CR, aging and immune responsiveness

[Guest guest]

Hi All, This again relates indirectly to the latest of the lab tests I

received the results of and, mainly, the experiments that should follow.

The below/attached on aging and immune responsiveness had a reference in it

and a short statement in its regard, regarding how aging affects and CR

interdicts changes in immunological status as related to cytokines. Then I

included below it the abstract for the CR paper referred to in the first

paper.

Neither paper was identified in an archives search using the Medline

identifier number.

How this relates to my being tested and experiments related to it is that

the doctor/experimentalist would like to check to not only measure the

cytokines, including interleukins mentioned in the papers. I also had the

antigen stimulation measured a few years back and the results showed a low

basal level of activity, but a greatly enhanced ability to respond to

antigen stimulation upon challenge in vitro. The experiments mentioned

above, might look at such things by seeing directly how my serum cytokines

allow monocytes from ad lib normal subjects perform relative to others

studied and the ad lib serum.

To me it all sounds good.

In addition, in the other CR list, Thin Man had been interested in the

immunological risks of CR with respect to infections. The two papers seem

to bang this concern. Further, I believe the results are in line with many

other factors. For example, testosterone is low with CR, but the

reproductive status of at least animals is maintained to a later age. So

CRONies may be benefiting from late-life higher testosterone levels.

Cheers, Al.

J Immunol 2002 Jun 15;168(12):6120-7

Early antigen-specific response by naive CD8 T cells is not altered with aging.

Li SP, Cai Z, Shi W, Brunmark A, M, Linton PJ.

Both a dramatic decline in CD8 responses and a switch to memory T cell

predominance occur with aging. The extent to which the loss of responsiveness is

the consequence of the accumulation of more differentiated vs intrinsically

defective T cells (or both) has been unclear. Using similar conditions of Ag

stimulation, we have examined the responses generated by CD8(+) cells isolated

from aged TCR transgenic mice. We found that the naive transgene(+) CD8(+) cells

from aged 2C mice expressed activation markers, produced IL-2, proliferated, and

differentiated into cytotoxic T cells as efficiently as their young

counterparts. The extent of responsiveness and the level of the responses were

comparable in both age groups regardless of the stimulatory conditions used,

i.e., partial costimulation/adhesion molecule expression on APCs, or

presentation of lower affinity peptide or diminished peptide concentrations. By

day 4 after Ag stimulation, no significant age-related differences were observed

in the number of effector cells generated nor in the levels of secreted IL-2 or

IFN-gamma. Upon restimulation of effector cells, IL-2 secretion and to a lesser

extent TNF-alpha expression, but not IFN-gamma secretion, were diminished with

age. These findings suggest that age-associated alterations in naive CD8 cell

function are not found after primary stimulation, but may become apparent upon

restimulation.

PMID: 12055223 [PubMed - indexed for MEDLINE]

" Introduction

The decline in cell-mediated immunity during aging has been implicated as a

factor in

the increased susceptibility of the elderly to infections. Substantial changes

in both the

function and phenotype of T cells in aged humans and rodents have been found (1,

2).

Among the functional changes are alterations in the profile of cytokines

produced (3,

4, 5), changes in the early events of signal transduction (6, 7, 8, 9),

decreased proliferation in response to TCR and

costimulus-mediated stimulation (10, 11, 12), and decreased IL-2

production (13). Among the phenotypic changes

is a dramatic shift toward an increased representation of T cells

expressing determinants typical of memory cells with

a concomitant decline in the proportion of T cells expressing

determinants typical of naive cells (3, 11, 14). Since many

of the functional alterations found in the aged may be

the consequence of the accumulation of memory T cells

rather than deficiencies intrinsic to the T cells of the aged,

many studies of T cell function have been reevaluated using

purified subset populations. " ...................

" Although our finding of slightly

diminished TNF-alpha expression is contrary to the findings

of others, diminished TNF- expression in the aged has

been observed in caloric restricted animals that possess

improved T cell function (41). In any case, the finding of

diminished IL-2 and possibly TNF-alpha upon antigen

(Ag) restimulation suggests that age-related differences intrinsic to CD8

cells may become apparent later in the response upon Ag

reexposure. This may be indicative of an increased rate

of maturation to the effector cell stage; however, more

thorough studies are necessary to determine whether

effector cell function is dramatically altered.

41. Fernandes G, Venkatraman JT, Turturro A, Attwood VG, Hart RW.

Effect of food restriction on life span and immune functions in long-lived

Fischer-344 x Brown Norway F1 rats.

J Clin Immunol. 1997 Jan;17(1):85-95.

Life-long food restriction is known to slow aging and reduce the rate of

occurrence of age-associated disease processes, but the mechanism by which this

is accomplished is unknown. In this study we have examined the effect of food

restriction on the proliferative response of spleen cells to mitogens and

lymphokine production in 6-, 18-, and 30-month-old AL and FR Fischer-344 x Brown

Norway (F-344 x BNF1) female rats whose average life span is 137 weeks on an ad

libitum (AL) diet and 177 weeks on a food-restricted (FR) diet. In addition, the

ability of food restriction to recall antigens was tested in 10-month-old rats

by immunizing them with keyhole limpet and hen's egg albumin and measuring

proliferative response of draining lymph node cells to these antigens. Our

results indicated that the spleen-cell proliferative response to

phytohemagglutinin and concanavalin A (Con A) was equal in 6- and 18-month-old

rats but declined significantly in 30-month-old AL rats compared to FR rats.

Although flow cytometric analyses did not reveal differences for CD4, CD8, and

Ig+ cells with age, a significant rise in memory T cells (Ox-22low) in both CD4+

and CD8+ T-cell subset lineage was noted in AL-fed rats at 30 months of age. In

FR rats, however, only a minimal shift of naive T cells (Ox-22high) to memory

cells was observed. In FR rats, the observed changes in the naive and memory

T-cell subsets correlate well with the observed higher levels of the

antiinflammatory interleukin-2 (IL-2) and lower levels of the proinflammatory

cytokines such as IL-6 and tumor necrosis factor-alpha. The ability of

food-restricted animals to recall antigens was lower compared to their

age-matched controls, though the proliferative response to T-cell mitogen Con A

and superantigen staphylococcal enterotoxin B was higher. These findings

indicate that food restriction may selectively act to maintain a lower number of

antigen-induced memory T cells with age, thereby maintaining the organism's

ability to produce higher levels of IL-2 with age. In summary, the increased

cell-mediated immune function noted in aged FR rats appears to be due to the

presence of a higher number of naive T cells, which are known to produce

elevated levels of the antiinflammatory cytokines, which may in part be

responsible for reducing the observed age-related rise in disease.

PMID: 9049789 [PubMed - indexed for MEDLINE]