving mammals, such as the
stands out from other fish because they possess elephant seal (Phociade). They have developed an
red muscle (due to an exceptionally high content of astonishing capacity to tolerate repeated cycles of
mitochondria). It was recently reported that the ischaemia and reperfusion to protect their organs
upstream open reading frame (uORF), which slows during deep dives. In theory, reoxygenation of
down production of the transcriptional coactivator hypoxic tissues results after the dive may also
peroxisome proliferator-activated receptor gamma generate ROS that overwhelm the antioxidant
coactivator 1 (PGC1a), was completely absent in capacity and result in cell damage. In order to
the Atlantic blue fish tuna [58]. This observation secure acceptable perfusion of the heart and brain
indicates that disruption of uORF may be an during apnoea-induced hypoxaemia in diving,
important evolutionary adaption in the animal there is an cardiovascular adjustment with height-
kingdom that allows high metabolic demand. ened constriction of peripheral arterial beds in
Despite the major influence of Nrf2-KEAP1 in several organs, including the liver and kidneys
regulating vertebrate antioxidant system, this tran- [63]. This uninterrupted vasoconstriction leads to
scription factor has been poorly investigated in almost total cessation of renal function and
marine species. However, since it was recently glomerular filtration rate decreases >90% [64].
reported that UBV-absorbing metabolites typically Thus, the seal kidney is considered extraordinary
found in seaweeds produced by cyanobacteria tolerant to repeated periods of ischaemia [65] and
activate Nrf2-KEAP1 [59] and another study due to their excellent antioxidant defence mecha-
showed that it play a major role in protection of nisms generation of the superoxide radical does
the early life stages of the Antarctic silverfish not translate into tissue damage [66]. The situation
(Pleuragramma antarctica) towards the environ- seems similar to the protective effect of experimen-
mental changes of pro-oxidant pressure during tal preconditioning before graft transplantation
ice melting [60], this cytoprotective system play a [67]. Elephant seals undergo prolonged periods of
role also in the oceans. food and water deprivation. As prolonged natural
periods of fasting in elephants seals activate Nrf2-
KEAP1 [68], it can be hypothesized that upregula-
Surviving hypoxia – clues provided in the animal kingdom
tion of this cytoprotective transcription contribute
One important survival tool is the ability to live to seals’ amazing capacity to protect their kidneys
with limited oxygen supplies. This is a major issue and liver during deep-sea dives. As we lack potent
for populations living at high altitudes. Systemic treatments to block effects of ischaemia and
hypoxaemia is common in the hospital setting; hypoxia in medicine, mammalian models that help
emerging evidence suggests that local tissue us to better understand tolerance against hypoxia-
hypoxaemia is an important feature of many ‘bur- anoxia are meaningful. Brain ischaemic precondi-
den of lifestyle’ diseases linked to repressed Nrf2- tioning protects against ischaemic injury via oxida-
KEAP1 expression and diminished mitochondrial tive signalling and Nrf2-KEAP1 activation [69].
biogenesis [15]. One of the best studied animals Thus, nutrients and drugs that stimulate Nrf2-
that lives in hypoxic environment is the naked mole KEAP1 should be tested in conditions with tissue
rat, which can survive in burrows with markedly hypoxia [15]. Indeed, many nutrients with rather
limited oxygen availability. They survive by down- potent Nrf2-stimulating effects, such as curcumin,
regulating their mitochondrial function and living carnosol and sulphoraphane, have consistently
in a glycolytic state, which allows them to reduce been reported to have beneficial effects in burden
their oxygen demands. One of the ways this hap- of lifestyle diseases, such as type 2 diabetes [70].
pens is by the production of fructose as its
metabolism helps shift the animal to a glycolytic
Physiological magicians in the animal kingdom – implications for
state [6, 61]. Since hypoxia causes a oxidative
burden of lifestyle diseases
stress, this rat handles this aspect by markedly
increasing its antioxidant systems, based on A good example of a magical metabolic feat is the
upregulation of Nrf2-KEAP1 [38]. Heat stress trig- capacity of the hummingbird (Sephanoides) to
gers accumulation of reactive oxygen species avoid diabetic complications. The hummingbird
(ROS), reduced proliferation and apoptosis; that have a heart rate of 1200 beats min 1 and wings
is, effective activity of Nrf2-KEAP1 may be more that flap 50 times min 1, feeds on a sugar-based
important in the future due to global warming [62]. nectar (rich in energy) every day and regularly
246 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2020, 287; 238–251Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
obtains blood glucose levels that would be consis- muscle mass just 48 h after feeding was accompa-
tent with severe diabetes, coupled with the devel- nied by increased gene expression of muscle-con-
opment of fatty liver (50% fat) [71]. Rapidly after tractile proteins, such as myosin [77]. Riquelme
feeding, extreme glucose levels was reported et al. [78] reported that despite high postprandial
(40 mmol L 1), which was accompanied by HbA1c levels of triglycerides (9 50) and fatty acids (9 3)
levels of 4.5%, that is higher than measured in there is no accumulation of triglycerides or fatty
most birds but lower than in nondiabetic humans acids in the python heart. In contrast, they
[72]. Every night, hummingbirds will burn off the observed a robust activation of fatty acid transport
fat in the liver and its glucose levels return to the pathways and oxidation combined with increased
normal range and during 20 h of flying across the expression and activity of the cardioprotective
Mexican Gulf they metabolize around 75% of the enzyme superoxide dismutase. Since injection of
fat reserves [71]. To support the high metabolic fuel this combination of three fatty acids promoted
requirements of hummingbirds, it has been pro- physiological heart growth in both mice and
posed that they possess the most biosynthetically python, it would be of interest to examine the
active livers in nature [73]. Moreover, they achieve effects of this specific fatty acid combination on the
the highest known mass-specific metabolic rates human heart. Increased expression of Nrf2-KEAP1
amongst vertebrates and their flight muscle is the was shown to be important in for the extreme
most O2 demanding skeletal muscle per unit tissue regenerative growth that occurs after the massive
mass known amongst vertebrates [74]. Although meals [79]. Since fasting increases the expression
they have remarkably high daily blood glucose of Nrf2-KEAP1 and antioxidant responses in
levels, and a pearly white liver, the bird does not mouse and humans [80] as well as in elephant
become diabetic in the sense of developing polyuria seals [68], periods of intermittent fasting may be a
(glucosuria), polydipsia and polyphagia. Neither do prerequisite for survival in extreme conditions in
they develop diabetic complications or progressive nature. Interestingly, diurnal intermittent fasting
liver disease. How hummingbirds tolerate blood during Ramadan increases the expression of Nrf2
glucose levels that cause serious microvascular in patients with overweight and obesity [81].
pathologies in diabetic patients remain unknown.
Understanding their protective mechanisms could From an evolutionary point of view, the absence of
give key insights into the management of diabetes. cardiac and renal damage in the giraffe (Giraffa)
could have major implications for cardiovascular
Increased and prolonged alcohol consumption can medicine. Their mean arterial pressure ranges
have devastating consequences in humans. Pen- from 210 to 325 mmHg to overcome the huge
tailed treeshrews (Ptilocercus lowii) living in the hydrostatic pressure needed to supply oxygen to
West Malaysian rainforest regularly consume fer- the brain 2.5–3.0 m above the heart. Although
mented alcoholic nectar from flower buds of the there are signs of arterial smooth hypertrophy and
Bertam palm (max alcohol concentration 3.8%) the weight of heart of giraffes is 2–4 times greater
[75]. As analysis of ethyl glucuronide (an alcohol than in other ruminants, there are no signs of
metabolite) in their hair showed concentrations functional, structural, renal nor cardiac damages
that in humans would indicate alcohol intoxica- that normally accompany cardiac hypertrophy
tion, biomimetic studies could resolve how they [82]. Their heart valves have evolved to adapt to
can obtain such a high metabolic tolerance for an extreme-pressure system with compact collagen
alcohol and mitigate the risk of continuous high construction [83]. A strong renal capsule support-
blood alcohol concentrations without any seem- ing high renal interstitial hydrostatic pressure
ingly adverse effects. Mimicking such a phenotype reduces the net filtration pressure and may protect
could eventually help combat human pathologies giraffe kidneys against high blood pressure [84].
related to alcohol abuse. The protective mechanisms in giraffes provide a
conjectural framework for experimental explo-
The enormous intermittent meals, such as a pig or rations into mechanisms as well as treatment and
a goat, consumed by Burmese pythons (Python prevention of hypertension, cardiovascular and
molurus) increase oxygen consumption markedly renal disease in humans.
and place an extreme load not only on the cardio-
vascular system but also on the other organs, such Hibernation is an ingenious survival strategy that
as intestines, kidneys and liver [76]. The extraor- evolved during evolution in certain species, such as
dinarily rapid 40% increase in heart ventricular bears, to conserve energy during long periods of
ª 2019 The Association for the Publication of the Journal of Internal Medicine 247
Journal of Internal Medicine, 2020, 287; 238–251Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
nutrient–water shortage, coldness and hypoxia. expected for larger body size and longer lifespan in
Since hibernating bears are forced to maintain a the animal kingdom. When number of necropsies
careful balance between metabolic supply and with tumours were plotted as a function of body
demand, they are used as a model to develop novel mass x lifespan, it was evident that whereas risk of
approaches to counteract burden of lifestyle dis- cancer was higher in species, such as Tasmanian
eases, such as chronic kidney disease [85], obesity- devil, cheetah and prairie dog, the risk of cancer
and sedentary-related diseases [86], organ preser- (5%) was lower than expected in elephants (Pro-
vation [87], ischaemic brain damage [88] osteo- boscidea) [99]. When the elephant genome was
porosis and muscle wasting [89]. It is notable that investigated, their cells demonstrated better apop-
many similarities exist between hibernation phe- totic responses following DNA damage (compared
notypes and various long-lived animal models [90]; to humans) and multiple copies of the tumour
that is, hibernation seems to retard biological suppressor gene p53 (TP53). Whereas humans
ageing in proportion to time spent in the hibernat- have one copy (two alleles) of the gene, elephants
ing state [91]. As Nrf2 (and FOXO) plays major roles had multiple copies of TP53 [99]. Although the
in the regulation of antioxidant defences in hiber- exact role of p53 remains to be determined, these
nating bat brains [92], upregulation of the Nrf2- findings represent an approach based on evolution
KEAP1 system may be a prerequisite to avoid organ to better understand mechanisms related to cancer
damage during hibernation [15]. Models of hiber- suppression.
nation have revealed considerable remodelling of
synaptic connections [93]; thus, studies of hiber- The inquisitive case of the naked mole rat repre-
nating animals, such as bears and dormouse (Glis sents another amazing example of cancer resis-
glis), may provide important information on how to tance in the animal kingdom. Out of 1000´s of
cure neurodegenerative diseases, such as Alzhei- necropsies, only two cases of cancer have been
mer, in which a reduction in synapse number is a reported in this long-lived rat [100]. Although many
consistent early feature. of the mechanisms that promote longevity, such as
protein resistance to unfolding, high levels of
autophagy and high Nrf2-KEAP1 expression may
Cancer resistance – lessons learned from nature
also contribute to their cancer resistance, not all
Cancer, an unavoidable risk of ageing, is a major mechanisms involved in longevity contribute to
cause of morbidity and mortality also in the animal cancer resistance [101]. A low mutation rate, better
kingdom. In pet dogs, cancer closely recapitulates protein homoeostasis, improvement in telomere
their human counterparts with respect to clinical maintenance and resistance against oxidative
presentation [94]. As our understanding regarding stress could contribute to their cancer resistance.
the molecular drivers of canine cancers has Surprisingly, high expression of hyaluronan in
become much better, unique opportunities have skin fibroblasts [102] may be another protective
emerged to better guide cancer drug development factor against cancer since naked mole rats lose
so that we earlier eliminate therapies likely to fail their cancer resistance when hyaluronan synthase
and therapies with true potential are optimized 2 is knock-downed. Thus, the thickness of this
prior to human studies. In contrast to common polymer not only provides skin elasticity needed for
belief, sharks do get cancer [95]; thus, there is no their life in burrows but may also control the cells
justification for using shark cartilage as a means to mechanical strength and regulate their growth.
prevent cancer [96]. Amongst animals with high
risk of cancer, the Tasmanian devil (Sarcophilus
Conclusion
harrisii) is of much interest since they have become
endangered due to a transmissible facial cancer Using a comparative physiological approach based
expansion by direct transport of living cancer cells on species that have made successful adaptations
due to a distinct mutational process through biting in nature should definitely broaden the approach
[97]. Lessons can also be learned from species in and likely lead to creative solutions to the medical
which risk of cancer is lower than expected, such problems of today, as well as for the future.
as elephants and naked mole rats. As a greater Emerging evidence suggests that answers on how
number of cells and cell divisions increase the to better manage a cluster of ‘modern burden of
likelihood of mutations that transform into malig- lifestyle’ diseases may be found in nature. It is
nancies, Peto et al. [98] hypothesized that the evident that across taxa upregulation of the cyto-
incidence of cancer does not increase as would be protective transcription factor Nrf2-KEAP1 and
248 ª 2019 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2020, 287; 238–251Biomimetics - natures roadmap to better health / P. Stenvinkel et al.
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