Dr Richard Mackenzie

CASE: Targeting NAD+ Metabolism and Immune Glycosylation to Modulate Biological Age and Resilience in Humans

University of Registration: Coventry University

Non-academic partner: Dr Richie Barclay, Dr Ralph Rogers (Muto Longevity)

Secondary Supervisor(s): Dr Martin Whitham

Project Outline

This PhD will explore how a novel nutritional intervention targets the molecular drivers of aging, with a focus on NAD⁺ metabolism, immune glycosylation, and systemic resilience. Aging is not merely the passage of time but arises from cumulative molecular damage, metabolic inflexibility, and chronic low-grade inflammation (“inflammaging”), which together underpin frailty and age-related disease [1,2]. The student will investigate whether boosting NAD⁺ levels, enhancing sirtuin activity, and modifying immunoglobulin G (IgG) glycosylation can slow or reverse these processes.

A central outcome will be biological age, measured using GlycanAge, which assesses the sugar modifications (glycans) attached to IgG antibodies. These glycans act as immune modulators, shifting from anti-inflammatory to pro-inflammatory profiles with age [3]. IgG glycan patterns explain ~60% of the variance in chronological age and correlate with cardiometabolic risk and systemic inflammation [4,5]. Thus, GlycanAge provides a sensitive biomarker of immune aging and inflammaging.

Another key focus is NAD⁺ biology. NAD⁺ is a fundamental coenzyme in energy metabolism, DNA repair, and redox reactions. It also serves as the substrate for sirtuins, enzymes that regulate mitochondrial biogenesis, stress resistance, and genomic stability [6]. NAD⁺ levels decline by 30–50% with age across tissues including liver, skeletal muscle, and immune cells, contributing to reduced resilience and impaired repair capacity [7]. Restoration of NAD⁺ via precursors such as nicotinamide riboside has been shown to improve cardiometabolic function and mitochondrial activity in humans [8].

Downstream of NAD⁺, the project will assess sirtuins and PGC-1α, central regulators of mitochondrial biogenesis and cellular energy balance. Enhancing this axis could directly link NAD⁺ repletion to functional improvements in energy metabolism and repair pathways [6,9].

Because aging is also characterised by chronic low-grade inflammation, the project will measure cytokine profiles (e.g., IL-6, TNF-α, IL-1β, IL-10). These inflammatory mediators influence both disease progression and IgG glycosylation status, creating reinforcing loops of immune aging [2,3].
In parallel, the study will assess autonomic nervous system function, particularly heart rate variability (HRV), which declines with age and predicts morbidity and mortality [10]. Reduced vagal tone and poor autonomic balance reflect diminished resilience to stress.

Finally, exercise-induced recovery will be used as a functional stress test, capturing markers such as inflammation, muscle enzymes, and HRV rebound. Linking molecular interventions to recovery dynamics provides a real-world measure of resilience and healthspan.

Importance

This project integrates molecular hallmarks of aging: NAD⁺ decline, mitochondrial dysfunction, inflammaging, and IgG glycosylation shifts, with functional measures of recovery and resilience. By combining GlycanAge with molecular and autonomic readouts, the studentship will generate a multidimensional picture of how nutritional strategies can meaningfully influence human aging biology. This research has the potential to inform translational approaches that not only extend lifespan but improve healthspan and quality of life.

1. Akbar, et al. (2013). Nature Immunology, 14(6), 512–519.
2. Franceschi, et al., (2018). Nature Reviews Endocrinology, 14(10), 576–590. h
3. Gudelj, et al. (2018). Glycobiology, 28(5), 281–295.
4. Kristic, et al. (2014). Molecular & Cellular Proteomics, 13(11), 1589–1598. h
5. Menni, et al. (2018). Nature Communications, 9(1),
6. Imai, et al. (2014). Trends in Cell Biology, 24(8), 464–471.
7. López-Otín, et al. (2013). Cell, 153(6), 1194–1217.
8. Martens, et al. (2018). Nature Communications, 9(1), 1286.
9. Yoshino, et al. (2018) Cell Metabolism, 27(3), 513–528.
10. Thayer, et al. (2010). Biological Psychology, 84(2), 121–129.

The role of extracellular vesicles in glucose metabolism and insulin sensitivity in aging humans

Secondary Supervisor(s): Dr Martin Whitham Turner

University of Registration: Coventry University

BBSRC Research Themes:

• Integrated Understanding of Health (Diet and Health)

Project Outline

Background

Extracellular vesicles (EVs) are secreted from most cells and seem to operate as intercellular messengers to facilitate cellular function in recipient cells (1). Our current research shows that EVs and their cargo change with the transition from normal glucose control to dysfunctional glucose metabolism in human volunteers (unpublished data). Mapping a group of individuals’ over a 9 month healthy life-style intervention, we not only saw changes in EVs found in circulation with the worsening of health, but also witness changes in EV and their protein cargo in those displaying improved health outcomes. Although these data are exciting, we still don’t know what the physiological relevance of these changes are. Thus, the planned proposal will now assess for changes in circulating EVs and their cargo in response to a series of experiments manipulating intravenous glucose and / or insulin concentrations in humans.

An exciting collaboration between the proposed supervisors aims to explore these findings under controlled experimental conditions to unpick the basic mechanisms involved. Dr Whitham’s research group examines the fundamental concept that in response to both physiological and pathological stimuli, the transfer of molecules from one tissue to another via EVs is a biologically meaningful event and importantly, that broad assessment of the molecular cargo will be insightful. Dr Mackenzie group has many years of experience in altering whole-body metabolism, under controlled clinical conditions, to assess the physiological relevance of a given intervention or treatment (2). This PhD project will use clinical procedures, including hyperinsulinemic-euglyemic clamps with and without lipid infusion to improve our understanding of the role of EVs in glucose metabolism and insulin resistance. This project will use the data steaming from the clinical human work to direct a series of in vitro laboratory experiments. More specifically, we plan to isolate key EVs and their cargo from human donors to treat different cell-lines. In doing so, we can assess if these EVs can improve insulin resistance in adipose and muscle as well as modify ß-cell function.

The proposed studentship will sit within this broad programme of research operating within a modern, ‘wet’ laboratory combining innovative, mass spectrometry-based proteomic analyses with a variety of EV isolation and nanoparticle imaging analysis methods. In addition, the candidate will become practiced in a number of in vivo clinical procedures applied to humans. More traditional laboratory approaches, such as Western Blot, RT-PCR and Cell culture, will also be employed. Experience of the more technical methods is preferred but not essential.

References

1.McIlvenna, L. & Whitham, M. Exercise, healthy ageing, and the potential role of small extracellular vesicles. 2023; 601, 22

2.Barclay, R., Beals, J., Drnevich, J., Imai, B., Yau, P., Ulanov, A., Villegas-Montes, M., Tillin, N., Watt, P., Burd, N. & Mackenzie R. (2020). Ingestion of lean meat elevates muscle inositol hexakisphosphate kinase 1 protein content independent of a distinct post-prandial circulating proteome in young adults with obesity. Metabolism 102 153996