The twilight of the immune system: The impact of immunosenescence in aging

Highlights

• Immunosenescence is a key mechanism driving a host of age-related pathologies.

• Inflammaging is likely a major consequence of immunosenescence.

• Immunosenescence also drives autoimmune, malignant and infectious disease in older adults.

Abstract

Cellular senescence is a critical part of human anti-tumor defence; however, the accumulation of senescent cells with age underpins a wide range of pathologies. Senescent change in immune cells, or immunosenescence, has a wide range of physiological effects and is at least partially responsible for many diseases associated with aging. Immunosenescence underpins inflammaging, increased vulnerability to infectious disease with age, malignant change in the elderly, and auto-immunity. Understanding the effects and mechanisms of immunosenescence will improve disease outcomes and prevention in older adults, and generate new treatments for common illnesses. In this review we summarize the key changes occurring in immunosenescence across each facet of the immune system, and identify their clinical correlates.

Introduction

The continuing advance of life expectancy worldwide is a triumph of medical research and health policy, and is associated with enormous benefits to the global community. With this, however, comes an imperative to better understand and manage conditions that disproportionately affect older adults. A key part of this is understanding the many and varied impacts of aging on human physiology, and how they translate into clinically relevant diseases, or health outcomes. The modern geroscience paradigm seeks to explore the processes underpinning aging, and identifies a number of key pillars of age-related physiological changes, such as proteostasis, stem cell dysfunction and epigenetic dysregulation [1]. One of the key components of geroscience is the process of senescence: a state of dysregulated function associated with growth cycle arrest [2]. Once thought to be non-functional and dormant, senescent cells are now known to be active, but dysregulated, causing a wide range of physiological effects [2]. Senescent cells drive tissue inflammation, degeneration and loss of function, with knock-on effects dependent on the local biological environment. While senescence occurs in almost all cells and physiological systems, immunosenescence conceivably has the most widespread impact on health. The term immunosenescence is widely used, but often poorly defined. In general, the term is incorrectly used to describe the general decline in immune function in later life, and the associated ‘inflammaging’ of advanced age [3]. However, this wording more correctly describes the changes associated with the aging of the immune system, to which senescent immune cells contribute. Immunosenescence refers specifically to the changes in immune cell function and subset composition which result from senescent change (Fig. 1).

Ongoing dysfunction of the immune system resulting from immunosenescence leads to a host of clinical exigencies, which make the medical management of the older adult challenging [4]. Most pathologies common to older people are impacted by immunosenescence, from malignancy and infection, to osteoporosis and neurodegenerative disease, rendering a better understanding of this mechanism critical in modern gerontology. Herein, we synthesize the recent literature on immunosenescence in both the innate and adaptive immune systems, with attention to its clinical impact in older people.