SPECIALTY GRAND CHALLENGE

published: 12 April 2021

doi: 10.3389/fragi.2021.676573

The Challenge of Unlocking the

Biological Secrets of Aging
Consuelo Borrás*
Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Center for Biomedical
Research on Frailty and Healthy Aging, INCLIVA Health Research Institute, Valencia, Spain

Keywords: lifespan, healthspan, biomarker of aging, animal model of aging, theory of aging

LIFESPAN VS. HEALTHSPAN

We are currently facing particular challenges related to demographic change. People are reaching
very long lives, and the average lifespan has increased considerably since the mid of the twentieth
century. The predictions are that citizens older than 65 will increase from 18% of the current
population to 28% in 2060. Moreover, citizens with more than 80 years old will increase from 5 to
12% during the same period, becoming as numerous as the young population in 2016 (Christensen
et al., 2009).
However, the increase in lifespan has led to a decrease in healthspan, i.e., the period of life
free from serious chronic diseases and disabilities (Christensen et al., 2009; Crimmins, 2015). This
suggests a situation characterized by an increase in age-related disability and dependency, which
will have an impact not only on the well-being and quality of life of the affected people but also on
the sustainability of health systems (Murray and Lopez, 2013).
This scenario constitutes the real challenge: unlocking the biological secrets of aging to
understand better this process, that will allow to develop adequate interventions to increase not
only life but also healthspan and diminish the medical, economic, and social issues associated with
old people.
Edited and reviewed by:
Barbara S. Rocha, THE PROCESS OF AGING
University of Coimbra, Portugal

*Correspondence: Aging is a very complex process, and therefore there are many definitions to describe it depending
Consuelo Borrás on the field involved. From a biological point of view, “aging is a progressive sequence of
consuelo.borras@uv.es age-related, widespread, more-or-less common changes observed in every individual of a given
species” (Harman, 1988). It is characterized by four postulates (Strehler, 1985; Vina et al., 2007).
Specialty section: It is universal: it must occur in all individuals of a species; intrinsic: endogenous factors cause
This article was submitted to
it, although exogenous factors can modulate it; progressive: changes must occur progressively
Molecular Mechanisms of Aging,
a section of the journal
during the lifespan, from early adulthood to the old ages; and deleterious: it arranges negative
Frontiers in Aging consequences for the individual.
Aging is not a disease: it is a physiological process that differs from disease because the
Received: 05 March 2021
Accepted: 17 March 2021
disease is selective (not universal), intrinsic and extrinsic (not only intrinsic), discontinuous (not
Published: 12 April 2021 progressive), and reversible.
Citation:
Aging starts early in life, after the development of the organism. It implies that, during many
Borrás C (2021) The Challenge of years, many exogenous factors can influence it (accelerators or decelerators of the rate of aging). It
Unlocking the Biological Secrets of may be different in the different individuals, leading to the heterogeneous distinctive of aging. Not
Aging. Front. Aging 2:676573. all individuals age at the same rate, nor do all organs of the same individual. The complexity of the
doi: 10.3389/fragi.2021.676573 aging process is the reason for the grand challenge of unlocking its biological secrets.

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Borrás Unlocking Biological Secrets of Aging

THEORIES OF AGING the decline of their functional capacities with age. One of the
best examples of frailty mouse models is the interleukin-10
As aging is multifaceted, many theories are trying to explain knockout mouse model since it develops an age-related decline in
the fundamental biological processes underneath it. In 1990 skeletal muscle strength and similar inflammation and weakness
Medvedev claimed that there are more than 300 theories of aging, pattern to frailty compared to control mice (Walston et al.,
and the number continues to increase (Medvedev, 1990). This 2008).
is the natural consequence of the very rapid progress in our Animal models have been, are, and will be essential
understanding of biological phenomena and the application to for studying the biological insights of the aging process
gerontological research of many new approaches and methods. and developing appropriate interventions. However, successful
Almost every major discovery in cell and molecular biology translation to humans is intricate. It constitutes a challenge
has spawned a new family of aging theories or new advanced and requires several careful considerations, including a proper
versions of older theories (Vina et al., 2013). This same author choice of the animal model, systematic experimental designs, and
also commented that the task of reviewing theories of aging information integration from bench to bedside.
has become much more difficult and that a large number of
these theories are very selective or outdated. On the other hand,
Vijg affirms that some old hypotheses from the beginnings BIOMARKERS OF AGING
of gerontological science made possible the great scientific
revolution in the understanding of aging that is now witnessing A biomarker of aging is a biological parameter of an organism
(Vijg, 2000). The author agrees with these views and Medvedev’s that either alone or in some multivariate composite will, in the
conclusion that the expectation that a truly unified or single- absence of disease, better predict biological age and functional
cause theory of aging will emerge is unrealistic. And it is generally capacity at some late age than will chronological age (Baker,
accepted that all the pieces of the aging puzzle are not yet 1988). The requirements that a biomarker of aging should include
available (Troen, 2003). However, we believe that it is possible to are to change progressively with age, to refer to parameters
offer preliminary solutions to this problem by integrating several relevant to health and longevity, to be minimally invasive, to be
complementary theories, classical and modern, which offer relatively easy to determine, and to be reproducible.
logical explanations of the changes occurring in the fundamental Most of the biomarkers are related to processes and pathways
levels of biological organization (Vina et al., 2007). In fact, many associated with the different theories of aging. As pointed out
authors have proposed a unified theory of aging (Kelly, 2011; some years ago by Lopez-Otin et al. (2013), parameters related
Barja, 2019). to the nine hallmarks of aging should be good candidates
Thus, we can affirm that there are many theories to explain the to be biomarkers of aging, if they meet the requirements
aging phenomenon, and even today is not known for sure what mentioned before. Those hallmarks are genomic instability,
the main causes underlying aging are. telomere attrition, epigenetic alterations, loss of proteostasis
(and autophagy), deregulated nutrient sensing, mitochondrial
dysfunction, cellular senescence, stem cell exhaustion, and altered
SEARCHING FOR GOOD MODELS OF intercellular communication. Moreover, oxidative stress-related
AGING parameters have been also proposed as good candidates as they
meet all the requirements for being aging biomarkers (Borras
Aging research can be conducted in many in vivo models, et al., 2003; Ingles et al., 2014). Other good candidates are those
which have their own benefits and limitations. Hence, the use parameters related to the so-called process of inflammaging and
of yeasts (Saccharomyces cerevisiae), nematodes (Caenorhabditis the immune system function. It is known to decline with age, and
elegans), fruit flies (Drosophila melanogaster), short-living fishes many scientists have proposed them as possible aging biomarkers
(Nothobranchius furzeri), rodents (mice and rats), dogs, and non- (Martinez De Toda et al., 2016; Fougere et al., 2017; Franceschi
human primates is common in aging studies and the selected et al., 2018).
model depends on the objective of the study. Table 1 shows the Although many processes underlying aging are known, and
model’s strengths and limitations in aging research (adapted from there are many proposed biomarkers of aging related to these
Folch et al., 2018). processes, there are no fully reliable aging biomarkers. Probably
Models shown in Table 1 are those not genetically modified, the best approximation to a trustful aging biomarker is that based
but of course, many other models are based on genetic on a set of several markers. For example, the “epigenetic clock”
modifications of a specific protein or a protein set that are based on a DNA methylation dataset has enabled accurate age
developed to investigate their role. For example, the Arf/p53 estimates for any tissue across the entire life course (Horvath and
mice model which lives longer demonstrated that p53 is involved Raj, 2018). Indeed, reprogramming the epigenetic clock resets the
in longevity (Matheu et al., 2007). Moreover, there are also aging clock, and the organism rejuvenates (Rando and Chang,
models developed for studying aging-related disorders such as 2012).
cardiovascular, bone, or neurodegenerative disease (Santulli et al., Certainly, a challenge is developing trustful aging biomarkers
2015). Finally, some models have been developed to simulate because it allows a better knowledge of the aging process, and at
frailty, a clinical syndrome common in the elderly (Howlett the same time, it enables developing appropriate interventions to
and Rockwood, 2014; Santulli et al., 2015), which is based on delay aging and promote successful aging.

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Borrás Unlocking Biological Secrets of Aging

TABLE 1 | Animal model’s strengths and limitations in aging research.

Models of Aging Strengths Limitations

Caenorhabditis elegans Short lifespan. Fast evaluation of interventions. Low costs. Invertebrate model. Low translationality to humans.
Drosophila melanogaster Short lifespan. Fast evaluation of interventions. Low costs. Invertebrate model. Low translationality to humans.
Saccharomyces cerevisiae Short lifespan. Fast evaluation of interventions. Low costs. Invertebrate model. Low translationality to humans.
Nothobranchius furzeri Appropriate for evaluation of interventions Organs are quite different from those in humans.
Senescence prone inbred strains Appropriate for evaluation of interventions Significant differences at a pharmacokinetic level.
Lifespan extension could vary between rodent’s genders.
Genetically heterogeneous (HET) Developed by the National Institute on Aging interventions Significant differences at a pharmacokinetic level.
mouse model testing program as the most adequate mammal mice model Lifespan extension could vary between rodent’s genders.
in aging
Rodent models of progeria Reduction in time, labor and costs for lifespan studies, as well Effects of premature aging, not aging itself. Significant
as the ability to target accelerated aging to specific organs. differences at a pharmacokinetic level.
Non-human primate models of aging Best extrapolation of the results to our species. Expensive. Long time to obtain results.

CONCLUDING REMARKS system dysregulation, nutrient sensing modulations, genetic and

epigenetic changes, mitochondrial energy collapse, intercellular
We are currently facing particular challenges related to an communication alterations, stem cell function dysregulation, and
increased lifespan. However, the increase in lifespan has led extracellular vesicles alterations.
to a decrease in healthspan. This scenario constitutes the
real challenge: unlocking the biological secrets of aging to
understand better this process, that will allow developing AUTHOR CONTRIBUTIONS
adequate interventions to increase not only life but also
healthspan and diminish the medical, economic, and social issues CB wrote the sections of the manuscript and contributed to
associated with old people. manuscript revision, read, and approved the submitted version.
“The molecular mechanisms of aging” specialty section
is delved into the basic mechanisms involved in aging FUNDING
to help better understand the aging process. Molecular
mechanisms of aging play an integral and interdisciplinary role This work was supported by PCIN-2017-117 of the Ministry
in modern science and include significant advances in areas of Economy and Competitiveness and the EU Joint
including, but not limited to, biomarkers of aging, senescence, Programming Initiative a Healthy Diet for a Healthy Life
altered proteostasis, autophagy, chromosomal alterations, redox (JPI HDHL INTIMIC-085).

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