Delivery of Therapeutics for Biogerontological Interventions: From Concepts to Experimental Design

By Wing-Fu Lai

Delivery of Therapeutics for Biogerontological Interventions: From Concepts to Experimental Design provides tactics on how to facilitate planning and research in interventive biogerontology. The book helps create clearer directions for the translation of existing advances in delivery technologies, from lab to practice. It is ideal as a starting point for scientists, clinicians and those interested in the field of biogerontology, biomedicine or nanotechnology, comprehensively discussing how to translate bench works to practicable tactics that retard the aging process. Using support from recent advances reported in literature, this title takes advantage of delivery technologies to develop biogerontological interventions, from concept to experimental design.

• Provides the first comprehensive reference to guide researchers through the process of intervention development, from concepts, to practicable interventions
• Covers the information needed to exploit the use of delivery technologies in intervention biogerontology
• Presents complete coverage of advances in the field, all of which are supported by full color photographs, figures and references

• Language: English
• Publisher: Academic Press
• Release date: Jul 2, 2019
• ISBN: 9780128172766

Wing-Fu Lai

Dr. Lai received his MSc degree in Materials Engineering and Nanotechnology from the City University of Hong Kong, and earned his PhD in Chemistry from the University of Hong Kong. Dr. Lai is currently an Associate Professor in the School of Food Science and Nutrition at the University of Leeds. He is also an Honorary Professor at Zhejiang Provincial People’s Hospital. Dr. Lai has been qualified as a Licensed Pharmacist and a Registered Dietitian in People's Republic of China, and is a Registered Nutritionist in the UK and a Fellow of the UK Higher Education Academy. He has received his Certified Food Scientist credential from the International Food Science Certification Commission in the United States.

Book preview

recombinase

Part I

From Concepts to Plans

Outline

Chapter 1 Theoretical frameworks for intervention development

Chapter 2 Available delivery technologies for intervention execution

Chapter 1

Theoretical frameworks for intervention development

Abstract

Lifespan prolongation is a long-held desire of mankind. With technological advances, the mechanism of aging has been unraveled over the years. Along with an increase in understanding of the aging process, the development and execution of antiaging interventions are no longer mere concepts, but are getting closer to reality. To develop an intervention to tackle aging and age-associated ailments, the first step is to select a feasible approach by which the aging process can be modulated. The objective of this chapter is to introduce different theoretical frameworks for understanding the aging process, and to discuss their implications for the development of biogerontological interventions. These frameworks will likely constitute the conceptual foundation of antiaging therapies that will be designed by using the technologies which will be covered in subsequent chapters of this book.

Keywords

Aging; gene; reductionism; lifespan; longevity; nucleic acid

Introduction

Aging is a biological process that is not only mediated by environmental factors but is also determined genetically. The latter has been supported by several studies [1–4], which have examined the concordance of longevity in monozygous and dizygous twins. Upon analysis of 2872 pairs of nonemigrant like-sex twins, the heritability of longevity has been estimated to be around 0.26 for males and 0.23 for females [5]. Until now, numerous molecular determinants of longevity and aging have been identified. One example is age-1. It involves nondauer development and normal senescence [6], and is one of the first gene mutants being shown to extend longevity [7]. Other examples of genes found to influence lifespan include daf-16, smk-1, hcf-1, AGTR1, and sir-2.1 [8–10].

By increasing understanding of the aging process, over the years a diversity of tactics [ranging from caloric restriction (CR) [11] to hormone replacement [12,13]] have been proposed for combating aging [14]. Now, the concept of antiaging has become more practical than that in the past, thanks to the advancement of genetic engineering and molecular technologies. In 2002, the idea of Strategies for Engineered Negligible Senescence (SENS) was proposed. SENS has revolutionized the biogerontological field by offering a framework for developing strategies to reverse pathogenic age-associated damage in a fragmented approach [15,16]. Based on this, a number of coping strategies to combat and reverse age-associated molecular and cellular changes (e.g., cellular senescence, nuclear mutations, mitochondrial mutations, lysosomal aggregates, extracellular aggregates and cross-links, and cell loss) have been designed [15,16]. Besides in vivo and clinical studies, research has been carried out on plant longevity (which is partly contributed by stem cell immortality, vascular autonomy, and epicormic branching) [17]. With years of research, not only has the aging mechanism been elucidated, but the fantasy of lifespan prolongation has also been made possible. Apart from SENS, other longevity strategies have been reported in literature [12,13,18–28]. Representative examples of these strategies are shown in Table 1.1.

Table 1.1

Despite these advances, at the moment clinically applicable interventions for combating aging are lacking, owing partly to the lack of efforts devoted to intervention development. This has been shown by an earlier article [29], which is the result of a database search on PubMed and Web of Science. During the database search, only seven articles have been found to work directly on the development of nucleic acid therapy for longevity enhancement and/or aging retardation. Other retrieved articles have been devoted to studying only one to two facets of the aging process (such as delayed angiogenesis [30], erectile dysfunction [31], memory impairment [32], thymic involution [33], and vascular dysfunction [34]) rather than tackling aging as a whole. Only two out of these seven articles have touched upon lifespan extension. One of them is Boghossian et al.’s [35] work, which has successfully extended the lifespan of the ob/ob mice from 55.5 weeks to 106.5 weeks by injecting a recombinant adeno-associated virus (AAV) encoding the leptin gene intracerebroventricularly into the mice. The other one is Chung et al.’s [36] study, which has attempted to prolong lifespan simply at the cellular level rather than the organismal level. Such a deficiency of research may partly be attributed to the challenge of manipulating lifespan as a polygenic trait [37]. Furthermore, being able to change the expression of a few genes in in vivo models does not necessarily mean that lifespan prolongation can be achieved in humans, which physiologically are much more complex than fruit flies and yeasts. Along with the fact that the long-term physiological price paid by genetic manipulation still has not been completely determined, the extent of experimental works to intervene with the aging process is limited. This has greatly impeded the development of biogerontological interventions.

A reductionist approach to understand aging

To design a biogerontological intervention, identifying an ideal intervention point is vital. This requires deep understanding of the aging mechanism. The reductionist approach is a common method to comprehend the aging process. This approach breaks the aging network into pieces (called subprocesses) and tries to understand how the pieces work at smaller and smaller levels of organization [38,39]. The viability of understanding aging in this manner has been supported scientifically by the discovery of an increasing number of subprocesses that have contributed to aging. One example of these subprocesses is DNA methylation. The involvement of DNA methylation in aging was first proposed by Vanyushin and coworkers [40], who have observed that the 5-methylcytosine (5-MeCyt) content of DNA from different organs (e.g., spleen, heart, and brain) has changed with age in mice. This observation has been supported by a subsequent study that has reported the correlation between aging and loss of global DNA methylation [41]. Recent studies on monozygotic twins have found that epigenetic changes are related to aging but are independent of the genetic sequence [42]. This has illustrated the complexity of aging by revealing how environmental factors and gene function may interact. Besides DNA methylation, posttranscriptional histone modifications (via ubiquitination, methylation, acetylation, and phosphorylation) are involved in epigenetic signaling. This has been reviewed in other articles [39,43].

Since the turn of the last century, the identification of longevity or antiaging genes has been facilitated by the advent of high-throughput technologies and genetic techniques [44–46]. Examples of studies on the genetics of aging are listed in Table 1.2 [38,47–55]. As our understanding of various age-associated pathways (e.g., insulin/insulin-like growth factor (IGF)-1 signaling) and genes (including those encoding Sod2, Ras, protein kinase A, Msn2, Msn4, and adenylate cyclase) has increased [56], lifespan prolongation is no longer a hypothetical notion. In fact, the feasibility of manipulating the aging network at the genetic level has already been revealed in literature. For instance, Wang and coworkers have reported that, though IDH4 human fibroblasts have shown signs of senescence upon the suppression of the activity of HuR (a ubiquitously expressed Elav-like RNA-binding protein), the senescent fibroblasts have been rejuvenated when the cellular level of HuR has been escalated [57]. In the in vivo context, a study performed by Hsieh and colleagues has also demonstrated that mutation of Pit1 has prolonged lifespan in Snell dwarf mice [58]. More recently, the relationship between longevity and gene function has been corroborated by Copeland et al. [59], who, by silencing the expression of selected genes encoding components of mitochondrial respiratory complexes I, III, IV, and V, have prolonged lifespan in Drosophila melanogaster (D. melanogaster). All evidence presented previously has not only enriched our understanding of genetics on longevity, but has also revealed the apparent reversibility of the aging process, thereby imbuing genetic manipulation with striking potential in antiaging medicine [37].

Table 1.2

Reliability theory of aging

Although the reductionist approach to understand aging has been well-supported by scientific evidence, it fails to explain the late-life mortality plateaus [60–62] and the compensation law of mortality [63]. The concept of the reliability theory has, therefore, been proposed as an alternative approach to understanding the aging process [64]. Reliability theory comprises a series of mathematical models and ideas to predict, estimate, and optimize the lifespan distribution of a system or its components. To describe the reliability of a system at time x, one may use the reliability function S(x). The definition of S(x) is provided below, where X is the failure time and F(x) is the standard cumulative distribution function in the probability theory:

(1.1)

To describe the relative rate for the decline of S(x), the hazard rate h(x) [also known as failure rate λ(x)] can be adopted. In demography, this rate is regarded as the mortality force μ(x).

(1.2)

A system in reality usually has a failure rate that comprises both aging and nonaging terms. A good example is the Gompertz–Makeham law of mortality, which contains the age-dependent Gompertz function (Reα,x) as well as the age-independent Makeham parameter (A) [63]. Reα,x designates the age-associated factors of mortality (e.g., age-associated diseases), whereas A represents those deaths led by age-independent causes (e.g., accidents):

(1.3)

As predicted by reliability theory, even if a human body is constructed from entirely nonaging elements where the failure rate does not change with age, the body will still deteriorate with age because it is redundant in irreplaceable elements. Owing to this redundancy, death may not happen at once, even as damage occurs. This allows all sorts of damage possibly to be accumulated. Here the accumulation of aging-independent defects in the human body, as suggested by the concept of reliability theory, could be the cause, rather than the consequence, of the aging process. When damage accumulates, the redundancy in the number of elements in a body decreases. In the end, the body will have no more redundancy. Any new damage imposed to the body will result in death.

Highlights for experimental design

1. The aging process can be comprehended by using either the reductionist approach or the reliability theory. The former dissects a system into different subprocesses, whereas the latter comprises diverse mathematical models and ideas to predict, estimate, and optimize the lifespan distribution of a system or its