ReviewReversibility of irreversible aging
Introduction
There are two principal routes to human longevity: slowing down the aging process and reversing it. Thus far, the former strategy has clearly been dominant. This is not unexpected – it is conceptually easier to come up with the ideas to slow down the emergence of age-related dysfunction (e.g. by targeting metabolism) than with the ways to rejuvenate organisms (i.e. convert them from an older to a younger state). Although researchers have largely focused on minimizing age-related deterioration, there is a fundamental need for novel strategies that can reverse the existing pathology and restore physiological function. While the ability to delay the onset of age-associated diseases (AADs) would undoubtedly be a great achievement of biomedicine, rejuvenation has the potential to alter the course of human civilization. While the clear path to the long-sought fountain of youth is as elusive as it has ever been, the opportunities the rejuvenation strategy offers, and the initial discoveries in this area, suggest that this research is worth all the effort, no matter how hard it is. However, since aging is known to be associated with the accumulation of numerous forms of damage and other deleterious changes, including those that cannot possibly be cleared up, is it even possible to rejuvenate an organism?
The issues related to rejuvenation arise from three main questions: how to define rejuvenation, how to characterize rejuvenation, and how to achieve rejuvenation. Although many longevity interventions have been developed by researchers in the field, the main questions related to rejuvenation remain unresolved. Even the definition of rejuvenation is controversial. Some define rejuvenation as a result of treating certain aging phenotypes. In this way, somehow, many interventions that have previously been defined as achieving rejuvenation may just slow down the aging process. In contrast, we can define rejuvenation as a means to move an organism from an older to a younger state. If so, only in vivo reprogramming can be treated as a known rejuvenation intervention because this is the only intervention proved mechanistically with regard to the reversal of the cells to the embryonic state. For the interventions that do not demonstrate a reversal to the embryonic state, such as rapamycin, calorie restriction, parabiosis, or senolytics, there is a need to quantify a possible rejuvenation effect, i.e. there is a need for a precise biomarker of aging.
In this review, we focus on the questions introduced above. We first examine aging and rejuvenation from the perspective of age-related deleterious changes that characterize the aging process, getting inspiration from the organisms that have variable aging phenotypes and those that seem to escape the aging process. We then introduce tools to assess rejuvenation, e.g. the epigenetic clock, and the biological principles behind biomarkers that assess the biological age. Finally, we dig into longevity interventions with the potential for rejuvenation, most notably heterochronic parabiosis and in vivo reprogramming, and the associated biological mechanisms.
Section snippets
Emergence of aging as a major public health threat
Until recently, diseases of aging, and aging itself, did not represent a major threat to public health. In the US, a hundred years ago the leading causes of death included pneumonia, tuberculosis, diphtheria and other currently much less harmless diseases. Advances in medicine, pharmacology and public health resulted in a dramatic decline in deaths from these infections, which in turn extended lifespan (CDC/NCHS, 2017). On the other hand, mortality due to heart disease, cancer, and metabolic
Elusive definition of aging
Most commonly, aging is regarded as an organismal phenomenon that involves an increased chance of dying and/or decreased function over time. Similar definitions are applicable to organ or tissue failure as well as to certain cell systems. However, while everybody can visually distinguish a young and an old person, and an experienced histologist may do the same for their organs and tissues, defining aging at the molecular and cellular levels has been challenging. Despite there being a compendium
Irreversible aging
There are organisms that age and there are those that do not. The former category includes the majority of multicellular and many unicellular organisms, and the latter includes symmetrically dividing unicellular organisms and some multicellular organisms that can replace all their cells from stem cells. Most of such multicellular organisms (such as sponges and jellyfish) are primitive in their organization and in this way are related to seemingly immortal unicellular organisms. This suggests
Epigenetic markers of aging
One of the contributions to aging comes from epigenetics. With age, the epigenetic landscape of cells changes dramatically, reflecting the patterns of damage accumulation. These changes are also reflected in chromatin remodeling and histone modifications. The large number of such changes and the ability to track them provide important insights into the aging process.
For example, extensive analysis of human DNA methylation (DNAm) resulted in the “epigenetic clock”, a set of CpG sites that
Epigenetic machinery involved in aging
If epigenetic patterns may reflect the aging process, can they be uncoupled from other molecular changes in the cell? Does epigenetics represent the root of aging? There is a strong reason to believe that strictly epigenetic mechanisms may regulate lifespan. Arguably, the most colorful illustration of this notion is the honey bee (Apis mellifera) caste differentiation mechanism. Queen bees can live up to 8 years (normally 3–5 years), while worker bees usually last only 6 weeks during foraging
Progeroid organs
Mammalian tissues and organs may unequally contribute to aging and may also age with different rates. The concept of particular organs contributing more to the aging process implies that lifespan is an evolutionary derived program that can be hacked by targeting these organs. The search for such targets began decades before biogerontology became mainstream science. At the beginning of the 20th century, when the molecular basis of life was still largely unknown, some people already claimed to
Heterochronic parabiosis
Heterochronic parabiosis (HP) experiments in rats in 1972 opened an entirely new avenue in the search for the molecular basis of aging (Conboy et al., 2013). HP is a surgical procedure of grafting syngenic animals of different age together, whereby they share circulatory systems, allowing the old animal prolonged access to the blood of the young. The original study showed that older parabionts tended to live longer than paired animals of the same age (Ludwig and Elashoff, 1972). Since then,
Reprogramming may reset the age of some cells in an organism
An important aspect of aging is the misregulation of gene expression which arises from the shift in the epigenetic state of the cell. For example, epigenetic marks on the DNA can be added or removed by intrinsic mechanisms and can be affected by extrinsic factors (e.g. smoking, diet, hypoxia) or developmental programs (differentiation). Once altered, such epigenetic changes can remain following many cell divisions, and if these marks are altered in the germline, these changes may be inherited
Practical roadblocks to epigenetic rejuvenation
Despite its overwhelming effectivity in vitro, reprogramming has severe limitations in vivo due to a high risk of serious side effects, e.g. massive cell dedifferentiation may lead to the loss of organ function and to teratoma formation (Abad et al., 2013; Ohnishi et al., 2014). Pluripotent cells may also acquire mutations in p53, other tumor suppressor genes, and oncogenes that promote cell proliferation. It is thus critical to carefully genotype such cells prior to their use in the clinic (
Telomerase activation
Telomeres are the DNA regions at the linear chromosome termini, having specific strand and chromatin structures. Inability to replicate telomeres leads to their shortening after each cell division, which is thought to define the Hayflick limit of cell division: upon losing a critical portion of telomeres, a cell is unable to divide. Telomerases are the enzymes that generate telomeric repeats using RNA templates and can allow certain cells to surpass the Hayflick limit. However, in multicellular
Wholistic aging
Reductionist approaches offered multiple helpful insights into the aging process, especially at the molecular and cellular levels. However, despite its broad utility, reductionism has some limitations (Lakatos, 1976), and this is particularly relevant in the case of gerontology, as aging is a strictly organismal phenomenon that should not be viewed as a scaled up cellular deterioration. Moreover, even though biological wholism can be regarded as an unnecessary and even counterproductive
Outlook
It is clear that to understand the potential for reversing the aging process, even in some parts of the organism, we need to understand the nature of aging and identify the targets for intervention. Over the years, numerous mechanistic theories of aging have been advanced. Most of them have some merit but seem to be incomplete. Although experiments have led to lifespan extension and, in some cases, to improvements in healthspan in various model organisms, whether true rejuvenation has ever been
Competing interests
The authors declare no conflict of interest.
Acknowledgements
Funding was provided by NIH and the Russian Federation grant 14.W03.31.0012.
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