Epigenetics has the potential to explain various biological phenomena that have heretofore defied complete explication. This review describes the various types of endogenous human developmental milestones such as birth, puberty, and menopause, as well as the diverse exogenous environmental factors that influence human health, in a chronological epigenetic context. We describe the entire course of human life from periconception to death and chronologically note all of the potential internal timepoints and external factors that influence the human epigenome. Ultimately, the environment presents these various factors to the individual that influence the epigenome, and the unique epigenetic and genetic profile of each individual also modulates the specific response to these factors. During the course of human life, we are exposed to an environment that abounds with a potent and dynamic milieu capable of triggering chemical changes that activate or silence genes. There is constant interaction between the external and internal environments that is required for normal development and health maintenance as well as for influencing disease load and resistance. For example, exposure to pharmaceutical and toxic chemicals, diet, stress, exercise, and other environmental factors are capable of eliciting positive or negative epigenetic modifications with lasting effects on development, metabolism and health. These can impact the body so profoundly as to permanently alter the epigenetic profile of an individual. We also present a comprehensive new hypothesis of how these diverse environmental factors cause both direct and indirect epigenetic changes and how this knowledge can ultimately be used to improve personalized medicine.

In this paper we present cellular senescence as the ultimate driver of the aging process, as a “causal nexus” that bridges microscopic subcellular damage with the phenotypic, macroscopic effect of aging. It is important to understand how the various types of subcellular damage correlated with the aging process lead to the larger, visible effects of anatomical aging. While it has always been assumed that subcellular damage (cause) results in macroscopic aging (effect), the bridging link between the two has been hard to define. Here, we propose that this bridge, which we term the “causal nexus”, is in fact cellular senescence. The subcellular damage itself does not directly cause the visible signs of aging, but rather, as the damage accumulates and reaches a critical mass, cells cease to proliferate and acquire the deleterious “senescence-associated secretory phenotype” (SASP) which then leads to the macroscopic consequences of tissue breakdown to create the physiologically aged phenotype. Thus senescence is a precondition for anatomical aging, and this explains why aging is a gradual process that remains largely invisible during most of its progression. The subcellular damage includes shortening of telomeres, damage to mitochondria, aneuploidy, and DNA double-strand breaks triggered by various genetic, epigenetic, and environmental factors. Damage pathways acting in isolation or in concert converge at the causal nexus of cellular senescence. In each species some types of damage can be more causative than in others and operate at a variable pace; for example, telomere erosion appears to be a primary cause in human cells, whereas activation of tumor suppressor genes is more causative in rodents. Such species-specific mechanisms indicate that despite different initial causes, most of aging is traced to a single convergent causal nexus: senescence. The exception is in some invertebrate species that escape senescence, and in non-dividing cells such as neurons, where senescence still occurs, but results in the SASP rather than loss of proliferation plus SASP. Aging currently remains an inevitable endpoint for most biological organisms, but the field of cellular senescence is primed for a renaissance and as our understanding of aging is refined, strategies capable of decelerating the aging process will emerge.

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Since time immemorial humans have utilized natural products and therapies for their healing properties. Even now, in the age of genomics and on the cusp of regenerative medicine, the use of complementary and alternative medicine (CAM) approaches represents a popular branch of health care. Furthermore, there is a trend towards a unified medical philosophy referred to as Integrative Medicine (IM) that represents the convergence of CAM and conventional medicine. The IM model not only considers the holistic perspective of the physiological components of the individual, but also includes psychological and mind-body aspects. Justification for and validation of such a whole-systems approach is in part dependent upon identification of the functional pathways governing healing, and new data is revealing relationships between therapies and biochemical effects that have long defied explanation. We review this data and propose a unifying theme: IM's ability to affect healing is due at least in part to epigenetic mechanisms. This hypothesis is based on a mounting body of evidence that demonstrates a correlation between the physical and mental effects of IM and modulation of gene expression and epigenetic state. Emphasis on mapping, deciphering, and optimizing these effects will facilitate therapeutic delivery and create further benefits.